IL-17A modulator

Abstract

The present invention relates to compounds that are IL-17A modulators. The compounds have structural formula I, as defined herein. The invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders involving modulation of IL-17A activity.

Description

Technical Field

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

Background Art

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

[0003] IL-17A is a 34-38 kDa variable glycosylated disulfide-linked homodimeric glycoprotein that shares approximately 50% homology with its closest family member, IL-17F, and both are secreted as either homodimers or heterodimers of IL-17AF [Non-Patent Document 1; Non-Patent Document 2].

[0004] Activation of naive CD4+ T cells in response to cytokines such as IL-6, transforming growth factor β (TGF-β), IL-23, STAT3, and RORγt leads to their differentiation into TH17 cells and the expression of pro-inflammatory mediators such as IL-17A. Furthermore, various cell types derived 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, δγ T cells, macrophages, and group 3 innate lymphocytes [Non-Patent Document 3; Non-Patent Document 4].

[0005] The cytokines IL-17A, IL-17F, and IL-17AF bind to the common heteromeric receptor complex IL-17RA and IL-17RC despite different affinities, and various cell types have been reported to express the IL-17RA subunit, but the highest responses to IL-17A are provided by epithelial cells, endothelial cells, keratinocytes, and fibroblasts [Non-Patent Document 5; Non-Patent Document 6; Non-Patent Document 7].

[0006] The binding of IL-17A to its receptor activates various signaling pathways such as nuclear factor (NF)-κB, phosphoinositide 3-kinase (PI3K), activator protein (AP1), CCAAT / enhancer-binding protein (C / EBP), and mitogen-activated protein kinase (MAPK), leading to pro-inflammatory gene expression and the secretion of various pro-inflammatory cytokines including IL-1β, IL-6, IL-8, TNFα, G-CSF, PGE2, and IFN-γ, as well as numerous chemokines and other effectors [Non-Patent Document 8; Non-Patent Document 9; Non-Patent Document 7]. By attracting and activating cells of the innate immune system to the site of inflammation, the induction of an inflammatory loop that is also mediated cooperatively with other cytokines such as TNFα, IFN-γ, and IL-1β is completed [Non-Patent Document 8].

[0007] These IL-17-mediated biological processes are involved in the pathology of many human diseases with immune components or autoimmunity, such as psoriasis, ankylosing spondylitis, axial spondyloarthritis, psoriatic arthritis, eczema, enthesitis-related arthritis, asthma (including severe asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, ulcerative colitis, Crohn's disease, atopic dermatitis, contact dermatitis, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, folliculopathy, peritonitis, multiple sclerosis, Guillain-Barré syndrome, irritable bowel syndrome, inflammatory bowel disease, Castleman's disease, pelvic inflammatory disease, systemic juvenile idiopathic arthritis (JIA), rheumatoid arthritis, giant cell arteritis, graft-versus-host disease, discoid lupus erythematosus, systemic lupus erythematosus, lupus nephritis, vasculitis, insulin-dependent type I diabetes, autoimmune diabetes, diabetic lipoid necrosis, pyoderma gangrenosum, hidradenitis suppurativa, papulopustular rosacea, lichen planus, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria, pain (especially pain related to inflammation), and have also been implicated in cancer (Non-Patent Document 10; Non-Patent Document 11). In addition, due to the new role of neuroinflammation in neurodegeneration, IL-17 has also been implicated in the progression of neurodegenerative disorders such as Alzheimer's disease (Non-Patent Document 12) and Parkinson's disease (Non-Patent Document 13). Furthermore, due to the major regulatory role of IL-17A in host defense, relevant pathological conditions also include viral, bacterial, fungal and parasitic infections. A relationship has also been observed between the serum levels of IL-17 at the time of admission to the intensive care unit and the development of sepsis, suggesting that an increase in IL-17 may increase susceptibility to septic complications and endotoxin shock related to infection [Non-Patent Document 14]. Its role in sepsis has also been suggested to extend to patients with sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury [Non-Patent Document 15]. Most recently, inhibition of IL-17 has been recommended for use in preventing acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) [Non-Patent Document 16].

[0008] Preclinical studies have demonstrated that IL-17A (as well as IL-17F and IL-17C) is elevated in psoriatic skin [Non-Patent Document 17; Non-Patent Document 18; Non-Patent Document 19; Non-Patent Document 20]. Th17 cells in the peripheral circulation and lesional skin of patients with psoriasis have also been shown to positively correlate with disease severity as measured by the Psoriasis Area and Severity Index (PASI) score [Non-Patent Document 21]. Serum IL-17A levels also significantly correlate with the PASI score [Non-Patent Document 22; Non-Patent Document 23; Non-Patent Document 24].

[0009] Animal model studies have supported the hypothesis that targeting the IL-17A pathway would be an effective treatment for psoriasis [Non-Patent Document 25; Non-Patent Document 26; Non-Patent Document 27], and clinical results using antibodies against IL-17A or IL-17RA have provided definitive verification and excellent efficacy has been observed [Non-Patent Document 28; Non-Patent Document 29; Non-Patent Document 30; Non-Patent Document 31; Non-Patent Document 32].

[0010] Elevated levels of IL-17A or IL-17F have been reported in several other diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), bone erosion, intra-abdominal abscess, allograft rejection, angiogenesis, atherosclerosis and asthma [e.g., Non-Patent Document 8; Non-Patent Document 33; Patent Document 1].

[0011] The anti-IL-17A therapeutic antibodies secukinumab and ixekizumab have shown evidence of positive effects when treating palmoplantar and nail psoriasis; [Non-Patent Document 34; Non-Patent Document 35; Non-Patent Document 36]; PsA [Non-Patent Document 37; Non-Patent Document 38] and AS [Non-Patent Document 39; Non-Patent Document 40]. A proof-of-concept study using secukinumab in MS also showed promising signs of efficacy [Non-Patent Document 41].

[0012] IL-17A expression has been shown to be increased in SLE patients and correlates with disease severity [Non-Patent Document 42; Non-Patent Document 43].

[0013] In addition, IL-17A has been reported to be associated with ocular surface disorders such as DES [Patent Document 2, Patent Document 3, and Patent Document 4; Non-Patent Document 44], and Th17 cells have been shown to be elevated in active uveitis and scleritis [Non-Patent Document 45]. IL-17A levels in tears were associated with the clinical severity of dry eye in patients with a range of systemic autoimmune or inflammatory diseases, including Sjögren's syndrome, Stevens-Johnson syndrome (SJS), SLE, filamentary keratitis, DES, meibomian gland dysfunction (MGD), and graft-versus-host disease (GVHD) [Non-Patent Document 46].

[0014] 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 [Non-Patent Document 47; Non-Patent Document 48; Non-Patent Document 49; Non-Patent Document 50; Non-Patent Document 51; Non-Patent Document 52; Non-Patent Document 53; Non-Patent Document 54]. An increase in IL-17A levels has been shown to correlate with poor prognosis in several cancer types, including malignant thyroid tumors, breast cancer, pancreatic cancer, gastric cancer, NSCLC, colorectal cancer, and head and neck cancer [Non-Patent Document 55; Non-Patent Document 54; Non-Patent Document 56; Non-Patent Document 57; Non-Patent Document 58; Non-Patent Document 59; Non-Patent Document 60; Non-Patent Document 61].

[0015] In summary, modulation of the IL-17A pathway, particularly modulation of IL-17A activity by inhibition of its interaction with the receptor IL-17RA, is considered a target for the treatment of conditions related to the immune system, as well as inflammation, cancer, and neurodegenerative disorders.

[0016] Patent Document 5, Patent Document 6, and Patent Document 7 describe a class of chemical compounds that modulate the activity of IL-17 and are useful in the treatment of medical conditions, including inflammatory diseases.

Prior Art Documents

Patent Documents

[0017] [Patent Document 1] US Patent Publication No. 2008 / 0269467 [Patent Document 2] PCT Publication No. WO2009 / 089036 [Patent Document 3] PCT Publication No. WO2010 / 062858 [Patent Document 4] PCT Publication No. WO2011 / 163452 [Patent Document 5] WO2013 / 116682 [Patent Document 6] WO2014 / 066726 [Patent Document 7] WO2018 / 229079 [Non-Patent Document]

[0018] [Non-Patent Document 1] K.F. Geoghegan et al., Protein Expression and Purification 2013, 87, 27 - 34 [Non-Patent Document 2] J.K. Kolls and A. Linden, Immunity 2004, 21, 467 - 476 [Non-Patent Document 3] D.J. Cua and C.M. Tato, Nat Rev Immunol 2010, 10, 479 - 489 [Non-Patent Document 4] W. Jin and C. Dong, Emerging Microbes & Infections 2013, 2, e60 [Non-Patent Document 5] T.A. Moseley et al., Cytokine Growth Factor Reviews. 2003, 14, 155 - 174 [Non-Patent Document 6] S.L. Gaffen, Nature Rev Immunol 2009, 9, 556 - 567

Non-Patent Document 7

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Non - Patent Document 58

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Non - Patent Document 60

Non - Patent Document 61

Summary of the Invention

Problems to be Solved by the Invention

[0019] Nevertheless, there is a continuing need for compounds capable of attenuating IL - 17A activity.

Means for Solving the Problems

[0020] In one aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0021] 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 additives.

[0022] In another aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0023] In another aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder associated with IL-17A activity.

[0024] In another aspect, the present invention relates to the use of a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof in the production of a medicament for use in the treatment of a disease or disorder associated with IL-17A activity.

[0025] In another aspect, the present invention relates to a method of treating a disease or disorder associated with IL-17A activity, the method comprising administering to a subject in need of 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.

[0026] Examples of diseases or disorders associated with IL-17A activity include diseases involving immune components or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer, and neurodegenerative disorders.

[0027] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of a disease involving immune components or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer, and neurodegenerative disorders.

[0028] In another aspect, the present invention provides the use of a compound or a pharmaceutically acceptable salt thereof in the production of a medicament for use in the treatment of a disease involving immune components or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer, and neurodegenerative disorders.

[0029] In another aspect, the present invention provides a method for treating an immune component or a disease associated with an autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative disorders, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0030] The present invention further provides a method for synthesizing a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof that is obtainable, obtained, or directly obtained by a synthesis method as defined herein.

[0032] In another aspect, the present invention provides a novel intermediate as defined herein that is suitable for use in any one of the synthesis methods specified herein.

[0033] The preferred, suitable, and optional features of any one particular aspect of the present invention are also the preferred, suitable, and optional features of any other aspect.

Mode for Carrying Out the Invention

[0034] Definition Unless otherwise defined, the following terms used in the specification and claims have the following meanings as specified below.

[0035] References to "treating" or "treatment" are to be understood to include the protection and alleviation of established symptoms of a condition. Thus, "treating" a situation, disorder or condition, or "treatment" thereof, includes: (1) preventing or delaying the onset of clinical symptoms of a situation, disorder or condition that is occurring in a human who may be suffering from or may be predisposed to the situation, disorder or condition but who has not yet experienced or manifested clinical or subclinical symptoms of the situation, disorder or condition; (2) inhibiting the situation, disorder or condition, i.e., preventing, reducing or delaying the occurrence or recurrence of the disease (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or attenuating the disease, i.e., causing at least one regression of the situation, disorder or condition or its clinical or subclinical symptoms.

[0036] "Therapeutically effective amount" means an amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0037] As used herein, the term "alkyl" refers to aliphatic hydrocarbon groups and includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight-chain version, and references to individual branched-chain alkyl groups such as "isopropyl" are specific only to the branched-chain version. For example, "C 1~6 alkyl" includes C 1~4 alkyl, C 1~3 alkyl, propyl, isopropyl and t-butyl. Similar rules apply to other radicals, for example "phenylC 1~6 alkyl" includes phenylC 1~4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0038] The term "alkylene" includes both straight-chain and branched-chain 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-chain alkyl groups bonded to oxygen alone. For example, "C 1~4 alkoxy" includes methoxy, ethoxy, isopropoxy, and t-butoxy.

[0040] The term "C m~n " used as a prefix refers to any group having from m to n carbon atoms.

[0041] "Cycloalkyl" means a hydrocarbon ring containing from 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 "halo" refers to fluoro, chloro, bromo, and iodo.

[0043] The terms "haloalkyl" or "haloalkoxy" are used herein to refer to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms have been replaced by 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", "carbocyclic ring" or "carbocycle" mean a non-aromatic saturated or partially saturated monocyclic, or fused, bridged or spiro bicyclic carbocyclic ring system. A monocyclic carbocyclic ring contains from about 3 to 12 (preferably from 3 to 7) ring atoms. A bicyclic carbocycle contains from 7 to 17 carbon atoms in the ring, preferably from 7 to 12 carbon atoms in the ring. The bicyclic carbocyclic ring may be a fused, spiro or bridged ring system.

[0045] The terms "heterocyclyl", "heterocyclic" or "heterocycle" mean non-aromatic saturated or partially unsaturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring systems. The monocyclic heterocyclic ring contains about 3 to 12 (preferably 3 to 7) ring atoms together with 1 to 5 (preferably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The bicyclic heterocycle contains 7 to 17 ring atoms, preferably 7 to 12 ring atoms, in the ring. The bicyclic heterocyclic ring may be a fused, spiro or bridged ring system. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiepin. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, 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 sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values for heterocyclyl groups bearing 1 or 2 oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Specific heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. Partially unsaturated heterocyclyl rings contain at least one double bond such as one or two double bonds. Examples of partially unsaturated heterocyclyl rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl and 2,3-dihydropyrrolyl. As will be understood by those skilled in the art, any heterocycle can be linked to another group via any suitable atom such as via a carbon or nitrogen atom. Preferably, the terms "heterocyclyl", "heterocyclic" or "heterocycle" will refer to 4-, 5-, 6- or 7-membered monocyclic rings as defined above.

[0046] "Bridged ring system" means a ring system in which two rings share more than two atoms, see, for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages 131 - 133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0047] "Spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., a heterocyclic ring is linked to a further carbocyclic or heterocyclic ring via a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane and 2-oxa-6-azaspiro[3.3]heptane.

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

[0049] Non-limiting examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl and imidazo[1,2-b][1,2,4]triazinyl groups.

[0050] Non-limiting examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0051] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl groups.

[0052] Bicyclic heteroaryl groups are, for example: A benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; A pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; A pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; A pyrrole ring condensed with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; A pyrazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; A pyrazine ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; An imidazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; An oxazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; An isoxazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; A thiazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; An isothiazole ring condensed with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; A thiophene ring condensed with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; A furan ring condensed with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; A cyclohexyl ring condensed with a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and A cyclopentyl ring condensed with a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms which may be a group selected from.

[0053] Particularly non-limiting examples of bicyclic heteroaryl groups containing a 6-membered ring condensed with a 5-membered ring include benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guanylinyl), indazolyl, benzodioxolyl, pyrrolopyridine and pyrazolopyridinyl groups, but are not limited thereto.

[0054] Particularly non-limiting examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0055] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In certain embodiments, aryl is phenyl or naphthyl, particularly phenyl.

[0056] This specification also utilizes several compound terms for describing groups containing more than one functional group. Such terms will be understood by those skilled in the art. For example, heterocyclyl C 1~4 alkyl is C substituted by heterocyclyl 1~4 alkyl.

[0057] The term "optionally substituted" refers to any of a substituted group, structure or molecule, as well as those that are unsubstituted.

[0058] When an optional substituent is selected from "one or more" groups, it should be understood that this definition includes all substituents selected from one of the specified groups or two or more of the specified groups. When there are multiple substituents, it is understood that the selected substituents may be the same or different.

[0059] When a numerical range is given, it is understood that the range includes the endpoints.

[0060] The term "compounds of the present invention" means the compounds disclosed herein both generically and specifically.

[0061] Compounds of the present invention In a first aspect, the present invention relates to a compound of formula I

Chemical formula

[0062] Compounds according to formula (I) may exist as a mixture of stereoisomers. Preferably, the compounds according to formula (I) have the following structure:

Chemical formula

[0063] Particular compounds of the invention are, for example, unless otherwise specified, 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 having any of the meanings defined above or in any of the following paragraphs (1) to (78), a compound of formula I, or a pharmaceutically acceptable salt thereof. To avoid misunderstanding, the present invention encompasses combinations of two or more substituent definitions as described in paragraphs (1) to (78): (1) X 1 , X 2 , X 3 and X 4 are each independently CH or N; (2)X 1 and X 2 and X 3 and X 4 Two of them are CR 5 and two are N; (3)X 2 and X 4 are N, and X 1 and X 3 are CR 5 ; (4)X 2 and X 4 are N, and X 1 and X 3 are CH; (5)X 1 and X 2 and X 3 and X 4 Three of them are CR 5 and the others are N; (6)X 1 is N, and X 2 and X 3 and X 4 are CR 5 ; (7)X 1 is N, and X 2 and X 3 and X 4 are CH; (8)X 2 is N, and X 1 and X 3 and X 4 are CR 5 ; (9)X 2 is N, and X 1 and X 3 and X 4 are CH; (10)X 1 and X 2 and X 3 and X 4 are all CR 5 ; (11)X 1 and X 2 and X 3 and X 4 are all CH; (12) Y is aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from halo, 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 haloalkyl; (13) Y is phenyl, optionally substituted by one or more substituents independently selected from halo, C 1~2 alkyl, C 1~2 alkoxy, C 1~2 alkylene-C 1~2 alkoxy and C 1~2 haloalkyl; (14) Y is a heteroaryl ring, optionally substituted by one or more substituents independently selected from halo, C 1~3 alkyl, C 1~2 alkoxy, C 1~2 alkylene-C 1~2 alkoxy and C 1~2 haloalkyl; (15) Y is a 5- to 6-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from chloro, fluoro, methyl and difluoromethyl; (16) Y is a 5- to 6-membered heteroaryl ring (such as methyl) substituted at the ortho position to the NHC(O)- moiety by methyl or ethyl; (17) Y is a 5- to 6-membered heteroaryl ring fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is halo, 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 1~2Optionally substituted with one or more substituents independently selected from haloalkyl; (18) Y is a 5-membered heteroaryl ring fused to a 5- or 6-membered heterocyclic ring, each of which is halo, C 1~2 alkyl, C 1~2 alkoxy, C 1~2 alkylene-C 1~2 alkoxy and C 1~2 Optionally substituted with one or more substituents independently selected from haloalkyl; (19) Y is pyrazolyl, pyrrolyl, isoxazolyl, oxadiazolyl or triazolyl substituted with one or more substituents independently selected from chloro, fluoro, methyl and difluoromethyl;

[0064] (20) Y is:

Chemical formula

Chemical formula

[0065] (22) Y is:

Chemical formula

[0066] (34)R 1 and R 2 together with the carbon atoms to which they are attached, [ka] forming a group selected from In the formula, * represents R 1 and R 2 is the carbon atom to which R 17 Each occurrence of halo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Haloalkyl and C 1~2 haloalkoxy, where m is 0, 1, 2 or 3;

[0067] (35)R 1 and R 2 together with the carbon atoms to which they are attached, [ka] forming a group selected from In the formula, * represents R 1 and R 2 is the carbon atom to which R 17 each occurrence of is independently selected from fluoro, methyl, trifluoromethyl, and methoxy, and m is 0, 1, or 2;

[0068] (36)R 1 and R 2 together with the carbon atoms to which they are attached, [Chemical formula] form a group selected from, wherein, * is the carbon atom to which R 1 and R 2 are attached, and each occurrence of R 17 is independently selected from hydrogen, fluoro, methyl, trifluoromethyl and methoxy;

[0069] (37)R 1 and R 2 together with the carbon atom to which they are attached are as follows: [Chemical formula] form, wherein, * is the carbon atom to which R 1 and R 2 are attached, and each R 17 is independently selected from hydrogen, fluoro, methyl and trifluoromethyl; (38)R 3 is hydrogen, fluoro or methyl; (39)R 3 is hydrogen; (40)R 3 is methyl; (41)R 4 is: (A) a 5- to 10-membered heteroaryl or C 3~7 cycloalkyl ring, each of which is optionally substituted by one or more substituents independently selected from hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 、C(O)NR 8 R 9 、CO2R 10 、C 1~3 alkylene-R 11 、C 3~7 cycloalkyl and heterocyclyl, where the C3~7 Cycloalkyl and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 and CO2R 10 ; or (B) is C 1~4 alkyl optionally substituted with hydroxy, halo, C 6 alkoxy, cyano, NR 7 R 10 or CO2R 1~6 ; or (C) is a 5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 , C 3~7 cycloalkyl and heterocyclyl; or (D) is a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclyl ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl ring, each of said rings being optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or (E) optionally fused with a 5- to 6-membered heteroaryl ring, and is hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 , C 3~7 a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; (42) R 4 is: (A) hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 , C 3~7 a 5- to 10-membered heteroaryl ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or (C) a 5- to 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; (D) a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclyl ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl ring, each of said rings being hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 , C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 , C 3~7 a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; (43) R 4 is: (A) hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11and C 3~7 a 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from cycloalkyl; (C) a 5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 and C 1~3 alkylene-R 11 optionally substituted by one or more substituents independently selected from; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 and C 1~3 alkylene-R 11 optionally substituted by one or more substituents independently selected from a partially unsaturated heterocyclic ring; (44) R 4 is: (A) hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 , C 1~3 alkylene-R 11 and C 3~7A 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from cycloalkyl; or (E) An optionally condensed 5- to 6-membered heteroaryl ring, hydroxy, halo, oxo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO2R 10 and C 1~3 alkylene-R 11 An optionally substituted partially unsaturated heterocyclic ring selected from one or more substituents independently selected from; (45) R 4 is a 5- to 10-membered heteroaryl, C 3~7 cycloalkyl or a 3- to 12-membered heterocyclyl ring, each of which is hydroxy, halo, 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 Optionally substituted by one or more substituents independently selected from; (46) R 4 is a 6- to 10-membered heteroaryl, C 3~7 cycloalkyl or a 3- to 7-membered heterocyclyl ring, each of which is hydroxy, halo, 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 Optionally substituted by one or more substituents independently selected from; (47)R 4 is a 5- to 10-membered heteroaryl ring optionally substituted by one or more substituents independently selected from halo, C 1~4 alkyl, C 1~2 alkoxy, C 1~2 fluoroalkyl, cyano, NR 6 R 7 , C 1~3 alkylene-R 11 and C 3~7 cycloalkyl; (48)R 4 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 fluoro, chloro, methyl, methoxy, trifluoromethoxy, cyano, NR 6 R 7 , CH2-R 11 and cyclopropyl; (49)R 4 is a 6- to 10-membered heteroaryl ring optionally substituted by one or more substituents independently selected from halo, C 1~4 alkyl, C 1~2 alkoxy, C 1~2 fluoroalkyl, cyano, NR 6 R 7 and C 1~3 alkylene-R 11 ; (50)R 4 is a C 1~2 cycloalkyl ring optionally substituted by one or more substituents independently selected from hydroxy, halo, C 1~2 alkyl, C 6 alkoxy, cyano, NR 7 R 8 , C(O)NR 9 R 1~3 and C 11 alkylene-R 3~7 ; (51)R 4 is hydroxy, fluoro, methyl, methoxy, cyano, NR 6 R7 and C(O)NR 8 R 9 optionally substituted with one or more substituents independently selected from 3~5 a C-cycloalkyl ring; (52)R 4 is hydroxy, halo, C 1~2 alkyl, C 1~2 alkoxy, C 1~2 fluoroalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 and C 1~3 alkylene-R 11 optionally substituted with one or more substituents independently selected from, a 3- to 7-membered heterocyclyl ring; (53)R 4 is hydroxy, methyl, methoxy, cyano, NR 6 R 7 and C(O)NR 8 R 9 optionally substituted with one or more substituents independently selected from, a 3- to 7-membered heterocyclyl ring; (54)R 4 is hydroxy, halo, C 1~2 alkoxy, cyano, NR 6 R 7 , C(O)NR 8 R 9 or CO2R 10 optionally substituted with, C 1~6 alkyl; (55)R 4 is hydroxy, fluoro, NR 6 R 7 or CO2R 10 optionally substituted with, C 2~5 alkyl; (56)R 4 is a 5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is halo, oxo, C 1~2 alkyl, C1~2 Alkoxy, C 1~2 Optionally substituted by one or more substituents independently selected from haloalkyl and cyano; (57)R 4 Is a 5- to 6-membered heteroaryl ring, said ring being fused to a 5-membered cycloalkyl or heterocyclyl ring, each of which is optionally substituted by one or more substituents independently selected from chloro, fluoro, methyl, methoxy and cyano; (58)R 4 Is a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclyl ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl ring, each of those rings being halo, oxo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Optionally substituted by one or more substituents independently selected from haloalkyl and cyano; (59)R 4 Is optionally fused to a 5- to 6-membered heteroaryl ring and is a partially unsaturated heterocyclic ring optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Optionally substituted by one or more substituents independently selected from haloalkyl and cyano; (60)R 4 Is a partially unsaturated heterocyclic ring optionally substituted by one or more substituents independently selected from fluoro, oxo and C 1~2 Alkyl; (61)R 4 Is a partially unsaturated heterocyclic ring optionally substituted by one or more substituents independently selected from oxo and methyl; (62)R 4 Is a partially unsaturated 6-membered N-containing heterocyclic ring substituted by one or more substituents independently selected from oxo and methyl; (63)R 4is fused to a 5- to 6-membered heteroaryl ring and is an optionally substituted partially unsaturated heterocyclic ring with one or more substituents independently selected from fluoro, oxo and C 1~2 alkyl; (64)R 4 is fused to a 5- to 6-membered heteroaryl ring and is an optionally substituted partially unsaturated heterocyclic ring with one or more substituents independently selected from oxo and methyl; (65)R 4 is fused to a 5-membered N-containing heteroaryl ring and is an optionally substituted partially unsaturated 6-membered N-containing heterocyclic ring with one or more substituents independently selected from oxo and methyl;

[0070] (66)R 4 is one of the following groups: [Chemical formula: [wherein: [Chemical formula: is the point of attachment to the remainder of the compound of formula I; R 18 is selected independently from hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 , C 1~3 alkylene-R 11 and C 3~7 cycloalkyl; R 19 is selected independently from hydrogen, C 1~4 alkyl, C 1~3 alkylene-R 11 and C 3~7 cycloalkyl; p is 0, 1 or 2] is selected from one of wherein, when R 4 is a bicyclic group and p is 1 or 2, each R18 The substituent may be present in any of the rings of the bicyclic group;

[0071] (67)R 4 is one of the following groups: [Chemical formula] [wherein: [Chemical formula] is the point of attachment to the remainder of the compound of formula I; R 18 is hydroxy, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, cyano, NR 6 R 7 C 1~3 alkylene-R 11 and C 3~7 cycloalkyl, independently selected; R 19 is hydrogen, C 1~4 alkyl, C 1~3 alkylene-R 11 and C 3~7 cycloalkyl, independently selected; p is 0, 1 or 2] selected from one of the following, wherein, when R 4 is a bicyclic group and p is 1 or 2, each R 18 substituent may be present in any of the rings of the bicyclic group;

[0072] (68)R 4 is one of the following groups: [Chemical formula] [wherein: [Chemical formula] is the point of attachment to the remainder of the compound of formula I; R 18is hydroxy, fluoro, chloro, methyl, methoxy, CF3, NR 6 R 7 , C 1~3 Alkylene-R 11 and cyclopropyl; R 19 is independently selected from hydrogen, methyl and cyclopropyl; p is 0, 1 or 2. is selected from one of Here, R 4 When is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of a bicyclic group; (69)R 5 is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl or cyano; (70)R 5 is hydrogen, fluoro, chloro or methyl; (71)R 5 is hydrogen; (72)R 5 is fluoro; (73)R 11 is hydroxy, halo, methoxy, cyano, NR 12 R 13 , C(O)R 14 or aryl; (74)R 11 is hydroxy, methoxy, cyano, NR 12 R 13 , C(O)R 14 or phenyl; (75)R 14 is hydroxy, methoxy or NR 15 R 16 is; (76)R 14 is NR 15 R 16 is; (77)R 15 and R 16together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl ring, the ring optionally containing additional heteroatoms selected from O, S or N, C 1~4 optionally substituted with alkyl; (78)R 15 and R 16 taken together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring, the ring optionally containing additional heteroatoms selected from O, S or N, and optionally substituted with methyl.

[0073] Preferably, X 1 From X 4 is as defined in any one of paragraphs (1) to (11) above. In one embodiment, X 1 From X 4 is as defined in any one of paragraphs (6) to (7) and (10) to (11) above. In a further embodiment, X 1 From X 4 is as defined in item (11) above. In a further embodiment, X 1 From X 4 is as defined in item (7) above.

[0074] Suitably, Y is as defined in any one of paragraphs (12) to (22) above. In one embodiment, Y is as defined in any one of paragraphs (19) to (22) above. In a further embodiment, Y is as defined in paragraph (22) above.

[0075] Preferably, R 1 and R 2 is as defined in any one of paragraphs (23) to (37) above. In one embodiment, R 1 and R 2 is as defined in any one of paragraphs (26) and (34) to (37) above. Preferably, R 1 and R 2 is as defined above in item (37).

[0076] Preferably, R 3 is as defined in any one of paragraphs (38) to (40) above. Preferably, R 3 is as defined above in item (39).

[0077] Preferably, R 4 is as defined in any one of paragraphs (41) to (68) above. In one embodiment, R 4 is as defined in any one of paragraphs (67) to (68) above. Preferably, R 4 is as defined above in item (68).

[0078] Preferably, R 5 is as defined in any one of paragraphs (69) to (72) above. Preferably, R 5 is as defined above in item (71).

[0079] Preferably, R 11 is as defined in any one of paragraphs (73) to (74) above. Preferably, R 11 is as defined above in item (74).

[0080] Preferably, R 14 is as defined in any one of paragraphs (75) to (76) above. Preferably, R 14 is as defined above in item (76).

[0081] Preferably, R 15 and R 16 is as defined in any one of paragraphs (77) to (78) above. Preferably, R 15 and R 16 is as defined above in item (78).

[0082] In a further group of compounds, the compound has the following structural formula IA, IB, IC or ID: [Chemical formula] [wherein, X 1 to X 4 , Y and R 4 are as defined above; each R 17 is independently selected from hydrogen, halo (such as fluoro), C 1~2 alkyl (such as methyl), C 1~2 alkoxy and C 1~2 haloalkyl; n is 1, 2, 3 or 4] has one of.

[0083] In a further group of compounds, the compound has one of the above structural formulas IA, IB, IC or ID, wherein X 1 to X 4 is as defined in any one of the above items (1) to (11); Y is as defined in any one of the above items (12) to (22); R 4 is as defined in any one of the above items (41) to (68); each R 17 is independently selected from hydrogen, halo (such as fluoro), C 1~2 alkyl (such as methyl), C 1~2 alkoxy and C 1~2 haloalkyl; n is 1, 2, 3 or 4.

[0084] In a further group of compounds, the compound has the structural formula IA shown above, wherein X 1 to X 4 is as defined in any one of the above items (6) to (7) or (10) to (11); Y is as defined in any one of the above items (19) to (22); R 4 is as defined in any one of the above items (67) to (68). In a further group of compounds, the compound has the structural formula IA shown above, wherein X 1 to X4 is as defined in item (11) above; Y is as defined in item (22) above; R 4 is as defined in item (68) above.

[0085] In a further group of compounds, the compound has the structural formula IB shown above, wherein X 1 from X 4 is as defined in any one of items (6) to (7) or (10) to (11) above; R 4 is as defined in any one of items (67) to (68) above. In a further group of compounds, the compound has the structural formula IA shown above, wherein X 1 from X 4 is as defined in item (11) above; R 4 is as defined in item (68) above.

[0086] In a further group of compounds, the compound has the structural formula IC shown above, wherein X 1 from X 4 is as defined in any one of items (6) to (7) or (10) to (11) above; Y is as defined in any one of items (19) to (22) above; R 4 is as defined in any one of items (67) to (68) above; each R 17 is independently selected from hydrogen, fluoro, methyl, methoxy and C 1~2 haloalkyl; n is 1, 2, 3 or 4. In a further group of compounds, the compound has the structural formula IC shown above, wherein X 1 from X 4 is as defined in item (11) above; Y is as defined in item (22) above; R 4 is as defined in item (68) above; each R 17 is independently selected from hydrogen, fluoro, methyl and trifluoromethyl; n is 1, 2, 3 or 4.

[0087] In a further group of compounds, the compound has the structural formula ID shown above, wherein X 1 to X 4 is as defined in any one of the above items (6) to (7) or (10) to (11); R 4 is as defined in any one of the above items (67) to (68); each R 17 is independently selected from hydrogen, fluoro, methyl, methoxy and C 1~2 haloalkyl; n is 1, 2, 3 or 4. In a further group of compounds, the compound has the structural formula ID shown above, wherein X 1 to X 4 is as defined in the above item (11); R 4 is as defined in the above item (68); each R 17 is independently selected from hydrogen, fluoro, methyl and trifluoromethyl; n is 1, 2, 3 or 4.

[0088] In a further group of compounds, the compound has the following structural formulae IE, IF, IG, IH, IJ, IK, IL or IM: [Chemical formula] [wherein Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above; each R 17 is independently selected from halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl and C 1~4 haloalkoxy; R 20 and R 21 are independently selected from hydrogen, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl and C 1~4 haloalkoxy; m is from 0 to 4] and has one of

[0089] In a further group of compounds, the compound has one of the structural formulas IE, IF, IG, IH, IJ, IK, IL or IM, wherein Y is as defined in any one of paragraphs (12) to (22) above; R 1 and R 2 are as defined in any one of paragraphs (23) to (37) above; R 3 is as defined in any one of paragraphs (38) to (40) above; R 4 is as defined in any one of paragraphs (41) to (68) above; each R 5 is independently as defined in any one of paragraphs (69) to (72) above; each R 17 is halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl and C 1~4 haloalkoxy independently selected therefrom; R 20 and R 21 are hydrogen, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl and C 1~4 haloalkoxy independently selected therefrom; m is from 0 to 4.

[0090] In a further group of compounds, the compound has the structural formula IE, IF, IG or IH shown above, wherein Y is as defined in any one of paragraphs (19) to (22) above; R 1 and R 2 are as defined in any one of paragraphs (31) to (37) above; R 3 is as defined in any one of paragraphs (38) to (40) above; R 4 is as defined in any one of paragraphs (67) to (68) above; each R 5is, independently, as defined in any one of the above items (70) to (71). In a further group of compounds, the compound has the structural formula IE, IF, IG or IH shown above, wherein Y is as defined in the above item (22); R 1 and R 2 are as defined in the above item (37); R 3 is as defined in the above item (39); R 4 is as defined in the above item (68); each R 5 is as defined in the above item (71).

[0091] In a further group of compounds, the compound has the structural formula IJ, IK, IL or IM shown above, wherein Y is as defined in any one of the above items (19) to (22); R 4 is as defined in any one of the above items (67) to (68); each R 5 is, independently, as defined in any one of the above items (70) to (71); each R 17 is independently selected from fluoro, methyl, methoxy and C 1~2 haloalkyl; R 20 and R 21 are independently selected from hydrogen, fluoro, methyl, ethyl, methoxy, C 1~2 haloalkyl and C 1~2 haloalkoxy; m is from 0 to 4. In a further group of compounds, the compound has the structural formula IJ, IK, IL or IM shown above, wherein Y is as defined in the above item (22); R 4 is as defined in the above item (68); each R 5 is as defined in the above item (71); each R 17 is independently selected from fluoro, methyl, methoxy and C 1~2 haloalkyl; R 20 and R 21 are independently selected from hydrogen, fluoro, methyl, ethyl, methoxy and C 1~2Independently selected from haloalkyl (such as trifluoromethyl); m is from 0 to 3.

[0092] Certain compounds of the present invention are as follows: (S)-N-(1-((4-(2,3-Dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 1); (S)-N-(1-((4-(3-Chloropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 2); (S)-N-(1-((4-(3-Methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 3); (S)-1-Methyl-N-(1-((4-(3-Methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 4); (S)-1-Methyl-N-(1-oxo-3,3-diphenyl-1-((4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)amino)propan-2-yl)-1H-pyrazole-5-carboxamide (Example 5); (S)-N-(1-((4-(3,5-Dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 6); (S)-1-Methyl-N-(1-((4-(3-(methylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 7); (S)-N-(1-((4-(3-(dimethylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 8); (S)-N-(1-((4-(3,5-dimethoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 9); (S)-N-(1-((4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 10); (S)-1-methyl-N-(1-((4-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 11); (S)-N-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 12); (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 13); (S)-N-(1-((4-(3,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 14); (S)-N-(1-((3-fluoro-4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 15); (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 16); (S)-N-(1-((4-(1,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 17); N-((2S)-1-((3-Fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 18); (S)-N-(1,1-Bis(4-fluorophenyl)-3-((4-(3-methoxypyridin-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 19); (S)-N-(1-((4-(3-Methoxypyridin-4-yl)-3-methylphenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 20); (S)-N-(1-((4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 21); (S)-N-(1-((4-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 22); (S)-N-(1-((2-Fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 23); (S)-N-(1-((3-Fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 24); (S)-3-Methoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide (Example 25); (S)-3,5-Dimethyl-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide (Example 26); (S)-3,5-Dimethoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide (Example 27); (S)-3-Fluoro-5-methoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide (Example 28); (S)-N-(1-((4-(1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3,5-difluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 29); (S)-N-(1-((3,5-Difluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 30); (S)-N-(1-((4-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 31); (S)-N-(1-((4-(3,5-Dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 32); 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); (S)-1-Ethyl-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 34); (S)-N-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 35); (S)-N-(1-((4-(3-fluoropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 36); (S)-N-(1-((4-(2,5-dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 37); (S)-N-(1-((4-(2,5-dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 38); (S)-N-(1-((4-(Imidazo[1,2-a]pyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 39); (S)-N-(1-((4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 40); (S)-N-(1-((4-(Imidazo[1,2-a]pyrimidin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 41); (S)-N-(1-((4-(3-(Hydroxymethyl)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 42); (S)-N-(1-((4-(3-Cyanopyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 43); (S)-N-(1-((4-(6,7-Dihydro-5H-cyclopenta[b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 44); (S)-1-Methyl-N-(1-((3-methyl-4-(pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 45); (S)-1-(Difluoromethyl)-N-(1-((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 46); (S)-N-(1-((3-Methoxy-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 47); (S)-N-(1-((3-Fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 48); (S)-1-Methyl-N-(1-oxo-1-((4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 49); (S)-1-Methyl-N-(1-((4-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 50); (S)-1-Methyl-N-(1-((4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 51); (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-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 52); (S)-N-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 53); (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 54); (S)-N-(1-((3-chloro-4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 55); (S)-N-(1-((4-(2,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 56); (S)-N-(1-((4-(2,3-Dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 57); (S)-N-(1-((3-Fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 58); (S)-1-Ethyl-N-(1-((3-fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 59); (S)-N-(1-((4-(3,5-Dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 60); (S)-N-(1-((4-(3,5-Dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 61); (S)-N-(1-((3-Fluoro-4-(1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 62); (S)-N-(1-((3-Fluoro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 63); (S)-N-(1-((3-Fluoro-4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 64); (S)-N-(1-((3-Fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 65); (S)-N-(1-((3-Fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthyridin-8-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 66); (S)-1-Ethyl-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 67); (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 68); (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 69); (S)-N-(1-((3-Fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 70); (S)-N-(1-((3-Fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 71); (S)-N-(1-((1’,2’-dimethyl-6’-oxo-1’,6’-dihydro-[3,3’-bipyridin]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 72); (S)-N-(1-((3’,5’-dimethyl-[3,4’-bipyridin]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 73); (S)-1-methyl-N-(1-((4-(5-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 74); (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 75); (S)-N-(1-((4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 76); (S)-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 77); (S)-1-methyl-N-(1-oxo-1-((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide (Example 78); (S)-4-(4-(2-(1-Methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridine 1-oxide (Example 79); (S)-N-(1-((3-Fluoro-4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 80); (S)-N-(1-((4-(3,6-Dihydro-2H-pyran-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 81); N-(1-(9H-Fluoren-9-yl)-2-((4-(3-methoxypyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 82); 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); N-((S)-2-((4-(3,5-Dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 84); 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); 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 86); 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); 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); 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-methyl-1H-pyrazole-5-carboxamide (Example 89); N-((S)-2-((3’,5’-Dimethyl-[3,4’-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 90); 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); N-((S)-2-((3’,5’-Dimethyl-[3,4’-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 92); 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); 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); 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); 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); 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); N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 98); N-((S)-2-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 99); N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 100); 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); 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); N-(1-Cyclooctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 103); N-(1-Cyclooctyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 104); N-(1-Cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 105); 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-pyrazole-5-carboxamide (Example 106); 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); (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); 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); 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); N-((S)-2-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 111); N-((S)-2-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 112); N-(1-cyclooctyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 113); (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 114); (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); (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 116); (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazole-5-carboxamide (Example 117); (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); (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); 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); (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 121); (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); (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); (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 124); 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); 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-pyrazole-5-carboxamide (Example 126); 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); (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); (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); (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); 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); (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 132); (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-triazole-5-carboxamide (Example 133); (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); 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); (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); (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); 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); 6-((S)-2-(1-Ethyl-1H-pyrazole-5-carboxamide)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3’,5’-dimethyl-[3,4’-bipyridine]1’-oxide (Example 139); 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); (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-triazole-5-carboxamide (Example 141); 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); (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); (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); 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-pyrazole-5-carboxamide (Example 145); 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-pyrazole-5-carboxamide (Example 146); 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-pyrazole-5-carboxamide (Example 147); (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); (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); (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); N-((S)-2-((3'-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 151); N-((S)-2-((2',3'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 152); N-((S)-2-((2',5'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 153); 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-pyrazole-5-carboxamide (Example 154); 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); 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-pyrazole-5-carboxamide (Example 156); (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); (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); 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); 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); (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); (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); (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); (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 164); (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 165); (S)-N-(1-Cycloheptyl-2-((5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 166); 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-triazole-5-carboxamide (Example 167); 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-triazole-5-carboxamide (Example 168); (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); (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 170); (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 171); (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); (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); (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 174); (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); (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 176); (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 177); (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); 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-pyrazole-5-carboxamide (Example 179); 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); (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); (S)-N-(1-cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 182); (S)-N-(1-cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 183); N-(1-(Bicyclo[2.2.1]heptan-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 184); 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-pyrazole-5-carboxamide (Example 185); 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-pyrazole-5-carboxamide (Example 186); 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); 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); 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-pyrazole-5-carboxamide (Example 189); (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); 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); 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); 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-pyrazole-5-carboxamide (Example 193); 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); (S)-N-(1-Cycloheptyl-2-oxo-2-((5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 195); N-((S)-2-((5-(3,5-Dimethylisothiazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 196); N-((S)-2-((5-(3,5-Dimethylisothiazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazole-5-carboxamide (Example 197); (S)-N-(1-Cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 198); 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-pyrazole-5-carboxamide (Example 199); 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-triazole-5-carboxamide (Example 200); 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); (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); N-((S)-2-((6-(3,5-Dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 203); 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-pyrazole-5-carboxamide (Example 204); 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-pyrazole-5-carboxamide (Example 205); 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); (S)-N-(1-cyclohexyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 207); (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 208); (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-triazole-5-carboxamide (Example 209); (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); 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-pyrazole-5-carboxamide (Example 211); 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-pyrazole-5-carboxamide (Example 212); 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); (S)-N-(1-cycloheptyl-2-oxo-2-((1’,2’,4’-trimethyl-6’-oxo-1’,6’-dihydro-[3,3’-bipyridin]-6-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 214); 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); (S)-N-(1-cycloheptyl-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 216); 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-pyrazole-5-carboxamide (Example 217); (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 218); 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-pyrazole-5-carboxamide (Example 219); or N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro[2.1.2 5 .2 3 nonan-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 220); comprising any one of the foregoing or a pharmaceutically acceptable salt thereof.

[0093] The various functional groups and substituents that make up the compounds of the present invention are typically selected such that the molecular weight of the compound does not exceed 1000. Further, as a general rule, the molecular weight of the compound is less than 750, for example, less than 700, or less than 650, or less than 600.

[0094] Suitable or preferred features of any compound of the present invention may also be suitable features of any other aspect.

[0095] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, or salts with organic bases that yield physiologically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0096] Compounds that have the same molecular formula but differ in the nature or sequence of the bonds between their atoms or in the arrangement of those atoms in space are called "isomers". Isomers that differ in the arrangement of those atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are mirror images that cannot be superimposed on each other are called "enantiomers". When a compound has an asymmetric center, for example, when 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 are described by the R and S ranking rules of Cahn and Prelog or by the way in which the molecule rotates plane-polarized light and are designated as dextrorotatory or levorotatory (i.e., as the (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0097] The compounds of the present invention can possess one or more asymmetric centers; accordingly, such compounds are 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 the individual enantiomers and their racemic or other mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4, 4th Edition, of "Advanced Organic Chemistry", J. March, John Wiley and Sons, New York, 2001) and include, for example, synthesis from optically active starting materials or resolution of the racemic form. Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereoisomeric and geometric isomers and mixtures thereof.

[0098] The present invention also encompasses the compounds of the present invention as defined herein, including one or more isotope 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; O may be in any isotopic form including 16O and 18O; and so on.

[0099] It should also be understood that certain compounds of the present invention may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms.

[0100] It should also be understood that certain compounds of the present invention may exhibit polymorphs, and that the present invention encompasses all such forms.

[0101] The compounds of the present invention may exist in a number of different tautomeric forms, and reference to a compound of the present invention includes all such forms. To avoid misunderstanding, if a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are still encompassed by the compounds of the present invention. Examples of tautomers include, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro, including keto, enol and enolate forms.

[0102]

Chemical formula

[0103] The compounds of the present invention containing an amine functional group can also form N-oxides. References herein to compounds of Formula I containing an amine functional group include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines of nitrogen-containing heterocycles or nitrogen atoms. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn.Comm. 1977, 7, 509-514) which reacts an amine compound with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0104] The compounds of the present invention are administered in the form of prodrugs which are broken down in the human or animal body to release the compounds of the present invention. The prodrugs can be used to change the physical or pharmacokinetic properties of the compounds of the present invention. Prodrugs are formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group is attached. Examples of prodrugs include in vivo cleavable ester derivatives formed from carboxy groups or hydroxy groups in the compounds of the present invention and in vivo cleavable amide derivatives formed from carboxy groups or amino groups in the compounds of the present invention.

[0105] Accordingly, the present invention encompasses compounds of formula I as defined above when made available by organic synthesis and when made available in the human or animal body by means of cleavage of their prodrugs. Accordingly, the present invention also encompasses compounds of formula I produced by means of organic synthesis and such compounds produced in the human or animal body by means of metabolism of precursor compounds, i.e., the compounds of formula I may be synthetically produced compounds or metabolically produced compounds.

[0106] Synthesis In the description of the synthesis methods described hereinafter and in the reference synthesis methods used to manufacture starting materials, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedure, are selected by those skilled in the art.

[0107] Those skilled in the art of organic synthesis will understand that the functional groups present in the various parts of the molecule must be compatible with the reagents and reaction conditions utilized.

[0108] The required starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in the appended examples in conjunction with the following representative process variants. Alternatively, the required starting materials can be obtained by procedures analogous to those exemplified which are within the ordinary skill of an organic chemist.

[0109] It will be appreciated that during the synthesis of the compounds of the present invention or during the synthesis of certain starting materials in the processes defined hereinafter, it may be desirable to protect certain substituent groups to prevent their unwanted reactions. A skilled chemist will know when such protection is required and how such protecting groups can be introduced and later removed.

[0110] For examples of protecting groups, see one of the many general textbooks on the subject, for example, "Protecting groups in Organic Synthesis (3rd Edition), John Wiley & Sons, NY (1999)", T. Greene and P. Wuts. Protecting groups can be removed by any convenient method that is described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being selected to achieve removal of the protecting group while minimizing perturbation of groups elsewhere in the molecule.

[0111] Thus, when the reactant contains groups such as, for example, amino, carboxy or hydroxy, it may be desirable to protect the groups in some of the reactions referred to herein.

[0112] As an 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 groups, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group, or an aroyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed by hydrogenation with a catalyst such as palladium on carbon or by treatment with a Lewis acid such as BF3.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or by treatment with hydrazine.

[0113] One skilled in the art will recognize that the compounds of the present invention can be prepared in a variety of ways by known methods. The compounds of formula I can be prepared by the methods described below, by the methods described in the experiments, or by similar methods. The routes described are only illustrative of some of the methods used in the synthesis of the compounds of formula I, and one skilled in the art will understand that the order of the reaction steps is not limited to that described. The assignment of nucleophiles and electrophiles is not limited to that described herein, and it will also be understood that in some cases it may be appropriate to reverse the assignment. Different approaches to synthetic chemical strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd Edition, S. Warren and P. Wyatt (2008).

[0114] A compound of formula I, or a pharmaceutically acceptable salt thereof [wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and Y are as previously defined] is prepared by reacting a carboxylic acid of formula III or a suitably reactive derivative of the carboxylic acid [wherein R 1 , R 2 , R 3 and Y are as previously defined in formula I] with an amine of formula II [wherein R 4 , X 1 , X 2 , X 3 and X 4 are as previously defined in formula I] (Scheme A, step i).

[0115] Alternatively, a compound of formula I, or a pharmaceutically acceptable salt thereof [wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X4 and Y are as previously defined] is the amine of formula IV [wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 are as previously defined in formula I] can be prepared by reacting with a carboxylic acid of formula V or a suitably reactive derivative of the carboxylic acid [wherein Y is as previously defined in formula I] (Scheme A, step ii).

[0116]

Chemical formula

[0117] The compound of formula III can be prepared by reacting a suitably protected amine of formula VI [wherein R 1 , R 2 and R 3 are as previously defined in formula I] with a carboxylic acid of formula V or a suitably reactive derivative of the carboxylic acid [wherein Y is as previously defined in formula I] (Scheme B, step i).

[0118] The compound of formula IV can be prepared by reacting a suitably protected carboxylic acid of formula VI or a suitably protected reactive derivative of the carboxylic acid [wherein R 1 , R 2 and R 3 are as previously defined in formula I] with an amine of formula II [wherein R 4 , X 1 , X 2 , X 3 and X 4 are as previously defined in formula I] (Scheme B, step ii).

[0119]

Chemical formula

[0120] Suitably reactive derivatives of the carboxylic acids of formula III, formula V and formula VI include, for example: acyl halides formed by the reaction of an acid with an inorganic acid chloride such as thionyl chloride; mixed anhydrides formed by the reaction of an acid with a chloroformate such as isobutyl chloroformate; esters formed by the reaction of an acid with an alcohol in the presence of an acid or a base; activated esters formed by the reaction of an acid with a phenol such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; or products of the reaction of an acid with an amide coupling agent such as dicyclohexylcarbodiimide. When the carboxylic acids of formula III and formula V are converted to esters, for example, by reaction of an acyl chloride with an organic alcohol such as methanol, this may be reacted with a suitable amine in the presence of an organometallic activator such as a Grignard reagent like isopropylmagnesium bromide. Typically, the carboxylic acid of formula III and the amine of formula II, or the carboxylic acid of formula V and the amine of formula IV, or the suitably protected carboxylic acid of formula VI and the amine of formula II are treated with an amide coupling agent such as HATU or T3P® in the presence of a non-nucleophilic base such as triethylamine, 2,4,6-trimethylpyridine or N,N-diisopropylethylamine in a suitable solvent such as DMF, ethyl acetate or MeCN.

[0121] One of ordinary skill in the art will appreciate that the conversion of the amino acids of formula VI to the compounds of formula III and formula IV will require a suitable synthetic strategy that may involve multiple steps. One of ordinary skill in the art will be able to identify such synthetic strategies, which may include the selection, preparation, and removal of suitable protecting groups.

[0122] Natural and non-natural amino acids of formula VI and their derivatives [wherein R 1 , R 2 and R 3is as defined in formula I] is either commercially available or can be prepared by methods known to those skilled in the art. For reviews on the synthesis of amino acids, see (a) C. Najera and J. M. Sansano, Chem Rev, 2007, 107, 4584; (b) R. M. Williams and J. A. Hendrix, Chem Rev, 1992, 92, 889; and (c) R. O. Duthaler, Tetrahedron, 1994, 50, 1539.

[0123] The carboxylic acids of formula V or their derivatives [wherein Y is as defined in formula I] are either commercially available or can be prepared by methods known to those skilled in the art. The 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 of organolithium or Grignard reagents with carbon dioxide; or transition metal-catalyzed carbonylation of aryl halides in the presence of water. The compounds of formula III or formula I can be directly formed by transition metal-catalyzed carbonylation of aryl halides in the presence of an amine of formula VI or formula IV.

[0124] [Chemical formula]

[0125] The amine of formula II [wherein R 4 , X 1 , X 2 , X 3 and X 4 are as previously defined in formula I] is either commercially available or can be prepared by methods known to those skilled in the art.

[0126] The compound of formula II is of formula VII [wherein R 4 is as defined in formula I] and of formula VIII [wherein X 1 , X 2, X 3 and X 4 is prepared from a compound as defined in formula I, where Z 1 and Z 2 is a functional group that facilitates the formation of a bond between R 4 and the phenyl / heteroaryl ring and is 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, when R 4 is heteroaryl, a suitable bond-forming reaction may be the Suzuki reaction, and either Z 1 or Z 2 is a boronic acid or boronic ester and the other is a halide. Typically, one of Z 1 or Z 2 is a boronic acid or boronic ester and the other is a halide. Compounds of formula VII and formula VIII are 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.

[0127] The amine of formula II can also be prepared from a compound of formula IX [wherein R 4 , X 1 , X 2 , X 3 and X 4 are as previously defined in formula I and Z 3 is a functional group that is converted to an amine via a known method] (Scheme C, step ii). Examples of known methods are; reduction when Z 3 is, for example, azide or nitro; rearrangement when Z 3 is, for example, a primary amide (Hofmann rearrangement), carboxylic acid (Schmidt rearrangement), or acyl azide (Curtius rearrangement); or, Z 3is H or a halide and involves C-N bond formation, such as nitration, followed by reduction or amination (e.g., Buchwald-Hartwig reaction).

[0128] The compound of formula IX [wherein R 4 , X 1 , X 2 , X 3 and X 4 are as defined above in formula I] is as described herein and is either commercially available or can be produced by methods known to those skilled in the art.

[0129] Pharmaceutical compositions The compounds of the present invention will usually, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Thus, according to a further aspect of the present invention, there is provided 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 additives, excipients or carriers.

[0130] The pharmaceutical compositions of the present invention can be manufactured and packaged in bulk form, such as powders or syrups, which can extract a safe and effective amount of the compound of the present invention and then be administered to a patient. Alternatively, the pharmaceutical compositions of the present invention can be manufactured and packaged in unit dosage forms, in which each physically discrete unit contains a safe and effective amount of the compound of the present invention. When manufactured in unit dosage forms, the pharmaceutical compositions of the present invention typically contain from 1 mg to 1000 mg.

[0131] The compositions of the present invention are suitable for oral use (e.g., as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration (e.g., via transdermal patches), administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as micronized powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing, or as suppositories for rectal dosing).

[0132] As used herein, "pharmaceutically acceptable additive" means a pharmaceutically acceptable material, composition or vehicle involved in imparting form or viscosity to a pharmaceutical composition. Each additive must be compatible with the other ingredients of the pharmaceutical composition when combined so as to avoid interactions that would substantially reduce the efficacy of the compounds of the present invention when administered to a patient and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each additive must of course be of a sufficiently high purity to render it pharmaceutically acceptable.

[0133] The pharmaceutical compositions of the present invention are manufactured using techniques and methods known to those of ordinary skill in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).

[0134] An effective amount of the compounds of the present invention for use in the therapy of proliferative diseases is an amount sufficient to palliate the symptoms of a proliferative disease, to slow the progression of a proliferative disease, or to reduce the risk of exacerbation in a patient having symptoms of a proliferative disease, in warm-blooded animals, particularly humans, on a symptomatic basis.

[0135] The amount of active ingredient to be combined with one or more additives to produce a single dosage form will necessarily vary depending on the host to be treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally be combined with a suitable and convenient amount of additive that can vary, for example, from about 5 to about 98 weight percent of the total composition, and will contain from 0.5 mg to 0.5 g of active agent (more preferably from 0.5 to 100 mg, for example from 1 to 30 mg).

[0136] The size of the dose for therapeutic or prophylactic purposes of the compounds of formula I will vary naturally according to well-known medical principles according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0137] When using the compounds of the present invention for therapeutic or prophylactic purposes, the compounds will generally be administered such that, assuming they are required in divided doses, a daily dose in the range of from 0.1 mg to 75 mg per kg of body weight is received. Generally, when a parenteral route is used, lower doses will be administered. Thus, for example, for intravenous or intraperitoneal administration, doses in the range of from 0.1 mg to 30 mg per kg of body weight will generally be used. Similarly, for administration by inhalation, doses in the range of from 0.05 mg to 25 mg per kg of body weight will be used. Oral administration can also be suitable, particularly in tablet form. Typically, a unit dosage form will contain from about 0.5 mg to 0.5 g of the compound of the present invention.

[0138] Route of administration The compounds of the present invention, or pharmaceutical compositions containing the active compound, are administered to a subject by any convenient route, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0139] The routes of administration are oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patch, ointment, etc.); transmucosal (including, e.g., by gum, film, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., via the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intramedullary, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, intrathecal and intrasternal; by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular, but not limited thereto.

[0140] Therapeutic uses and applications The compounds of the present invention are high affinity binders to human IL-17A and potent modulators of human IL-17A activity and are thus useful as therapeutic compounds in the treatment or prevention of human diseases resulting from IL-17A activity.

[0141] The compounds of the present invention are high affinity binders to human IL-17A and potent modulators of human IL-17A activity and can be useful as pharmacological standards for use in the development of new biological assays and in the search for new pharmacological agents. Thus, the compounds of the present invention can be useful as radioactive ligands in assays for detecting pharmacologically active compounds.

[0142] Thus, in one aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0143] In another aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by IL-17A activity.

[0144] In another aspect, the present invention relates to the use of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by IL-17A activity.

[0145] In another aspect, the present invention relates to a method of treating a disease or disorder in which IL-17A activity is involved, the method comprising administering to a subject in need of 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.

[0146] Examples of specific diseases or disorders that can be treated using the compounds of formula (I) and their pharmaceutically acceptable salts are as follows: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer and hematological malignancies, particularly acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-related arthritis, endotoxin shock associated with infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, infectious diseases (viruses, bacteria, fungi and parasites), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, liver fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic inflammatory disease, pain (particularly pain associated with inflammation), periodontitis, peritonitis, Peyronie's disease, folliculitis, psoriasis, psoriatic arthritis (PsA), renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), transplant rejection, type I diabetes, ulcerative colitis, uveitis and vasculitis, including but not limited to any one of these.

[0147] Modulators of IL-17 activity are administered to inhibit or reduce the severity of corneal ocular surface inflammatory disorders, including ocular inflammatory disorders (WO2009 / 089036), such as dry eye syndrome (DES). As a result, the compounds according to the invention are useful in the treatment or prevention of IL-17-mediated ocular inflammatory disorders, such as IL-17-mediated corneal ocular surface inflammatory disorders including dry eye syndrome. Corneal ocular surface inflammatory disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness grafts, selective endothelial transplantation, corneal neovascularization, artificial corneal transplantation surgery, corneal ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndromes, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye diseases, conjunctivitis and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome-related keratoconjunctivitis sicca, non-Sjogren's syndrome-related keratoconjunctivitis sicca, keratitis sicca, xerosis syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.

[0148] Combination therapy The compounds of the invention are administered alone as monotherapy or in combination with one or more additional therapeutic agents. The choice of one or more additional therapeutic agents will of course vary depending on the disease or condition being treated and its severity.

[0149] It is common to use combination therapy to treat certain medical conditions.

[0150] According to a particular aspect of the invention, there is provided a combination suitable for use in the treatment of a disease or condition in which IL-17 activity is involved, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0151] According to this aspect of the invention, acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer and hematological malignancies, particularly acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-related arthritis, endotoxin shock related to infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, infectious diseases (viruses, bacteria, fungi and parasites), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, liver fibrosis, Lyme arthritis, meningitis, myocarditis, encephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic inflammatory disease, pain (particularly pain related to inflammation), periodontitis, peritonitis, Peyronie's disease, folliculitis, psoriasis, psoriatic arthritis (PsA), renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), transplant rejection, type I diabetes, ulcerative colitis, uveitis, vasculitis, dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness grafts, selective endothelial transplantation, corneal neovascularization, artificial corneal transplantation surgery, corneal ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye diseases, conjunctivitis and a suitable combination for use in the prevention or treatment of microbial keratitis, comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents is provided.

[0152] Examples of these additional therapeutic agents include corticosteroids (administered topically or systemically), vitamin D analogs, anthralin, retinoids, calcineurin inhibitors, salicylic acid, methotrexate, cyclosporine, leflunomide, sulfasalazine, azathioprine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), ustekinumab (Stelara), golimumab (Simponi), guselkumab, PDE inhibitors (such as apremilast), thioguanine, hydroxyurea, dimethyl fumarate, TYK2 inhibitors (such as ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, seladelpar, ganitumab, lestaurtinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, BMS-986165), JAK inhibitors including NSAIDs (such as naproxen, indomethacin), but not limited to these.

[0153] In a further aspect of the invention, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0154] As used herein, when the term "combination" is used, it should be understood to refer to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In a further aspect of the invention, "combination" refers to sequential administration. When the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effects of the combination.

[0155] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents and associated with a pharmaceutically acceptable excipient or carrier.

[0156] One or more additional therapeutic agents may include further compounds of the invention. Accordingly, in certain embodiments, there is provided a pharmaceutical composition comprising two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable excipient or carrier.

[0157] The combinations referred to above are conveniently presented for use in the form of pharmaceutical formulations and, accordingly, pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable excipient or carrier represent a further aspect of the invention.

[0158] Such combination treatments are effected by simultaneous, sequential or separate dosing regimens of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0159] Such combination therapy employs a compound of the invention within the dosage ranges described herein and other pharmaceutically active agents within approved dosage ranges or within dosages described in relevant publications.

[0160] General Procedures: The methods for producing the compounds of the invention are illustrated in the examples below. Starting materials are made according to procedures known in the art or as illustrated herein, or are commercially available. Commercially available reagents were used without further purification. Where reaction temperatures are not included, reactions were typically carried out at ambient temperature (or room temperature), which is 17 - 27 °C.

[0161] Those skilled in the art will appreciate that reaction temperatures, reaction times and reagent amounts may vary from those described herein.

[0162] Compound names were generated using ChemDraw Professional version 20.0.0.41.

[0163] The compounds described in the present invention 1When characterized by 1H NMR spectroscopy, spectra were recorded on a JEOL ECX300 (300 MHz), JEOL ECX400 (400 MHz), or Bruker Avance III UltraShield 400 (400 MHz) instrument. When temperature was not included, spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

[0164] When the compounds described in the present invention were characterized by LCMS data, retention times and molecular weights were determined using the conditions set forth below.

[0165] Method 1: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210–350 nm) and QDa mass detector). Column: CrossBridge C18, 2.5 μm, 2.1 × 50 mm (flow rate 0.8 mL / min). Run time: 1.30 minutes. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2–98% B in 0.80 minutes, hold at 98% B until 1.30 minutes.

[0166] Method 2: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210–350 nm) and QDa mass detector). Column: CrossBridge C18, 2.5 μm, 2.1 × 50 mm (flow rate 0.8 mL / min). Run time: 1.40 minutes. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2–98% B in 1.20 minutes, hold at 98% B until 1.40 minutes.

[0167] Method 3: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 2 - 95% B and 5% C with A added over 4.0 min, hold at 95% B 5% C until 4.60 min, column temperature 40 °C.

[0168] Method 4: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 2 - 95% B and 5% C with A added over 1.2 min, hold at 95% B 5% C until 1.40 min, column temperature 40 °C.

[0169] Method 5: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: CrossBridge C18, 2.5 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2 - 98% B over 4.0 min, hold at 98% B until 4.60 min.

[0170] Method 6: Waters Acquity UPLC system (binary pump with PDA (210 - 350 nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 4.6 min. Conditions: water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2 - 98% B over 4.0 min, hold at 98% B until 4.60 min, column temperature 40 °C

[0171] Method 7: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CrossBridge C18, 2.5 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 5.00 min. Conditions: 2% ammonia in water [eluent D], MeCN [eluent C], water [eluent A]. Gradient: 2 - 95% C in A with 5% D added in 4.50 min, held at 95% C until 5.00 min, column temperature 40 °C.

[0172] Method 8: Waters Acquity UPLC system (binary pump with PDA (210 - 350 nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 1.4 min. Conditions: water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2 - 98% B in 1.2 min, held at 98% B until 1.40 min, column temperature 40 °C.

[0173] Method 9: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.7 mL / min). Run time: 5.00 min. Conditions: water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2 - 95% B in 4.50 min, held at 95% B until 5.00 min.

[0174] Method 10: Waters Acquity UPLC system (binary pump with PDA (210 - 350 nm) and QDa mass detector). Column: CrossBridge BEH C18, 2.5 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 4.80 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2 - 98% B in 4.0 min, held at 98% B until 4.70 min.

[0175] Method 11: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CrossBridge BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 5 - 95% B in 4.50 min, hold at 95% B until 5.00 min, column temperature 40 °C.

[0176] Method 12: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CrossBridge BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 2 - 95% B in 4.0 min, hold at 95% B until 4.60 min, column temperature 40 °C.

[0177] Method 13: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% throughout]. Gradient: 2 - 95% B in 4.0 min, hold at 95% B until 4.60 min, column temperature 40 °C.

[0178] Method 14: Agilent 6140 Series quadrupole mass spectrometer with multimode source (monitored at 254 nm). Column: Phenomenex Luna® C18(2)-HST column, 2.5 μm, 50×2.0 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 in 3.75 min.

[0179] Method 15: Agilent 6140 Series Quadrupole Mass Spectrometer with Multi-Mode Source (monitored at 254 nm). Column: Phenomenex Luna® C18(2)-HST column, 2.5 μm, 50×2.0 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 in 5.5 minutes.

[0180] Method 16: Agilent 6140 Series Quadrupole Mass Spectrometer with Multi-Mode Source (monitored at 254 nm). Column: Phenomenex Luna® C18(2)-HST column, 2.5 μm, 50×2.0 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 in 3.5 minutes.

[0181] Method 17: Waters Acquity UPLC H-Class System (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2 - 95% B in 4.0 minutes, held at 95% B until 4.60 minutes, column temperature 40 °C.

[0182] Method 18: Waters Acquity UPLC H-Class System (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CrossBridge BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. 2 - 95% B over 4.5 minutes, held at 95% B until 5.00 minutes, column temperature 40 °C.

[0183] Method 19: Agilent 6140 Series Quadrupole Mass Spectrometer with multimode source (monitored at 254 nm). Column: Phenomenex Kinetix® C18 100 Å, 1.7 μm, 50×2.1 mm. Conditions: Mobile phase A contained 0.1% formic acid in 18 MΩ water, and mobile phase B contained 0.1% formic acid in HPLC grade acetonitrile (flow rate 0.8 ml / min). Gradient: 5 - 95% B in 5 minutes.

[0184] Method 20: Waters Acquity UPLC H-Class System (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 1.40 minutes. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 50 - 95% B and 5% C with A added in 1.2 minutes, held at 95% B 5% C until 1.40 minutes, column temperature 40 °C.

[0185] Method 21: Waters Acquity UPLC H-Class System (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% throughout]. Gradient: 2 - 20% B in 3.0 minutes, 95% B at 4.0 minutes, held at 95% B until 4.60 minutes, column temperature 40 °C.

[0186] Method 22: Waters Acquity UPLC H-Class System (quaternary pump with PDA (210 - 350 nm) and QDa mass detector). Column: BEH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 1.40 minutes. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; 5% throughout]. Gradient: 2 - 50% B and 5% C with A added in 1.0 minute, 95% B at 1.8 minutes, held at 95% B 5% C until 2.0 minutes, column temperature 40 °C.

[0187] Method 23: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1×50 mm (flow rate 0.8 mL / min). Conditions: water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% throughout]. Gradient: 2 - 20% B in 1.0 min, 95% B at 1.8 min, hold at 95% B until 2.0 min, column temperature 40 °C.

[0188] Method 24: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210 - 350 nm) and SQD mass detector). Column: CrossBridge C18, 2.5 μm, 2.1×50 mm (flow rate 0.8 mL / min). Run time: 1.80 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2 - 50% B in 1.00 min, hold at 98% B until 1.80 min, column temperature 40 °C.

[0189] Method 25: Agilent 1260. Column: XSelect CSH C18, 130 Å, 2.5 μm, 4.6×30 mm. Conditions: 0.1% formic acid [eluent A], MeCN [eluent B] (flow rate 2.5 mL / min). Gradient: 5 - 95% B in 4 min, column temperature 40 °C.

[0190] Method 26: Agilent 1260 (binary pump, HiP sampler, column compartment, DAD: 260 + / - 90 nm, G6150 MSD: ESI); Column: Cortecs C18, 2.6 μm, 30×2.1 mm. Conditions: 0.1% NH3 in water [eluent A], MeCN [eluent B] (flow rate 1.35 mL / min). Gradient: 5 - 100% B in 2.5 min, hold at 100% B until 3 min, column temperature 40 °C.

[0191] Method 27: Agilent 1260 (Quaternary pump, HiP sampler, column compartment, DAD: 260 + / - 90 nm, G6150 MSD: ESI); Column: Cortex C18, 2.6 μm, 30 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], MeCN [eluent B] (flow rate 1.35 mL / min). Gradient: 5 - 100% B in 2.5 min, held at 100% B until 3 min, column temperature 40 °C.

[0192] Method 28: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity QDa detector). Column: Waters BEH C18 column, 1.7 μm, 30 × 2.1 mm. Conditions: 0.1% NH3 in water [eluent A], MeCN [eluent B] (flow rate 0.77 mL / min). Gradient: 2 - 100% B in 3 min, column temperature 40 °C.

[0193] Method 29: Agilent 1260 (Agilent VWD or DAD detector at 254 nm and Agilent MSD detector) Column: CrossBridge BEH C18, 130 Å, 2.5 μm, 4.6 × 30 mm. Conditions: 0.1% NH3 in water [eluent A], MeCN [eluent B] (flow rate 2.5 mL / min). Gradient: 5 - 95% B in 4 min, column temperature 40 °C.

[0194] Preparative HPLC was carried out using various preparative systems or mass-directed automated fractionation (MDAP) systems with variable wavelength UV detection as described below:

[0195] Method 1: Waters FractionLink preparative HPLC system with Waters 3100 mass detector (2545 pump, 2998 UV / VIS detector, 2767 liquid handler). Column: Waters CrossBridge OBD C18 column, XSelect CSH C18 (5 μm, 19 × 150 mm) or as specified. Conditions: Eluent selected from MeOH, MeCN with modifier selected from formic acid (0.1%) and ammonium oxide (0.1%) as specified. Gradient as specified.

[0196] Method 2: Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) using a Waters Crossbond Prep OBD C18, 5 μm, 19 mm i.d. × 50 mm column and a flow rate of 20 mL / min. Basic reverse-phase HPLC (water / acetonitrile / 0.005 M ammonia solution) using a standard gradient from 10% acetonitrile / 90% water to 95% acetonitrile / 5% water. For collection of fractions from the HPLC, UV detection, e.g., 254 nM, is used.

[0197] Method 3: Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) using a Waters Crossbond Prep OBD C18, 5 μm, 19 mm i.d. × 50 mm column and a flow rate of 20 mL / min. Acidic reverse-phase HPLC (water / acetonitrile / 0.1% formic acid) using a standard gradient from 5% acetonitrile / 95% water to 95% acetonitrile / 5% water. For collection of fractions from the HPLC, UV detection, e.g., 254 nM, is used.

[0198] Method 4: Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) using a Waters Crossbond Prep OBD C18, 5 μm, 19 mm i.d. × 50 mm column and a flow rate of 20 mL / min. Acidic reverse-phase HPLC (water / acetonitrile / 0.1% trifluoroacetic acid) using a standard gradient from 5% acetonitrile / 95% water to 95% acetonitrile / 5% water. For collection of fractions from the HPLC, UV detection, e.g., 254 nM, is used.

[0199] Method 5: Use a Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) with a Waters XSelect CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, eluting at a flow rate of 40 mL / min with a gradient of 0.1% formic acid in water - MeCN over 12.5 minutes. The at-column dilution pump provides 2 mL / min of MeCN throughout the method, which is included in the following MeCN percentages. Gradient information: 0.0 - 0.5 minutes, 25% MeCN; 0.5 - 10.5 minutes, ramping from 25% MeCN to 55% MeCN; 10.5 - 10.6 minutes, ramping from 55% MeCN to 100% MeCN; 10.6 - 12.5 minutes, held at 100% MeCN. UV detection over the full wavelength range is performed using PDA as well as QDA and ELS detectors.

[0200] Method 6: Use a Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) with a Waters CrossBridge BEH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, eluting at a flow rate of 40 mL / min with a gradient of 0.3% ammonia in water - MeCN over 12.5 minutes. The at-column dilution pump provides 2 mL / min of MeCN throughout the method, which is included in the following MeCN percentages. Gradient information: 0.0 - 0.5 minutes, 30% MeCN; 0.5 - 10.5 minutes, ramping from 30% MeCN to 60% MeCN; 10.5 - 10.6 minutes, ramping from 60% MeCN to 100% MeCN; 10.6 - 12.5 minutes, held at 100% MeCN. UV detection over the full wavelength range is performed using PDA as well as QDA and ELS detectors.

[0201] Fractional supercritical fluid chromatography (SFC) was performed on a Waters Investigator SFC composed of 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 fraction collection module. In the general method, liquid CO2 (Airproducts) and an appropriate modifier as defined were used. UV detection was at 254 nM.

[0202] Abbreviations:

Table 1-1

Table 1-2

[0203] Intermediate 1.1: 4-(2,3-Dimethylpyridin-4-yl)aniline A suspension of 4-bromo-2,3-dimethyl-pyridine (3.3 g, 18 mmol, CAS: 259807-91-5), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 hours. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 100% EtOAc) to afford the title compound (2.6 g). LCMS (Method 1): 0.64 min, 199.1 [M+H] +

[0204] Intermediate 1.2: 4-(3-Chloropyridin-4-yl)aniline 3-Chloro-4-iodopyridine (0.25 g, 1.0 mmol, CAS: 77332-79-7), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 4 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.18 g). The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.63 min, 205.1 [M+H] +

[0205] Intermediate 1.3: 4-(3-Methoxypyridin-4-yl)aniline To a solution of (3-methoxy-4-pyridyl)boronic 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) was added XPhos Pd G2 (1.8 g, 0.23 mmol) and the reaction was heated at 80 °C for 6 h. The reaction mixture was diluted with water and the crude product was extracted into EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane) to afford the title compound (0.25 g). LCMS (Method 2): 0.54 min, 201.1 [M+H] +

[0206] Intermediate 1.4: 4-(3-Methylpyridin-4-yl)aniline 4-Chloro-3-methylpyridine hydrochloride (0.20 g, 1.2 mmol, CAS: 19524-08-4), 4-aminophenylboronic acid hydrochloride (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) were heated at 80 °C for 3 hours according to the procedure described for Intermediate 1.1 to produce the title compound (61 mg). The crude product was purified by flash column chromatography (eluting with 60 - 80% EtOAc in heptane). LCMS (Method 2): 0.57 min, 185.1 [M+H] +

[0207] Intermediate 1.5: 4-(3-(Trifluoromethyl)pyridin-4-yl)aniline 4-Chloro-3-(trifluoromethyl)pyridine hydrochloride (0.20 g, 0.92 mmol, CAS: 732306-24-0), 4-aminophenylboronic acid hydrochloride (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) were heated at 80 °C for 6 hours according to the procedure described for Intermediate 1.1 to produce the title compound (75 mg). The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.71 min, 239.1 [M+H] +

[0208] Intermediate 1.6: 4-(3,5-Dimethylpyridin-4-yl)aniline A stirred suspension of 4-chloro-3,5-dimethyl-pyridine (0.40 g, 2.8 mmol, CAS: 143798-73-6), 4-aminophenylboronic acid hydrochloride (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) was added Pd(dppf)Cl2 (0.21 g, 0.28 mmol), and then heated at 120 °C for 2 h by microwave irradiation. The reaction mixture was filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 10-30% EtOAc in DCM) to give the title compound (0.15 g). LCMS (method 3): 1.42 min, 199.1 [M+H] +

[0209] Intermediate 1.7: 4-(4-aminophenyl)-N-methylpyridin-3-amine Intermediate 1.7a: Methyl (E)-N-(4-iodopyridin-3-yl)formimidate 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 to reflux for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (2.4 g), which was used without further purification. LCMS (method 2): 0.66 min, 262.9 [M+H] +

[0210] Intermediate 1.7b: 4-iodo-N-methylpyridin-3-amine A suspension of Intermediate 1.7a (2.6 g, 9.9 mmol) in anhydrous THF (20 mL) was added dropwise with LiAlH4 (5.2 mL, 5.2 mmol, 1 M in THF) at -5 °C under argon. The reaction mixture was stirred at -5 °C for 30 minutes, then warmed to 0 °C and quenched with saturated aqueous NH4Cl. The mixture was diluted with EtOAc, filtered through a pad of Celite (registered trademark), washed with EtOAc, the filtrate was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane) to afford the title compound (0.58 g). LCMS (Method 2): 0.60 min, 234.9 [M+H] +

[0211] Intermediate 1.7: 4-(4-Aminophenyl)-N-methylpyridin-3-amine Intermediate 1.7b (0.15 g, 0.64 mmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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) were heated at 70 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.14 g). The crude product was purified by flash column chromatography (eluting with 100% EtOAc) and by reverse phase column chromatography on a Biotage Isolera One (trademark) (30 g C18 column, eluting with 0 - 40% MeCN in 0.1 M NH4HCO3 buffer, pH 10). LCMS (Method 2): 0.50 min, 200.1 [M+H] +

[0212] Intermediate 1.8: 4-(4-Aminophenyl)-N,N-dimethylpyridin-3-amine Intermediate 1.8a: 4-Iodo-N,N-dimethylpyridin-3-amine To a solution of 4-iodopyridin-3-amine (0.5 g, 2.3 mmol, CAS: 105752-11-2) in anhydrous DMF (40 mL) was added sodium hydride (60% dispersion in mineral oil, 0.27 g, 6.8 mmol) at room temperature under argon. The mixture was stirred at room temperature for 30 minutes, then cooled to 0 °C, and iodomethane (0.42 mL, 6.8 mmol) was added dropwise at 0 °C over 10 minutes. The reaction was stirred at 0 °C for 3 hours. The mixture was quenched with 2 M aqueous NaOH and extracted into EtOAc. The combined organics were washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 20% EtOAc in hexanes) to afford the title compound (0.35 g). LCMS (Method 2): 0.70 min, 248.9 [M+H] +

[0213] Intermediate 1.8: 4-(4-Aminophenyl)-N,N-dimethylpyridin-3-amine Intermediate 1.8a (0.15 g, 0.60 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 70 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (75 mg). The crude product was purified by reverse phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 0 - 40% MeCN in pH 10 0.1 M NH4HCO3 buffer solution) and flash column chromatography (eluting with 90% EtOAc in hexanes). LCMS (Method 2): 0.63 min, 214.1 [M+H] +

[0214] Intermediate 1.9: 4-(3,5-Dimethoxypyridin-4-yl)aniline 4-Bromo-3,5-dimethoxypyridine (0.20 g, 0.92 mmol, CAS: 1033610-45-5), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 90 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.18 g). The crude product was purified by flash column chromatography (eluting with 100% EtOAc). LCMS (Method 2): 0.52 min, 231.1 [M+H] +

[0215] Intermediate 1.10: 4-(3-Fluoro-5-methoxypyridin-4-yl)aniline 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-dioxaborolan-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) were heated at 80 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.17 g). The crude product was purified by flash column chromatography (eluting with 60% EtOAc in hexane). LCMS (Method 2): 0.58 min, 219.1 [M+H] +

[0216] Intermediate 1.11: 5-(4-Aminophenyl)-6-methylpyridin-2(1H)-one 5-Bromo-6-methyl-pyridin-2-ol (0.50 g, 2.6 mmol, CAS: 54923-31-8), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 20 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.14 g). The crude product was purified by flash column chromatography (eluting with 50-100% EtOAc in heptane). LCMS (Method 2): 0.38 min, 201.1 [M+H] +

[0217] Intermediate 1.12: 5-(4-Aminophenyl)-1,4-dimethylpyridin-2(1H)-one Intermediate 1.12a: 5-Bromo-1,4-dimethylpyridin-2(1H)-one To a suspension of 5-bromo-4-methyl-pyridin-2-ol (0.15 g, 0.80 mmol, CAS: 164513-38-6) in acetone (10 mL) was added potassium carbonate (0.52 g, 3.8 mmol), followed by iodomethane (0.22 mL, 3.6 mmol). The resulting mixture was stirred at room temperature for 6 h. The precipitate was removed by filtration, washed with acetone, and the solution was concentrated to dryness in vacuo. The crude product was purified by flash column chromatography (eluting with 0-15% MeOH in EtOAc) to give the title compound (0.20 g). LCMS (Method 4): 0.48 min, 204.0 [M+H] +

[0218] Intermediate 1.12: 5-(4-Aminophenyl)-1,4-dimethylpyridin-2(1H)-one Intermediate 1.12a (0.20 g, 0.97 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 4 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.11 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 0.42 min, 215.1 [M+H] +

[0219] Intermediate 1.13: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one Intermediate 1.13a: 5-bromo-1,6-dimethylpyridin-2(1H)-one To a suspension of 5-bromo-6-methyl-pyridin-2-ol (0.5 g, 2.7 mmol, CAS: 54923-31-8) in acetone (33 mL) was added potassium carbonate (1.7 g, 13 mmol), followed by iodomethane (0.74 mL, 12 mmol), and the resulting mixture was stirred at room temperature for 6 h. The precipitate was removed by filtration, washed with acetone, and the solution was concentrated to dryness in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 60 - 100% EtOAc in heptane, followed by 0 - 10% MeOH in EtOAc) to give the title compound (0.37 g). LCMS (Method 4): 0.52 min, 203.9 [M+H] +

[0220] Intermediate 1.13: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one Intermediate 1.13a (0.17 g, 0.79 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 85 °C for 1 hour according to the procedure described for Intermediate 1.3 to produce the title compound (0.13 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane, followed by 0 - 10% MeOH in EtOAc). LCMS (Method 4): 0.50 min, 215.1 [M+H] +

[0221] Intermediate 1.14: 4-(3,5-Dimethylpyridin-4-yl)-3-fluoroaniline 4-Chloro-3,5-dimethyl-pyridine (0.20 g, 1.4 mmol, CAS: 143798-73-6), 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were used to produce the title compound (0.1 g) according to the procedure described for Intermediate 1.6 and heated at 120 °C for 1 hour by microwave irradiation. The crude product was purified by flash column chromatography (eluting with 50 - 100% EtOAc in heptane). LCMS (Method 4): 0.66 min, 217.1 [M+H] +

[0222] Intermediate 1.15: 3-Fluoro-4-(3-methylpyridin-4-yl)aniline 4-Chloro-3-methyl-pyridine hydrochloride (0.25 g, 1.5 mmol, CAS: 19524-08-4), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were used to produce the title compound (0.17 g) according to the procedure described for Intermediate 1.6 and heated at 120 °C for 1 hour by microwave irradiation. The crude product was purified by flash column chromatography on silica gel (eluting with 70% EtOAc in heptane). LCMS (Method 4): 0.62 min, 203.0 [M+H] +

[0223] Intermediate 1.16: 5-(4-Amino-2-fluorophenyl)-1,6-dimethylpyridin-2(1H)-one Intermediate 1.13a (0.23 g, 1.14 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were used to produce the title compound (0.16 g) according to the procedure described for Intermediate 1.1 and heated at 80 °C for 5 hours. The crude product was purified by flash column chromatography (eluting with 2% MeOH in EtOAc). LCMS (Method 3): 1.07 min, 233.1 [M+H] +

[0224] Intermediate 1.17: 5-(4-Amino-2-fluorophenyl)-1,4-dimethylpyridin-2(1H)-one Intermediate 1.12a (0.28 g, 1.4 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 5 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.19 g). The crude product was purified by flash column chromatography on silica gel (eluting with 2% MeOH in EtOAc). LCMS (Method 4): 0.49 min, 233.1 [M+H] +

[0225] Intermediate 1.18: 3-Fluoro-4-(3-fluoropyridin-4-yl)aniline 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-dioxaborolan-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) were heated at 85 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.26 g). The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 0.69 min, 237.0 [M+H] +

[0226] Intermediate 1.20: 4-(3-Methoxypyridin-4-yl)-3-methylaniline Intermediate 1.20a: N-(4-(3-Methoxypyridin-4-yl)-3-methylphenyl)acetamide 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) were heated at 80 °C for 3 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.27 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40–100% EtOAc in heptane). LCMS (Method 2): 0.54 min, 257.1 [M+H] +

[0227] Intermediate 1.20: 4-(3-Methoxypyridin-4-yl)-3-methylaniline 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) was stirred at 80 °C for 4 h. The mixture was diluted with water and extracted into EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (130 mg), which was used without further purification. LCMS (Method 2): 0.56 min, 215.1 [M+H] +

[0228] Intermediate 1.21: 4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)aniline 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-dioxaborolan-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) were heated at 80 °C for 2 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.53 g). The crude product was purified by flash column chromatography (eluting with 66% EtOAc in heptane). LCMS (Method 2): 0.54 min, 210.1 [M+H] +

[0229] Intermediate 1.22: 4-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline To a stirred solution of Intermediate 1.21 (0.1 g, 0.48 mmol) in THF (2 mL) was added dropwise borane dimethyl sulfide complex (0.27 mL, 2.9 mmol) at room temperature under an argon atmosphere and the mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction was quenched with MeOH at 0 °C, followed by water and ethanolamine and then heated to reflux for 2 min. The mixture was extracted with EtOAc and the combined organics were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse phase column chromatography on Biotage Isolera One™ (16 g C18 column, eluting with 25 - 50% MeCN in 0.1 M NH4HCO3 buffer, pH 10) to afford the title compound (35 mg). LCMS (Method 5): 1.05 min, 212.1 [M+H] +

[0230] Intermediate 1.23: 2-Fluoro-4-(3-methoxypyridin-4-yl)aniline (3-Methoxy-4-pyridyl)boronic acid (0.25 g, 1.6 mmol, CAS: 1008506-24-8), 2-fluoro-4-iodo-aniline (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 title compound (0.16 g) was prepared. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in hexanes). LCMS (Method 2): 0.59 min, 219.1 [M+H] +

[0231] Intermediate 1.24: 3-Fluoro-4-(3-methoxypyridin-4-yl)aniline (3-Methoxy-4-pyridyl)boronic acid (0.25 g, 1.6 mmol, CAS: 1008506-24-8), 3-fluoro-4-iodo-aniline (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 title compound (0.15 g) was prepared. The crude product was purified by flash column chromatography (eluting with 60% EtOAc in hexanes). LCMS (Method 2): 0.57 min, 219.1 [M+H] +

[0232] Intermediate 1.29: 5-(4-Amino-2,6-difluorophenyl)-1,6-dimethylpyridin-2(1H)-one Intermediate 1.29a: 3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline A solution of 4-bromo-3,5-difluoro-aniline (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) was added dropwise with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 mL, 16 mmol) at room temperature, and the reaction mixture was stirred at 100 °C for 4 h. The mixture was filtered through Celite® and washed with EtOAc, diluted with water, and extracted into EtOAc. The combined organics were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 120 g, eluting with 0-45% EtOAc in heptane) to give the title compound (0.86 g). LCMS (method 3): 1.14 min, 254.0 [M-H] -

[0233] Intermediate 1.29: 5-(4-Amino-2,6-difluorophenyl)-1,6-dimethylpyridin-2(1H)-one 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) was added XPhos Pd G2 (20 mg, 0.02 mmol) at room temperature and under argon. The reaction mixture was heated to 45 °C and an additional portion of Intermediate 1.29a (3 × 35 mg, 0.42 mmol) was added in small portions over 3 h. The reaction mixture was filtered through Celite® and washed with EtOAc. The filtrate was diluted with water and the crude product was extracted into EtOAc. The combined organics were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo, and the crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 45 g, eluting with 20-100% EtOAc in heptane) to give the title compound (0.10 g). LCMS (method 3): 1.19 min, 251.0 [M+H]+

[0234] Intermediate 1.30: 3,5-Difluoro-4-(3-methoxypyridin-4-yl)aniline (3-Methoxy-4-pyridyl)boronic acid (0.17 g, 1.1 mmol, CAS: 1008506-24-8), 4-Bromo-3,5-difluoro-aniline (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 title compound (0.11 g) was prepared. The crude product was purified by flash column chromatography (eluting with 40 - 100% EtOAc in heptane). LCMS (Method 3): 1.47 min, 237.1 [M+H] +

[0235] Intermediate 1.31: 4-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)aniline hydrochloride Intermediate 1.31a: tert-Butyl (4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)carbamate hydrochloride tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.44 g, 1.4 mmol, CAS: 330793-01-6), 4-Bromo-3,5-dimethyl-1H-pyrazole (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 while heating by microwave irradiation, the title compound (0.27 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One (trademark) (ZIP spherical silica column 30 g, eluting with 20 - 100% EtOAc in heptane). LCMS (Method 4): 0.84 min, 288.2 [M+H] +

[0236] Intermediate 1.31b: tert-Butyl (4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)carbamate 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) was added bromomethylbenzene (0.10 mL, 0.83 mmol), and the reaction mixture was heated at 55 °C for 3 days. The solvent was concentrated in vacuo, and the crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 30 - 100% EtOAc in heptane) to afford the title compound (0.11 g). LCMS (Method 4): 1.06 min, 378.3 [M+H] +

[0237] Intermediate 1.31: 4-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)aniline hydrochloride 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 in vacuo to afford the title compound (78 mg). The crude product was used without further purification. LCMS (Method 4): 0.82 min, 278.2 [M+H] +

[0238] Intermediate 1.34: 6-(4-Amino-2-fluorophenyl)pyridazin-3(2H)-one 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 a solution of tripotassium phosphate (1.8 M aqueous solution, 1.28 mL, 2.3 mmol) were used to prepare the title compound (0.13 g) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography (eluting with 20 - 100% EtOAc in heptane, followed by 10% MeOH in DCM). LCMS (Method 4): 0.38 min, 206.2 [M+H] +

[0239] Intermediate 1.35: 4-(4-Amino-2-fluorophenyl)pyridin-2(1H)-one 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 4 h according to the procedure described for Intermediate 1.6 to prepare the title compound (0.29 g). The crude product was purified by flash column chromatography (eluting with 5% MeOH in EtOAc). LCMS (Method 4): 0.39 min, 205.0 [M+H] +

[0240] Intermediate 1.37: 4-(2,5-Dimethylpyrimidin-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.31 g, 1.4 mmol, CAS: 214360-73-3), 4-chloro-2,5-dimethyl-pyrimidine (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) were heated at 80 °C for 4 h according to the procedure described for Intermediate 1.6 to produce the title compound (0.24 g). The crude product was purified by flash column chromatography (eluting with 40 - 50% EtOAc in heptane). LCMS (Method 2): 0.49 min, 200.1 [M+H] +

[0241] Intermediate 1.40: 4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 3 h according to the procedure described for Intermediate 1.6 to produce the title compound (0.25 g). The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.40 min, 213.1 [M+H] +

[0242] Intermediate 1.41: 4-(Imidazo[1,2-a]pyrimidin-3-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.33 g, 1.5 mmol, CAS: 214360-73-3), 3-bromoimidazo[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) were heated at 60 °C for 2 h according to the procedure described for Intermediate 1.6 to produce the title compound (0.21 g). The crude product was purified by flash column chromatography (eluting with 5% MeOH in EtOAc). LCMS (Method 2): 0.39 min, 211.1 [M+H] +

[0243] Intermediate 1.42: (4-(4-Aminophenyl)pyridin-3-yl)methanol hydrochloride Intermediate 1.42a: tert-Butyl N-[4-(3-formyl-4-pyridyl)phenyl]carbamate 4-Chloropyridine-3-carbaldehyde (0.2 g, 1.4 mmol, CAS: 114077-82-6), tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.45 g, 1.4 mmol), Pd(dppf)Cl2 (0.12 mg, 0.14 mmol) and sodium carbonate (0.45 g, 4.3 mmol) were heated at 80 °C for 4 h according to the procedure described for Intermediate 1.6 to produce the title compound (0.4 g). The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 2): 0.82 min, 299.1 [M+H] +

[0244] Intermediate 1.42b: tert-Butyl N-[4-[3-(hydroxymethyl)-4-pyridyl]phenyl]carbamate To a solution of intermediate 1.42a (0.2 g, 0.67 mmol) in MeOH (3 mL) was added sodium borohydride (51 mg, 1.4 mmol), and the reaction was stirred at room temperature for 1.5 h. The reaction was diluted with water and extracted into EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (0.16 g), which was used without further purification. LCMS (method 2): 0.70 min, 301.1 [M+H] +

[0245] Intermediate 1.42: (4-(4-aminophenyl)pyridin-3-yl)methanol hydrochloride Intermediate 1.42b (0.16 g, 0.54 mmol) was mixed with HCl (3 M in 1,4-dioxane, 4 mL, 0.54 mmol), and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (0.13 g), which was used without further purification. LCMS (method 2): 0.40 min, 201.1 [M+H] +

[0246] Intermediate 1.44: 4-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.18 g, 0.81 mmol, CAS: 214360-73-3), 4-chloro-6,7-dihydro-5H-cyclopenta[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) were heated at 80 °C for 5 h according to the procedure described for intermediate 1.6 to produce the title compound (65 mg). The crude product was purified by flash column chromatography (eluting with 50 - 100% EtOAc in heptane). LCMS (method 2): 0.62 min, 211.1 [M+H] +

[0247] Intermediate 1.47: 3-methoxy-4-(3-methoxypyridin-4-yl)aniline (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) were heated at 80 °C for 16 h according to the procedure described for Intermediate 1.6 to produce the title compound (32 mg). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40–100% EtOAc in heptane). LCMS (Method 2): 0.52 min, 231.1 [M+H] +

[0248] Intermediate 1.48: 6-(4-Amino-2-fluorophenyl)-2-methylpyridazin-3(2H)-one (3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.18 g, 0.77 mmol, CAS: 819057-45-9), 6-chloro-2-methyl-pyridazin-3-one (0.11 g, 0.77 mmol, CAS: 10071-38-2), XPhos Pd G2 (12 mg, 0.02 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.3 mL, 2.3 mmol) were used to produce the title compound (0.15 g) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography (eluting with 50–100% EtOAc in heptane). LCMS (Method 4): 0.48 min, 220.0 [M+H] +

[0249] Intermediate 1.51: 5-(4-Aminophenyl)-1-methylpyridin-2(1H)-one 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.26 g, 1.2 mmol, CAS: 214360-73-3), 5-bromo-1-methyl-pyridin-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) were used to prepare the title compound (0.18 g) according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 60 - 100% EtOAc in heptane, then 7% MeOH in EtOAc). LCMS (Method 24): 0.64 min, 201.1 [M+H] +

[0250] Intermediate 1.52: 4-(4-aminophenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one To a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 mg, 0.89 mmol, CAS: 214360-73-3) and 4-bromo-1,6-dihydropyrrolo[2,3-c]pyridin-7-one (0.19 mg, 0.89 mmol, CAS: 1361481-62-0) in degassed ethanol (24 mL) and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.5 mL, 2.7 mmol), XPhos (85 mg, 0.18 mmol) and XPhos Pd G2 (70 mg, 0.09 mmol) were added and the reaction mixture was heated at 100 °C for 1 h by microwave irradiation. The solvent was removed in vacuo and the residue was triturated with toluene. The crude product was purified twice by flash 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] +

[0251] Intermediate 1.53: 4-(4-amino-2-methoxyphenyl)pyridin-3-yl)methanol dihydrochloride tert-Butyl N-[4-[3-(hydroxymethyl)-4-pyridyl]-3-methoxy-phenyl]carbamate (0.1 mg, 0.17 mmol, CAS: 1622889-96-6) was dispersed in HCl (3 M in CPME, 2.3 mL, 6.9 mmol) under an argon atmosphere and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound (52 mg), which was used without further purification. LCMS (Method 2): 0.42 min, 231.1 [M+H] +

[0252] Intermediate 1.54: 5-(4-Amino-2-(trifluoromethyl)phenyl)-1,6-dimethylpyridin-2(1H)-one 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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 a solution of tripotassium phosphate (1.8 M aqueous solution, 1 mL, 1.9 mmol) were heated at 100 °C for 1.5 h according to the procedure described for Intermediate 1.3 to produce the title compound (0.11 g). The crude product was purified by flash column chromatography (eluting with 100% EtOAc). LCMS (Method 3): 1.38 min, 283.1 [M+H] +

[0253] Intermediate 1.55: 3-Chloro-4-(3,5-dimethylpyridin-4-yl)aniline 3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.34 g, 1.3 mmol, CAS: 877160-63-9), 4-chloro-3,5-dimethyl-pyridine (0.17 g, 1.2 mmol, CAS: 143798-73-6), XPhos Pd G2 (95 mg, 0.12 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.8 mL, 3.6 mmol) were used to prepare the title compound (96 mg) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 80 g, eluting with 5 - 70% EtOAc in DCM). LCMS (Method 4): 0.74 min; 233.1 [M+H] +

[0254] Intermediate 1.56: 4-(2,5-dimethylpyridin-4-yl)-3-fluoroaniline 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.36 g, 1.5 mmol, CAS: 819057-45-9), 4-chloro-2,5-dimethyl-pyridine (0.22 g, 1.5 mmol, CAS: 22282-80-0), XPhos Pd G2 (12 mg, 0.02 mmol), and a solution of potassium carbonate (1.8 M aqueous solution, 2.5 mL, 4.5 mmol) were used to prepare the title compound (0.29 g) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography (eluting with 90% EtOAc in heptane). LCMS (Method 3): 1.64 min, 217.1 [M+H] +

[0255] Intermediate 1.57: 4-(2,3-dimethylpyridin-4-yl)-3-fluoroaniline 4-Bromo-2,3-dimethyl-pyridine (0.25 g, 1.3 mmol, CAS: 259807-91-5), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 16 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.18 g). The crude product was purified by flash column chromatography (eluting with 90% EtOAc in heptane). LCMS (Method 4): 0.68 min, 217.1 [M+H] +

[0256] Intermediate 1.59: 4-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-3-fluoroaniline 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-dioxaborolan-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) were used to produce the title compound (0.5 g) as a mixture of positional isomers and 4-(1-benzyl-5-methyl-1H-pyrazol-4-yl)-3-fluoroaniline according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 50 - 100% EtOAc in heptane). LCMS (Method 4): 0.83 min, 282.1 [M+H] +

[0257] Intermediate 1.60: 4-(3,5-Dimethylisoxazol-4-yl)-3-fluoroaniline 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.77 g, 3.2 mmol, CAS: 819057-45-9), 4-bromo-3,5-dimethyl-isoxazole (0.38 mL, 3.2 mmol, CAS: 10558-25-5), XPhos Pd G2 (51 mg, 0.06 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 5.4 mL, 9.6 mmol) were heated at 100 °C for 2 hours according to the procedure described for Intermediate 1.3 to produce the title compound (0.15 g). The crude product was purified by flash column chromatography (eluting with 30 - 50% EtOAc in heptane) and reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 60 g, eluting with 0 - 50% MeCN in a 0.1% formic acid solution containing 0.1% formic acid in water). LCMS (Method 3): 1.52 min, 207.0 [M+H] +

[0258] Intermediate 1.62: 4-(1-Benzyl-1H-pyrazol-4-yl)-3-fluoroaniline 1-Benzyl-4-bromo-pyrazole (0.4 g, 1.7 mmol, CAS: 50877-41-3) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.4 g, 1.7 mmol, CAS: 819057-45-9), XPhos Pd G2 (27 mg, 0.03 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 2.8 mL, 5.1 mmol) were heated at 90 °C for 1 hour according to the procedure described for Intermediate 1.3 to produce the title compound (0.22 g). The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 12 g, eluting with 30 - 100% EtOAc in heptane). LCMS (Method 4): 0.80 min, 268.1 [M+H] +

[0259] Intermediate 1.63: 5-(4-Amino-2-fluorophenyl)-1-methylpyrimidin-2(1H)-one 5-Bromo-1-methyl-pyrimidin-2-one (0.25 g, 1.3 mmol, CAS: 14248-01-2) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.4 g, 1.7 mmol, CAS: 819057~45-9), XPhos Pd G2 (20 mg, 0.03 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 2.1 mL, 3.9 mmol) were heated by microwave irradiation at 120 °C for 1 hour according to the procedure described for Intermediate 1.3 to produce the title compound (0.1 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 45 g, eluting with 0-15% MeOH in DCM). LCMS (Method 21): 0.93 min, 220.3 [M+H] +

[0260] Intermediate 1.64: 5-(4-Amino-2-fluorophenyl)pyrimidin-2(1H)-one 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-dioxaborolan-2-yl)aniline (0.7 g, 3 mmol, CAS: 819057-45-9), XPhos Pd G2 (36 mg, 0.05 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 3.8 mL, 6.9 mmol) were heated by microwave irradiation at 120 °C for 1 hour according to the procedure described for Intermediate 1.3 to produce the title compound (0.26 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 80 g, eluting with 0-20% MeOH in DCM). LCMS (Method 21): 0.66 min, 206.0 [M+H] +

[0261] Intermediate 1.66: 8-(4-Amino-2-fluorophenyl)-1,6-naphthyridin-5(6H)-one 8-Bromo-6H-1,6-naphthyridin-5-one (0.11 g, 4.9 mmol, CAS: 155057-97-9) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.12 g, 5.1 mmol, CAS: 819057-45-9), XPhos Pd G2 (77 mg, 0.1 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 8.1 mL, 15 mmol) were heated at 100 °C for 2 hours according to the procedure described for Intermediate 1.3 to produce the title compound (0.52 g). The crude product was purified by flash column chromatography (eluting with 33 - 100% EtOAc in heptane, then 10 - 50% MeOH in DCM with 5% triethylamine), and then triturated with heptane. LCMS (Method 3): 0.88 min, 256.0 [M+H] +

[0262] Intermediate 1.67: 5-(4-Amino-2-fluorophenyl)pyridazin-3(2H)-one 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-dioxaborolan-2-yl)aniline (0.59 g, 2.5 mmol, CAS: 819057-45-9), XPhos Pd G2 (35 mg, 0.05 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 3.8 mL, 6.8 mmol) were heated at 100 °C for 20 hours according to the procedure described for Intermediate 1.3 to produce the title compound (0.24 g). The crude product was purified by flash column chromatography (eluting with 0 - 10% MeOH in EtOAc), and then triturated with heptane. LCMS (Method 13): 0.79 min, 206.0 [M+H] +

[0263] Intermediate 1.68: 3-Fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)aniline 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-dioxaborolan-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 title compound (0.6 mg) was prepared. The crude product was purified by flash column chromatography on silica gel (eluting with 40% EtOAc in heptane). LCMS (Method 4): 0.69 min, 258.0 [M+H] +

[0264] Intermediate 1.69: 7-(4-Amino-2-fluorophenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one 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-dioxaborolan-2-yl)aniline (0.51 g, 2.2 mmol, CAS: 819057-45-9), XPhos Pd G2 (62 mg, 0.08 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 3.3 mL, 5.9 mmol), according to the procedure described for Intermediate 1.3, heated by microwave irradiation at 120 °C for 1 hour to produce the title compound (0.26 g). The crude product was purified by flash column chromatography (eluting with 10 - 20% MeOH in DCM with 5% Et3N). LCMS (Method 21): 0.63 min, 245.0 [M+H] +

[0265] Intermediate 1.71: 6-(4-Amino-2-fluorophenyl)-1-methylpyridin-2(1H)-one 6-Bromo-1-methyl-pyridin-2-one (0.19 g, 1.0 mmol, CAS: 163452-70-8) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.24 g, 1.0 mmol, CAS: 819057-45-9), XPhos Pd G2 (32 mg, 0.04 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.7 mL, 3.0 mmol) were heated at 85 °C for 1 hour by microwave irradiation according to the procedure described for Intermediate 1.3 to produce the title compound (0.19 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 0.49 min, 219.1 [M+H] +

[0266] Intermediate 1.72: 6’-Amino-1,2-dimethyl-[3,3’-bipyridin]-6(1H)-one 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.25 g, 1.1 mmol, CAS: 827614-64-2), 5-bromo-1,6-dimethyl-pyridin-2-one (0.3 g, 1.1 mmol, CAS: 889865-54-7), XPhos Pd G2 (18 mg, 0.02 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.9 mL, 3.3 mmol) were heated at 85 °C for 1 hour by microwave irradiation according to the procedure described for Intermediate 1.3 to produce the title compound (0.23 g). The crude product was purified by reverse-phase column chromatography on Biotage Isolera One™ (C18 column 30 g, eluting with 1 - 40% MeCN / 0.1% ammonia in H2O / 0.1% ammonia solution). LCMS (Method 4): 0.36 min, 216.1 [M+H] +

[0267] Intermediate 1.73: 3’,5’-Dimethyl-[3,4’-bipyridin]-6-amine 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.25 g, 1.1 mmol, CAS: 827614-64-2), 4-chloro-3,5-dimethyl-pyridine (0.16 g, 1.1 mmol, CAS: 143798-73-6), XPhos Pd G2 (18 mg, 0.02 mmol), and a solution of potassium carbonate (1.8 M aqueous solution, 1.9 mL, 3.4 mmol) were heated by microwave irradiation at 85 °C for 2 h according to the procedure described for Intermediate 1.3 to produce the title compound (0.22 g). The crude product was purified by reverse-phase column chromatography on Biotage Isolera One™ (C18 column 30 g, eluting with 10–70% MeCN / 0.1% ammonia in H2O / 0.1% ammonia solution). LCMS (Method 4): 0.49 min, 200.1 [M+H] +

[0268] Intermediate 1.74: 4-(1-Benzyl-5-methyl-1H-pyrazol-4-yl)aniline A mixture of 1-benzyl-4-bromo-5-methyl-1H-pyrazole (CAS: 916080-12-1) and 1-benzyl-4-bromo-3-methyl-1H-pyrazole (0.54 g, 2.2 mmol, CAS: 137968-32-2), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.57 g, 2.6 mmol, CAS: 214360-73-3), XPhos Pd G2 (34 mg, 0.04 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 3.6 mL, 6.5 mmol) were heated by microwave irradiation at 85 °C for 1 h according to the procedure described for Intermediate 1.3 to give the title compound (0.57 g) as a mixture of positional isomers and 4-(1-benzyl-3-methyl-1H-pyrazol-4-yl)aniline. The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 30 - 100% EtOAc in heptane). LCMS (Method 4): 0.75 min, 264.1 [M+H] + , 0.77 min, 264.1 [M+H] +

[0269] Intermediate 1.75: 4-(4-Amino-2-fluorophenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 a solution of tripotassium phosphate (1.8 M aqueous solution, 2.1 mL, 3.7 mmol) were heated by microwave irradiation at 120 °C for 1.5 h according to the procedure described for Intermediate 1.3 to produce the title compound (0.14 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 40 g, eluting with 25 - 100% EtOAc in heptane). LCMS (Method 3): 0.98 min, 259.1 [M+H] +

[0270] Intermediate 1.76: 4-(7-Methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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 a solution of tripotassium phosphate (1.8 M aqueous solution, 1.5 mL, 2.6 mmol) were heated by microwave irradiation at 100 °C for 30 min according to the procedure described for Intermediate 1.3 to produce the title compound (0.21 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 25 g, eluting with 50 - 100% EtOAc in heptane). LCMS (Method 4): 0.61 min, 240.1 [M+H] +

[0271] Intermediate 1.77: 6-(4-Amino-2-fluorophenyl)-1-benzylpyridin-2(1H)-one Intermediate 1.77a: 1-Benzyl-6-chloro-pyridin-2-one To a solution of 6-chloropyridin-2-ol (0.2 g, 1.5 mmol, CAS: 16879-02-0) and potassium carbonate (0.53 g, 3.9 mmol) in acetone (15 mL) was added bromomethylbenzene (0.18 mL, 1.5 mmol, CAS: 100-39-0), and the reaction mixture was heated at 55 °C for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 40–100% EtOAc in heptane) to give the title compound (0.2 g). 1 H 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).

[0272] Intermediate 1.77: 6-(4-Amino-2-fluorophenyl)-1-benzylpyridin-2(1H)-one Intermediate 1.77a (0.2 g, 0.93 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 g, 0.93 mmol, CAS: 819057-45-9), XPhos Pd G2 (15 mg, 0.02 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 1.6 mL, 2.8 mmol) were heated by microwave irradiation at 85 °C for 1 h according to the procedure described for Intermediate 1.3 to produce the title compound (0.2 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 40–100% EtOAc in heptane). LCMS (Method 4): 1.06 min, 295.1 [M+H] +

[0273] Intermediate 1.78: 2-(4-(4-Aminophenyl)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethan-1-one Intermediate 1.78a: 2-(4-Chloro-3-pyridyl)-1-pyrrolidin-1-yl-ethanone 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 was added T3P® (50% w / w in EtOAc; 3.2 mL, 5.0 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.38 g), which was used without further purification. LCMS (Method 22): 0.70 min, 189.1 [M-Cl] +

[0274] Intermediate 1.78: 2-(4-(4-Aminophenyl)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethan-1-one The title compound (0.2 g) was prepared by heating Intermediate 1.78a (0.34 g, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.41 g, 1.9 mmol, CAS: 214360-73-3), XPhos Pd G2 (123 mg, 0.15 mmol), and a solution of potassium carbonate (2 M aqueous solution, 3.1 mL, 6.3 mmol) at 100 °C for 2 h according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (SiliCycle silica column 40 g, eluting with 0-20% MeOH in EtOAc). LCMS (Method 22): 0.66 min, 282.1 [M+H] +

[0275] Intermediate 1.80: 6-(4-Amino-2-fluorophenyl)pyrimidin-4(3H)-one The title compound (0.2 g) was prepared by heating 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 a solution of tripotassium phosphate (1.8 M aqueous solution, 6.4 mL, 11.5 mmol) at 85 °C for 1 hour by microwave irradiation according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography (eluting with 0-10% MeOH in EtOAc). LCMS (Method 23): 0.73 min, 206 [M+H] +

[0276] Intermediate 1.84: 4-(1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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), tripotassium phosphate (4.2 g, 31 mmol) were heated at 80 °C for 1 hour by microwave irradiation according to the procedure described for Intermediate 1.3 to produce the title compound (1.1 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 100 g, eluting with 0-100% EtOAc in heptane). 11H NMR (400 MHz, 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).

[0277] Intermediate 1.87: 4-(4-Aminophenyl)pyridin-2(1H)-one 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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) were heated at 80 °C for 2 h according to the procedure described for Intermediate 1.6 to produce the title compound (80 mg). The crude product was purified by flash column chromatography (eluting with 5% MeOH in EtOAc, followed by 5% MeOH in DCM). LCMS (Method 4): 0.36 min, 187.1 [M+H] +

[0278] Intermediate 1.88: 4-(Imidazo[1,2-a]pyridin-5-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.33 g, 1.5 mmol, CAS: 214360-73-3), 5-bromoimidazo[1,2-a]pyridine (0.25 g, 1.3 mmol, CAS: 69214-09-1), XPhos Pd G2 (20 mg, 0.03 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 2.1 mL, 3.8 mmol) were heated at 85 °C for 1 h by microwave irradiation according to the procedure described for Intermediate 1.3 to produce the title compound (61 mg). The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 0.56 min, 210.1 [M+H] +

[0279] Intermediate 1.99: 5-(1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine Intermediate 1.99a: 4-Bromo-1-[(4-methoxyphenyl)methyl]-3,5-dimethyl-pyrazole 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) was added 1-(bromomethyl)-4-methoxy-benzene (0.57 g, 2.9 mmol, CAS: 2746-25-0). The mixture was heated at 55 °C for 18 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 12 g, eluting with 0 - 30% EtOAc in heptane) to give the title compound (0.53 g). 11H NMR (400 MHz, 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).

[0280] Intermediate 1.99b: tert-Butyl N-[5-[1-[(4-methoxyphenyl)methyl]-3,5-dimethyl-pyrazol-4-yl]-2-pyridyl]carbamate The title compound (0.61 g) was prepared by heating to reflux for 19 h according to the procedure described for Intermediate 1.3 from Intermediate 1.99a (0.49 g, 1.7 mmol), tert-Butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (0.53 g, 1.7 mmol, CAS: 910462-31-6), XPhos Pd G2 (26 mg, 0.03 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 2.8 mL, 5.0 mmol). The crude product was purified by flash column chromatography (eluting with 0 - 80% EtOAc in heptane). LCMS (Method 14): 1.88 min, 409.2 [M+H] +

[0281] Intermediate 1.99: 5-(1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine To a solution of Intermediate 1.99b (0.6 g, 1.5 mmol) in 1,4-dioxane (4 mL) was added HCl (4 M in 1,4-dioxane; 0.54 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 20 h, then an additional 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 a further 2.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with saturated aqueous NaHCO3 and brine. The combined organics were concentrated in vacuo. The crude product was purified by flash column chromatography (20 - 100% EtOAc in heptane) to give the title compound (0.27 g).1 1H NMR (400 MHz, 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).

[0282] Intermediate 1.104: tert-Butyl 4-(4-aminophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate

[0283] tert-Butyl 4-bromo-3,5-dimethyl-pyrazole-1-carboxylate (0.2 g, 0.73 mmol, CAS: 1040276-87-6), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were heated at 85 °C for 1 h according to the procedure described for Intermediate 1.3 to produce the title compound (70 mg). The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica cartridge 40 g, eluting with 0 - 10% MeOH in DCM). 1 1H NMR (400 MHz, 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).

[0284] Intermediate 1.106: 5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.35 g) was prepared by heating to reflux for 20 h 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-dioxaborolan-2-yl)pyrazole (1.1 g, 5 mmol, CAS: 1047644-76-7), XPhos Pd G2 (79 mg, 0.1 mmol), and a solution of tripotassium phosphate (1.8 M aqueous solution, 8.3 mL, 15 mmol) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 0-10% MeOH in DCM). LCMS (Method 14): 1.06 min, 189.2 [M+H] +

[0285] Intermediate 1.125: 5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine To a solution of tert-butyl N-(5-iodo-2-pyridyl)carbamate (0.9 g, 2.8 mmol, CAS: 375853-79-5) in 1,4-dioxane (14 mL) were added tributyl-(3,5-dimethyltriazol-4-yl)stannane (2.2 g, 5.6 mmol, CAS: 1047637-17-1), triethylamine (1.2 mL, 8.4 mmol) and copper(I) iodide (80 mg, 0.42 mmol). 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 was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organics were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 100 g, eluting with 0-100% EtOAc in heptane) to yield the title compound (0.3 g). 11H NMR (400 MHz, 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).

[0286] Intermediate 1.125a: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridine To a solution of 5-bromo-2-chloro-pyridine (4.6 g, 24 mmol, CAS: 53939-30-3) in DMA (100 mL) was added 1,4-dimethyl-1H-1,2,3-triazole (4.6 g, 48 mmol, CAS: 60166-43-0), 2,2-dimethylpropanoic acid (0.73 g, 7.2 mmol), K2CO3 (6.6 g, 48 mmol) and PEPPSI™-IPr catalyst (0.33 g, 0.28 mmol). The mixture was heated at 120 °C for 20 h. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc, then the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 340 g, 0 - 70% EtOAc in heptane) to afford the title compound (1.6 g). 1 1H NMR (400 MHz, CDCl3) δ: 8.39 (dd, 1H), 7.63 (dd, 1H), 7.51 (dd, 1H), 3.97 (s, 3H), 2.33 (s, 3H).

[0287] Intermediate 1.138: 6-(3,5-Dimethylisoxazol-4-yl)pyridin-3-amine The title compound (0.18 g) was prepared by heating 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) at 145 °C for 3 hours by microwave irradiation according to the procedure described for Intermediate 1.6. The crude product was purified by reverse-phase column chromatography on Biotage Isolera One™ (C18 column 50 g, eluting with 5 - 100% MeCN in aqueous buffer with 0.005 M NH4OH). LCMS (Method 14): 1.21 min, 190.2 [M+H] +

[0288] Intermediate 1.140: 5-(5-methylpyrimidin-4-yl)pyridin-2-amine The title compound (0.24 g) was prepared by heating 4-chloro-5-methyl-pyrimidine (0.25 g, 2.0 mmol, CAS: 51957-32-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) at 80 °C for 3 hours according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 0 - 7% MeOH in DCM) and flash column chromatography on Biotage Isolera One™ (silica column 4 g, eluting with 0 - 7% MeOH in DCM). 1 H NMR (400 MHz, 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).

[0289] Intermediate 1.142: 5-(3-(Methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-amine The title compound (0.2 g) was prepared by heating 4-bromo-3-(methoxymethyl)-5-methyl-isoxazole (0.57 g, 2.76 mmol, CAS: 1000894-06-3), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) at 120 °C for 1 hour according to the procedure described for Intermediate 1.1. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 0 - 100% EtOAc in heptane). LCMS (Method 14): 1.18 min, 220.2 [M+H] +

[0290] Intermediate 1.143: 2-Chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine Intermediate 1.143a: 5-(3,5-Dimethyl-4H-1,2,4-triazol-4-yl)-2-methoxypyridine A solution of dimethylacetamide dimethyl acetal (0.18 g, 13.3 mmol, CAS: 18871-66-4) and acetohydrazide (0.98 g, 13.3 mmol, CAS: 1068-57-1) in acetonitrile (5 mL) was heated at 50 °C for 30 minutes, then 6-methoxypyridin-3-amine (0.15 g, 12.1 mmol, CAS: 6628-77-9), acetic acid (7.5 mL) and acetonitrile (2.5 mL) were added. The reaction was heated at 120 °C for 20 hours and then concentrated in vacuo. The crude product was triturated with diethyl ether to afford the title compound (0.72 g). LCMS (Method 14): 1.24 min, 205.2 [M+H] +

[0291] Intermediate 1.143b: 5-(3,5-Dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one To a solution of Intermediate 1.143a (0.68 g, 3.3 mmol) in acetic acid (7.7 mL) was added HBr (48% aqueous solution; 7.5 mL, 66 mmol). The reaction mixture was heated at 80 °C for 6 hours and then concentrated in vacuo. The residue was azeotroped from a mixture of EtOAc and heptane (1:1). The crude product was triturated with diethyl ether to afford the title compound (0.65 g). 1 H NMR (400 MHz, MeOD) δ: 8.05 (d, 1H), 7.73 (dd, 1H), 6.75 (d, 1H), 2.53 (s, 6H).

[0292] Intermediate 1.143: 2-Chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine Phosphorus oxychloride (2.5 mL, 26 mmol) was added to Intermediate 1.143b (0.5 g, 2.6 mmol) and the reaction was heated to reflux for 20 hours. The mixture was concentrated in vacuo and then a mixture of MeOH / H2O (1:1) was slowly added. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 0 - 10% MeOH in DCM) to afford the title compound (0.41 g). LCMS (Method 14): 1.22 min, 209.2 [M+H] +

[0293] Intermediate 1.145: 6-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-3-amine The title compound (0.91 g) was prepared by heating to reflux for 24 h from 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.13 g, 5.5 mmol, CAS: 1047644-76-7), 6-chloropyridin-3-amine (0.71 g, 5.5 mmol, CAS: 5350-93-6), XPhos Pd G2 (87 mg, 0.11 mmol) and tripotassium phosphate (2.5 M aqueous solution; 6.6 mL, 16.6 mmol) according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 10% MeOH in DCM). LCMS (Method 14): 1.22 min, 189.2 [M+H] +

[0294] Intermediate 1.146: 4-Methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.85 g) was prepared by heating at 120 °C for 16 h from 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.7 g, 8 mmol, CAS: 847818-74-0), 5-bromo-4-methyl-pyridin-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) according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 12 g, eluting with 0 - 10% MeOH in DCM). LCMS (Method 19): 0.52 min, 189.2 [M+H] +

[0295] Intermediate 1.147: 2-(1,4-Dimethyl-1H-pyrazol-5-yl)pyrimidin-5-amine The title compound (0.66 g) was prepared by heating to reflux for 24 h according to the procedure described for Intermediate 1.3 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-dioxaborolan-2-yl)pyrazole (1.0 g, 4.7 mmol, CAS: 1047644-76-7), XPhos Pd G2 (73 mg, 0.09 mmol) and tripotassium phosphate (2.5 M aqueous solution; 5.6 mL, 16.6 mmol). The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 10% MeOH in DCM). LCMS (Method 19): 1.25 min, 190.2 [M+H] +

[0296] Intermediate 1.150: 5-(5-(Methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-amine Intermediate 1.150a: 4-Bromo-5-(methoxymethyl)-3-methylisoxazole 5-(Methoxymethyl)-3-methyl-isoxazole (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 one portion. The reaction was heated at 55 °C for 20 h under argon. The reaction was cooled to room temperature and then diluted with diethyl ether and washed with water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.7 g). 1 H NMR (400 MHz, MeOD) δ: 4.53 (s, 2H), 3.37 (s, 3H), 2.28 (s, 3H).

[0297] Intermediate 1.150: 5-(5-(Methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-amine The title compound (0.22 g) was prepared by heating intermediate 1.150a (1.6 g, 7.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) at 120 °C for 1 hour according to the procedure described for intermediate 1.1. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 0 - 100% EtOAc in heptane). 1 H NMR (400 MHz, 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)

[0298] Intermediate 1.151: 3'-Methoxy-2'-methyl-[3,4'-bipyridine]-6-amine The title compound (0.2 g) was prepared by heating 4-chloro-3-methoxy-2-methyl-pyridine (0.50 g, 3.2 mmol, CAS: 107512-34-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-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) at 80 °C for 3 hours according to the procedure described for intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 0 - 5% MeOH in DCM). 1 H NMR (400 MHz, 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).

[0299] Intermediate 1.152: 2’,3’-dimethyl-[3,4’-bipyridin]-6-amine The title compound (0.5 g) was prepared by heating 4-bromo-2,3-dimethyl-pyridine (0.50 g, 2.7 mmol, CAS: 259807-91-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-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) at 80 °C for 3 hours according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One (trademark) (silica column 10 g, eluting with 0 - 5% MeOH in DCM). 1 H NMR (400 MHz, 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).

[0300] Intermediate 1.153: 2’,5’-dimethyl-[3,4’-bipyridin]-6-amine The title compound (0.17 g) was prepared by heating 4-chloro-2,5-dimethyl-pyridine (0.50 g, 3.5 mmol, CAS: 22282-80-0), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-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) at 80 °C for 20 h according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 10 g, eluting with 0 - 5% MeOH in DCM) and an SCX cartridge (5 g, washed with MeOH and eluted with 2 M methanolic ammonia). 1 H NMR (400 MHz, 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).

[0301] 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 A solution of 1,1-dimethoxypropan-2-one (1 g, 8.5 mmol, CAS: 6342-56-9) and 4-methylbenzenesulfonohydrazide (1.6 g, 8.5 mmol, CAS: 1576-35-8) in MeOH (2 mL) was stirred at room temperature for 10 minutes. Ethanamine (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 minutes by microwave irradiation. The mixture was concentrated in vacuo and the residue was dissolved in DCM and H2O. The phases were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.99 g), which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ: 7.30 (s, 1H), 4.38 (qt, 2H), 2.38 - 2.33 (m, 3H), 1.54 (tt, 3H).

[0302] Intermediate 1.157: 2-Chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine The title compound (0.27 g) was prepared by heating intermediate 1.157a (0.98 g, 8.8 mmol), 5-bromo-2-chloro-pyridine (0.85 g, 4.4 mmol, CAS: 53939-30-3), PEPPSI™ IPr catalyst (60 mg, 0.09 mmol), 2,2-dimethylpropanoic acid (0.14 g, 1.3 mmol) and potassium carbonate (1.2 g, 8.8 mmol) at 130 °C for 2 hours according to the procedure described for intermediate 1.125a. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 10 g, eluting with 0 - 70% EtOAc in heptane) and reverse phase preparative HPLC (method 2). LCMS (method 14): 1.55 min, 223.6 [M+H] +

[0303] Intermediate 1.158: 4-(5-Chloropyrazin-2-yl)-3,5-dimethylisoxazole The title compound (0.52 g) was prepared by heating 2-bromo-5-chloro-pyrazine (1 g, 5.2 mmol, CAS: 912773-21-8), (3,5-dimethylisoxazol-4-yl)boronic acid (1.1 g, 7.8 mmol, CAS: 16114-47-9), Pd(dppf)Cl2 (0.19 mg, 0.26 mmol) and sodium carbonate (2.2 g, 21 mmol) at 120 °C for 16 h according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 12 g, eluting with 0 - 10% MeOH in DCM). LCMS (Method 19): 2.09 min, 210.2 [M+H] +

[0304] Intermediate 1.161: 2-chloro-5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine The title compound (0.26 g) was prepared by heating 1-cyclopropyl-4-methyl-triazole (1.1 g, 8.8 mmol, CAS: 2370890-05-2), 5-bromo-2-chloro-pyridine (0.85 g, 4.4 mmol, CAS: 53939-30-3), PEPPSI™ IPr catalyst (60 mg, 0.09 mmol), 2,2-dimethylpropanoic acid (0.14 g, 1.3 mmol) and potassium carbonate (1.2 g, 8.8 mmol) at 130 °C for 2 h according to the procedure described for Intermediate 1.125a. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 0 - 70% EtOAc in heptane) and reverse phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H] +

[0305] Intermediate 1.162: 5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-amine The title compound (0.56 g) was prepared by heating 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) at 80 °C for 16 h according to the procedure described for Intermediate 1.6. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 25 g, eluting with 0–2% MeOH in DCM). LCMS (Method 14): 1.26 min, 208.2 [M+H] +

[0306] Intermediate 1.165: 2-chloro-5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine The title compound (0.16 g) was prepared from 5-bromo-2-chloro-pyrimidine (0.25 g, 1.3 mmol, CAS: 32779-36-5), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 purified by flash column chromatography on Biotage Isolera One™ (silica column 12 g, eluting with 0–2% MeOH in DCM). LCMS (Method 14): 1.51 min, 209.2 [M+H] +

[0307] Intermediate 1.173: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine Intermediate 1.173a: 1-cyclopropyl-2,2-diethoxy-ethanone A solution of 2,2-diethoxy-N-methoxy-N-methyl-acetamide (3.35 g, 17.5 mmol, CAS: 1378705-69-1) in anhydrous THF (80 mL) was cooled to -78 °C under argon. A solution of bromo(cyclopropyl)magnesium (1 M in MeTHF; 21 mL, 21 mmol, CAS: 23719-80-4) was added slowly and the mixture was stirred at -78 °C for 3 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (3.0 g). 1 H NMR (400 MHz, 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).

[0308] Intermediate 1.173b: 4-Cyclopropyl-1-methyl-1H-1,2,3-triazole To a stirred solution of Intermediate 1.173a (2 g, 11.6 mmol) in MeOH (25 mL) was added 4-methylbenzenesulfonohydrazide (2.8 g, 15.1 mmol, CAS: 1576-35-8) and the mixture was stirred at room temperature for 1 h. A further portion of 4-methylbenzenesulfonohydrazide (0.64 g, 3.4 mmol) was added and the mixture was stirred at room temperature for 1 h. Methanamine (1.3 mL, 15.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) were then 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 in vacuo and the residue was dissolved in water and DCM. The aqueous layer was extracted with DCM and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, 2 - 65% EtOAc in heptane) to afford the title product (0.66 g). 11H NMR (400 MHz, 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).

[0309] Intermediate 1.173: 5-(4-Cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine To a solution of Intermediate 1.173b (0.3 g, 2.4 mmol) in toluene (6.1 mL) were added 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) under argon. The reaction mixture was stirred at 120 °C for 40 h. Additional portions of palladium(II) acetate (55 mg, 0.24 mmol), triphenylphosphine (0.13 g, 0.49 mmol), potassium carbonate (0.34 g, 2.5 mmol) and 5-bromo-2-chloropyridine (0.47 g, 2.4 mmol) 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 organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 12 g, 2 - 80% EtOAc in heptane) to afford the title compound (0.22 g). 1 1H NMR (400 MHz, 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).

[0310] Intermediate 1.174: 5-(4-Chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (1.1 g) was prepared by heating 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.3 g, 9.5 mmol, CAS: 1430057-83-2), 5-bromopyridin-2-amine (1.1 g, 6.40 mmol, CAS: 1072-97-5), XPhos Pd G2 (0.25 g, 0.32 mmol) and tripotassium phosphate (0.5 M aqueous solution; 25 mL, 13 mmol) at 60 °C for 18 h according to the procedure described for Intermediate 1.3. The crude product was purified by flash column chromatography (eluting with 0 - 5% MeOH in DCM). 1 H NMR (400 MHz, CDCl3) δ: 8.04 (dd, 1H), 7.46 - 7.39 (m, 2H), 6.56 (dd, 1H), 4.71 (s, 2H), 3.73 (s, 3H).

[0311] Intermediate 1.179: 6-(1,4-Dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-amine 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-dioxaborolan-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 purified by flash column chromatography on a Biotage Isolera One™ (silica column 20 g, eluting with 20 - 100% EtOAc in heptane). 1 H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.37 (s, 1H), 6.86 - 6.74 (m, 1H), 3.82 (s, 3H), 2.01 (d, 3H).

[0312] Intermediate 1.190: 2-(5-(6-Chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide Intermediate 1.190a: N,N-Dimethyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)acetamide To a solution of 2-(4-methyltriazol-1-yl)acetic acid (0.11 g, 8.1 mmol, CAS: 887405-58-5) and N-methylmethanamine (2 M in THF; 12 mL, 24 mmol) in DMF (25 mL) was added T3P® (50% w / w solution in EtOAc; 7.2 mL, 12 mmol). The reaction was stirred at room temperature for 20 h and then concentrated in vacuo. The residue was diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, the combined organics were washed with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 0–10% MeOH in DCM) to afford the title compound (0.7 g). LCMS (Method 14): 1.01 min, 169.2 [M+H] +

[0313] Intermediate 1.190: 2-(5-(6-Chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide A solution of Intermediate 1.190a (0.64 g, 3.1 mmol), 5-bromo-2-chloro-pyridine (0.59 g, 3.1 mmol, CAS: 53939-30-3), pivalic 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 by microwave irradiation at 120 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc and quenched with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 0 - 100% EtOAc in heptane then 0 - 10% MeOH in DCM) to give the title compound (71 mg). 1 H NMR (400 MHz, 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).

[0314] Intermediate 1.193: 5-(6-aminopyridin-3-yl)-1-methyl-1H-pyrazole-4-carbonitrile The title compound (0.21 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.53 g, 2.4 mmol, CAS: 827614-64-2), 5-bromo-1-methyl-pyrazole-4-carbonitrile (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 by microwave irradiation at 120 °C for 1 hour. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 0 - 100% EtOAc in heptane then 0 - 10% MeOH in DCM). LCMS (Method 14): 0.78 min, 200.2 [M+H] +

[0315] Intermediate 1.195: 5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-amine Divided into three separate batches, a mixture of 2,4,5-trimethyl-4H-pyrazol-3-one hydrochloride (1.5 g, 9.2 mmol, CAS: 1285259-23-5), N-phenyl-bis(trifluoromethanesulfonamide) (3.5 g, 9.7 mmol) and sodium carbonate (2.9 g, 27.6 mmol) in THF (33 mL) was heated by microwave irradiation at 110 °C for 6 minutes. The mixture was cooled to room temperature, then 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (3.1 g, 14 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.34 g, 0.46 mmol) and water (15 mL) were added and the mixture was heated by microwave irradiation at 110 °C for 45 minutes. The batches were combined and the mixture was filtered through a pad of celite. The solvent was concentrated in vacuo and the crude product was purified by flash column chromatography (eluting with 0 - 5% MeOH in DCM) to give the title compound (1.4 g). LCMS (Method 14): 0.97 min, 203.2 [M+H]+

[0316] Intermediate 1.196: 5-(3,5-Dimethylisothiazol-4-yl)pyridin-2-amine The title compound (0.14 g) was prepared by heating 4-iodo-3,5-dimethyl-isothiazole (0.2 g, 0.82 mmol, CAS: 113234-27-8), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) at 100 °C for 18 h according to the procedure described for Intermediate 1.1. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 2-10% MeOH in DCM). 1 H NMR (400 MHz, 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).

[0317] Intermediate 1.207: 6-(3,5-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-amine 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-dioxaborolan-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) was added with water (1 mL), Pd-170 (26 mg, 0.04 mmol) and potassium carbonate (0.24 g, 1.7 mmol). 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 in vacuo. The crude product was purified by flash column chromatography on Teledyne ISCO CombiFlash® (silica column 12 g, eluting with 0 - 100% 3:1 EtOAc:EtOH in isohexane) to afford the title compound as a brown oil (0.21 g). LCMS (method 28): 1.42 min, 319.5 [M+H] +

[0318] Intermediate 1.214: 6’-amino-1,2,4-trimethyl-[3,3’-bipyridin]-6(1H)-one The title compound (90 mg) was prepared from 5-bromo-1,4,6-trimethyl-pyridin-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 purified by flash column chromatography on Teledyne ISCO CombiFlash® (silica column 12 g, eluting with 0 - 10% MeOH in DCM). LCMS (method 29): 0.44 min, 230.2 [M+H] +

[0319] Intermediate 1.216: 5-(1,3,5-Trimethyl-1H-pyrazol-4-yl)pyridin-2-amine The title compound (79 mg) was prepared from 4-bromo-1,3,5-trimethyl-pyrazole (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 purified by flash column chromatography on a Teledyne ISCO CombiFlash® (silica column 12 g, eluting with 0-10% MeOH in DCM). LCMS (Method 26): 0.53 min, 203.2 [M+H] +

[0320] Intermediate 1.219: 5-(1-Methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.45 g) was prepared by heating 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-dioxaborolan-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) according to the procedure described for Intermediate 1.1 at 80 °C for 18 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 50 g, eluting with 2-4% MeOH in DCM), then by an SCX cartridge (10 g, washed with MeOH and eluted with 2M methanolic ammonia). LCMS (Method 14): 1.18 min, 243.2 [M+H] +

[0321] Intermediate 2.1: tert-Butyl (S)-(1-((4-(2,3-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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) at room temperature were added triethylamine (0.16 mL, 1.2 mmol) and T3P® (50% w / w solution in EtOAc; 1.1 mL, 1.8 mmol), and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 75–100% EtOAc in heptane) to afford the title compound (0.15 g). LCMS (Method 2): 1.02 min, 522.3 [M+H] +

[0322] Intermediate 1.219: 5-(1-Methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-amine 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-dioxaborolan-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) were heated at 80 °C for 18 h according to the procedure described for Intermediate 1.1 to produce the title compound (0.45 g). The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 50 g, eluting with 2 - 4% MeOH in DCM), then by SCX cartridge (10 g, washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 14): 1.18 min, 243.2 [M+H] +

[0323] Intermediate 2.2: tert-Butyl (S)-(1-((4-(3-chloropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.2 (0.18 g, 0.89 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.18 g, 0.89 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.7 mL, 2.7 mmol) and triethylamine (0.31 mL, 2.22 mmol) were used to produce the title compound (0.48 g) according to the procedure described for Intermediate 2.1 and used without further purification. LCMS (Method 2): 1.02 min, 528.2 [M+H] +

[0324] Intermediate 2.3: tert-Butyl (S)-(1-((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.3 (0.25 g, 1.3 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.43 g, 1.25 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 2.4 mL, 3.8 mmol) and triethylamine (0.35 mL, 2.5 mmol), following the procedure described for Intermediate 2.1, gave the title compound (0.57 g). The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.98 min, 524.3 [M+H] +

[0325] Intermediate 2.4: tert-Butyl (S)-(1-((4-(3-Methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.4 (61 mg, 0.33 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.11 g, 0.82 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 0.21 mL, 0.33 mmol) and triethylamine (0.11 mL, 0.82 mmol), following the procedure described for Intermediate 2.1, gave the title compound (0.21 g), which was used without further purification. LCMS (Method 2): 1.00 min, 508.3 [M+H] +

[0326] Intermediate 2.5: tert-Butyl (S)-(1-oxo-3,3-diphenyl-1-((4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)amino)propan-2-yl)carbamate Intermediate 1.5 (75 mg, 0.31 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.11 g, 0.31 mmol, CAS: 138662-63-2), T3P® (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, the title compound (0.16 g) was prepared and used without further purification. LCMS (Method 2): 1.06 min, 562.3 [M+H] +

[0327] Intermediate 2.6: tert-butyl (S)-(1-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.6 (0.15 g, 0.76 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.26 g, 0.76 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.4 mL, 2.3 mmol) and triethylamine (0.32 mL, 2.27 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.27 g) was prepared. The crude product was purified by flash column chromatography (eluting with 60 - 70% EtOAc in heptane). LCMS (Method 3): 2.72 min, 522.3 [M+H] +

[0328] Intermediate 2.7: tert-butyl (S)-(1-((4-(3-(methylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.7 (0.14 g, 0.35 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.12 g, 0.35 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.3 mL, 1.1 mmol) and triethylamine (0.15 mL, 1.05 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.16 g) was prepared, the reagents were added at 0 °C, and the mixture was stirred at room temperature for 3 h. The crude product was purified by reverse-phase column chromatography on Biotage Isolera One™ (C18 column 30 g, eluting with 30 - 80% MeCN in 0.1 M NH4HCO3 buffer, pH 10). LCMS (Method 2): 0.96 min, 523.3 [M+H] +

[0329] Intermediate 2.8: tert-Butyl (S)-(1-((4-(3-(Dimethylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.8 (75 mg, 0.35 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.13 g, 0.37 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.3 mL, 1.1 mmol) and triethylamine (0.17 mL, 1.23 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.14 g) was prepared, the reagents were added at 0 °C, and the mixture was stirred at room temperature for 1.5 h. The crude product was purified by reverse-phase column chromatography on Biotage Isolera One™ (C18 column 30 g, eluting with 30 - 80% MeCN in 0.1 M NH4HCO3 buffer, pH 10). LCMS (Method 2): 1.02 min, 537.3 [M+H] +

[0330] Intermediate 2.9: tert-Butyl (S)-(1-((4-(3,5-dimethoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.9 (0.10 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.15 g, 0.44 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 0.84 mL, 1.3 mmol) and triethylamine (0.21 mL, 1.54 mmol), following the procedure described for Intermediate 2.1, the title compound (0.16 g) was prepared. The crude product was purified by flash column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 2): 0.97 min, 554.3 [M+H] +

[0331] Intermediate 2.10: tert-Butyl (S)-(1-((4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.10 (90 mg, 0.41 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.14 g, 0.41 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 0.79 mL, 1.2 mmol) and triethylamine (0.2 mL, 1.4 mmol), following the procedure described for Intermediate 2.1, the title compound (98 mg) was prepared, adding the reagents at 0 °C and stirring the mixture at room temperature for 2 h. The crude product was purified by flash column chromatography (eluting with 40% EtOAc in hexane). LCMS (Method 2): 1.00 min, 542.3 [M+H] +

[0332] Intermediate 2.11: tert-Butyl (S)-(1-((4-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.11 (0.12 g, 0.57 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.20 g, 0.57 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol) and triethylamine (0.28 mL, 2.0 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.20 g) was prepared. The crude product was purified by flash column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 2): 0.86 min, 524.3 [M+H] +

[0333] Intermediate 2.12: tert-butyl (S)-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.12 (0.11 g, 0.53 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.18 g, 0.53 mmol, CAS: 138662-63-2), T3P® (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, the title compound (0.28 g) was prepared and used without further purification. LCMS (Method 4): 0.91 min, 538.3 [M+H] +

[0334] Intermediate 2.13: tert-butyl (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.13 (0.15 g, 0.70 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.24 g, 0.70 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.3 mL, 2.1 mmol) and triethylamine (0.24 mL, 1.75 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.29 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, 40 - 100% EtOAc in heptane, followed by elution with 5% MeOH in EtOAc). LCMS (Method 4): 0.94 min, 538.3 [M+H] +

[0335] Intermediate 2.14: tert-butyl (S)-(1-((4-(3,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.14 (0.10 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.15 g, 0.44 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 0.84 mL, 1.3 mmol) and triethylamine (0.18 mL, 1.32 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.11 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluted with 20 - 80% EtOAc in heptane). LCMS (Method 4): 1.04 min, 540.3 [M+H] +

[0336] Intermediate 2.15: tert-butyl (S)-(1-((3-fluoro-4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.15 (0.16 g, 0.79 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.27 g, 0.79 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.5 mL, 2.4 mmol) and triethylamine (0.33 mL, 2.37 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.20 g) was prepared. The crude product was purified by flash column chromatography (eluting with 70% EtOAc in heptane). LCMS (Method 3): 2.71 min, 526.3 [M+H] +

[0337] Intermediate 2.16: tert-butyl (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.16 (0.16 g, 0.69 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.24 g, 0.69 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.3 mL, 2.1 mmol) and triethylamine (0.29 mL, 2.07 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.12 g) was prepared. The crude product was purified by flash column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 3): 2.49 min, 556.3 [M+H] +

[0338] Intermediate 2.17: tert-butyl (S)-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.17 (0.19 g, 0.81 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.28 g, 0.81 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 1.6 mL, 2.4 mmol) and triethylamine (0.34 mL, 2.43 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.16 g) was prepared. The crude product was purified by flash column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 4): 0.92 min, 556.3 [M+H] +

[0339] Intermediate 2.18: tert-butyl ((2S)-1-((3-fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.18 (0.26 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.38 g, 1.1 mmol, CAS: 138662-63-2), T3P® (50% w / w solution in EtOAc; 2.1 mL, 3.3 mmol) and triethylamine (0.46 mL, 3.3 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.10 g) was prepared. The crude product was purified by flash column chromatography (eluting with 40% EtOAc in heptane). LCMS (Method 3): 2.78 min, 560.3 [M+H] +

[0340] Intermediate 2.19: tert-butyl (S)-(1,1-bis(4-fluorophenyl)-3-((4-(3-methoxypyridin-4-yl)phenyl)amino)-3-oxopropan-2-yl)carbamate A stirred solution of Intermediate 1.3 (0.10 g, 0.50 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3,3-bis(4-fluorophenyl)propanoic acid (0.19 g, 0.50 mmol, CAS: 481055-29-2) and triethylamine (0.14 mL, 1.0 mmol) in EtOAc (4 mL) was added HATU (0.20 g, 0.52 mmol) at room temperature, and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 100% EtOAc) to give the title compound (0.28 g). LCMS (Method 2): 0.98 min, 560.3 [M+H] +

[0341] Intermediate 2.29: tert-butyl (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3,5-difluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate To a solution of Intermediate 1.29 (0.10 g, 0.41 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenyl-propanoic 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 T3P® (50% w / w solution in EtOAc; 1.0 mL, 1.6 mmol) at room temperature and the reaction mixture was stirred for 18 h. The mixture was diluted with saturated aqueous NaHCO3 and the crude product was extracted into EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by reverse phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 20 - 80% 0.1% ammonia in MeCN in 0.1% aqueous ammonia) to give the title compound (36 mg). LCMS (Method 3): 2.55 min, 574.2 [M+H]+

[0342] Intermediate 2.30: tert-Butyl (S)-(1-((3,5-difluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.30 (0.11 g, 0.47 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.17 g, 0.49 mmol, CAS: 138662-63-2) and T3P® (50% w / w solution in EtOAc; 0.42 mL, 0.70 mmol), following the procedure described for Intermediate 2.1, the title compound (0.14 g) was prepared. The crude product was purified by flash chromatography (eluting with 50 - 100% EtOAc in heptane). LCMS (Method 4): 1.04 min, 560.3 [M+H] +

[0343] Intermediate 2.31: tert-Butyl (S)-(1-((4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.31 (78 mg, 0.25 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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), following the procedure described for Intermediate 2.19, the title compound (0.14 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 10 g, eluting with 30 - 100% EtOAc in heptane). LCMS (Method 4): 1.11 min, 601.4 [M+H] +

[0344] Intermediate 2.33: tert-Butyl ((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (73 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 0.73 mL, 1.2 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by flash column chromatography (eluting with 10% methanol in EtOAc). LCMS (Method 4): 0.98 min, 468.3 [M+H] +

[0345] Intermediate 2.34: tert-Butyl (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate A solution of intermediate 2.34 (0.13 g, 0.62 mmol), (2S)-2-(tert-butoxycarbonylamino)-3,3-diphenyl-propanoic acid (0.47 g, 1.4 mmol, CAS: 138662-63-2), DMAP (31 mg, 0.12 mmol) in DCM (3 mL) and MeCN (1.5 mL) was added with EDCI (299 mg, 1.56 mmol), and the reaction mixture was stirred at room temperature under argon for 21 h. Additional (2S)-2-(tert-butoxycarbonylamino)-3,3-diphenyl-propanoic acid (0.23 g, 0.69 mmol) and EDCI (0.13 g, 0.69 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 50 - 100% EtOAc in heptane) to afford the title compound (0.19 g). LCMS (method 4): 0.89 min, 429.2 [M - Boc + H] +

[0346] Intermediate 2.35: tert-butyl (S)-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate The title compound (0.19 g) was prepared from intermediate 1.35 (215 mg, 1.05 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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 flash column chromatography (eluting with 5% MeOH in EtOAc). LCMS (method 3): 2.30 min, 528.2 [M + H] +

[0347] Intermediate 2.36: tert-Butyl (S)-(1-((4-(3-Fluoropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate 4-(3-Fluoropyridin-4-yl)aniline (0.35 g, 1.8 mmol, CAS: 928322-47-8), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.66 g, 1.8 mmol, CAS: 138662-63-2) and T3P® (50% w / w solution in EtOAc; 3.5 mL, 5.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.45 g) was prepared. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 1): 1.01 min, 512.3 [M+H] +

[0348] Intermediate 2.37: tert-Butyl (S)-(1-((4-(2,5-Dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.37 (0.1 g, 0.5 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.17 g, 0.5 mmol, CAS: 138662-63-2) and T3P® (50% w / w solution in EtOAc; 0.91 mL, 1.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.45 g) was prepared. The crude product was used directly without further purification. LCMS (Method 2): 0.97 min, 523.3 [M+H] +

[0349] Intermediate 2.38: tert-Butyl (S)-(1-((4-(2,5-Dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate 4-(2,5-Dimethylpyridin-4-yl)aniline (52 mg, 0.26 mmol, CAS: 71153-40-7), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (90 mg, 0.26 mmol, CAS: 138662-63-2) and T3P® (50% w / w solution in EtOAc; 0.5 mL, 0.79 mmol), according to the procedure described for Intermediate 2.1, the title compound (46 mg) was prepared. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 8): 0.65 min, 521.9 [M+H] +

[0350] Intermediate 2.42: tert-Butyl (S)-(1-((4-(3-(Hydroxymethyl)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.42 (0.28 g, 1.2 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic 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 title compound (0.34 g) was prepared. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 2): 0.88 min, 524.3 [M+H] +

[0351] Intermediate 2.43: tert-Butyl (S)-(1-((4-(3-Cyanopyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate 4-(4-Aminophenyl)nicotinonitrile (25 mg, 0.13 mmol, CAS: 2090576-40-0), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (44 mg, 0.13 mmol, CAS: 138662-63-2), triethylamine (0.04 mL, 0.32 mmol) and T3P® (50% w / w solution in EtOAc; 0.24 mL, 0.38 mmol), according to the procedure described for Intermediate 2.1, the title compound (66 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 2): 0.97 min, 419.2 [M - Boc + H] +

[0352] Intermediate 2.47: tert-Butyl (S)-(1-((3-Methoxy-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.47 (68 mg, 0.29 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (98 mg, 0.29 mmol, CAS: 138662-63-2), triethylamine (0.1 mL, 0.71 mmol) and T3P® (50% w / w solution in EtOAc; 0.55 mL, 0.86 mmol), according to the procedure described for Intermediate 2.1, the title compound (75 mg) was prepared. The crude product was used directly without further purification. LCMS (Method 2): 0.96 min, 554.3 [M + H] +

[0353] Intermediate 2.48: tert-Butyl (S)-(1-((3-Fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.48 (0.15 g, 0.67 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.24 g, 0.70 mmol, CAS: 138662-63-2), triethylamine (0.28 mL, 2.0 mmol) and T3P® (50% w / w solution in EtOAc; 0.59 mL, 1.0 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.21 g) was prepared. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 0.96 min, 543.2 [M+H] +

[0354] Intermediate 2.49: tert-butyl (S)-(1-oxo-1-((4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)carbamate 5-(4-Aminophenyl)pyridin-2(1H)-one (87 mg, 0.47 mmol, CAS: 1159819-58-5), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.16 g, 0.47 mmol, CAS: 138662-63-2), triethylamine (0.04 mL, 0.32 mmol) and T3P® (50% w / w solution in EtOAc; 0.89 mL, 1.4 mmol), according to the procedure described for Intermediate 2.1, the title compound (52 mg) was prepared. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40-100% EtOAc in heptane, then 5% MeOH in EtOAc). LCMS (Method 2): 0.84 min, 510.3 [M+H] +

[0355] Intermediate 2.50: tert-butyl (S)-(1-((4-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate 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-diphenylpropanoic acid (0.18 g, 0.51 mmol, CAS: 138662-63-2), triethylamine (0.18 mL, 1.3 mmol) and T3P® (50% w / w solution in EtOAc; 0.98 mL, 1.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (35 mg) was prepared. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, 60 - 100% EtOAc in heptane, then eluting with 7% MeOH in EtOAc). LCMS (Method 2): 0.86 min, 524.9 [M+H] +

[0356] Intermediate 2.51: tert-Butyl (S)-(1-((4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.51 (0.18 g, 0.91 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.31 g, 0.91 mmol, CAS: 138662-63-2), triethylamine (0.32 mL, 2.3 mmol) and T3P® (50% w / w solution in EtOAc; 1.74 mL, 2.7 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.46 g) was prepared. The crude product was used directly. LCMS (Method 2): 0.88 min, 524.3 [M+H] +

[0357] Intermediate 2.52: tert-Butyl (S)-(1-oxo-1-((4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.52 (0.1 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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), except that DMF was used as the solvent instead of EtOAc, the title compound (0.13 mg) was prepared according to the procedure described for Intermediate 2.19. The crude product was purified by flash column chromatography (eluting with 4% MeOH in EtOAc). LCMS (Method 3): 2.38 min, 549.3 [M+H] +

[0358] Intermediate 2.53: tert-butyl (S)-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.53 (51 mg, 0.17 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (68 mg, 0.20 mmol, CAS: 138662-63-2), DIPEA (0.12 mL, 0.67 mmol) and HATU (76 mg, 0.20 mmol), except that it was in an EtOAc / MeCN (2:1) solvent mixture, the title compound (38 mg) was prepared according to the procedure described for Intermediate 2.19. The crude product was purified by flash column chromatography (eluting with 10% MeOH in DCM). LCMS (Method 2): 0.88 min, 554.3 [M+H] +

[0359] Intermediate 2.54: tert-butyl (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.54 (0.1 g, 0.38 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.14 g, 0.39 mmol, CAS: 138662-63-2), triethylamine (0.28 mL, 2.0 mmol) and T3P® (50% w / w solution in EtOAc; 0.59 mL, 2.0 mmol), according to the procedure described for Intermediate 2.1, the title compound (56 mg) was prepared. The crude product was purified by flash column chromatography (eluting with 100% EtOAc). LCMS (Method 4): 0.99 min, 606.3 [M+H] +

[0360] Intermediate 2.55: tert-Butyl (S)-(1-((3-Chloro-4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.55 (0.11 g, 0.47 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.16 g, 0.47 mmol, CAS: 138662-63-2), triethylamine (0.2 mL, 1.4 mmol) and T3P® (50% w / w solution in EtOAc; 0.9 mL, 1.4 mmol), according to the procedure described for Intermediate 2.1, the title compound (65 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 0 - 50% EtOAc in heptane). LCMS (Method 4): 1.08 min, 556.3 [M+H] +

[0361] Intermediate 2.56: tert-Butyl (S)-(1-((4-(2,5-Dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.56 (0.15 g, 0.69 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.24 g, 0.69 mmol, CAS: 138662-63-2), triethylamine (0.29 mL, 2.1 mmol) and T3P® (50% w / w solution in EtOAc; 1.3 mL, 2.1 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.1 g) was prepared. The crude product was purified by flash column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 1.06 min, 540.3 [M+H] +

[0362] Intermediate 2.57: tert-butyl (S)-(1-((4-(2,3-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.57 (0.11 g, 0.51 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.17 g, 0.51 mmol, CAS: 138662-63-2), triethylamine (0.21 mL, 1.5 mmol) and T3P® (50% w / w solution in EtOAc; 0.97 mL, 1.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.12 g) was prepared. The crude product was purified by flash column chromatography (eluting with 70% EtOAc in heptane). LCMS (Method 3): 2.80 min, 540.3 [M+H] +

[0363] Intermediate 2.59: tert-butyl (S)-(1-((4-(1-benzyl-5-methyl-1H-pyrazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.59 (0.25 mg, 0.89 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.3 g, 0.88 mmol, CAS: 138662-63-2), and T3P® (50% w / w solution in EtOAc; 1.7 mL, 2.7 mmol), following the procedure described for Intermediate 2.1, the title compound (0.28 g) was prepared as a mixture of positional isomers and tert-butyl (S)-(1-((4-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate. The crude product was purified by flash column chromatography on Biotage Isolera One™ (SiliCycle silica column 25 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 1.12 min, 605.3 [M+H] +

[0364] Intermediate 2.60: tert-butyl (S)-(1-((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.60 (0.15 g, 0.75 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.27 g, 0.79 mmol, CAS: 138662-63-2), triethylamine (0.31 mL, 2.2 mmol), and T3P® (50% w / w solution in EtOAc; 1.3 mL, 2.2 mmol), following the procedure described for Intermediate 2.1, the title compound (0.22 g) was prepared. The crude product was purified by flash column chromatography (eluting with 25% EtOAc in heptane). LCMS (Method 4): 1.08 min, 430.2 [M - Boc+H] +

[0365] Intermediate 2.62: tert-Butyl (S)-(1-((4-(1-Benzyl-1H-pyrazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.62 (240 mg, 0.83 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (282 mg, 0.83 mmol, CAS: 138662-63-2), triethylamine (0.35 mL, 2.48 mmol) and T3P® (50% w / w solution in EtOAc; 1.58 mL, 2.48 mmol), following the procedure described for Intermediate 2.1, the title compound (65 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 25 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 1.11 min, 591.3 [M+H] +

[0366] Intermediate 2.63: tert-Butyl (S)-(1-((3-Fluoro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 2.63 (95 mg, 0.43 mmol), (2S)-2-(tert-Butoxycarbonylamino)-3,3-diphenyl-propanoic 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), following the procedure described for Intermediate 2.34, the title compound (64 mg) was prepared. The crude product was purified by reverse phase chromatography on Biotage Isolera One™ (C18 column 60 g, eluting with 15 - 65% MeCN in 0.1% pH 10 0.1M NH4HCO3 buffer solution). LCMS (Method 3): 2.27 min, 543.2 [M+H] +

[0367] Intermediate 2.64: tert-Butyl (S)-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.64 (0.26 g, 1.3 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.48 g, 1.4 mmol, CAS: 138662-63-2), triethylamine (0.53 mL, 3.8 mmol) and T3P® (50% w / w solution in EtOAc; 2.3 mL, 3.8 mmol), following the procedure described for Intermediate 2.1, the title compound (0.14 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 80 g, eluting with 0 - 10% MeOH in DCM). LCMS (Method 3): 1.72 min, 529.2 [M+H] +

[0368] Intermediate 2.66: tert-Butyl (S)-(1-((3-fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthyridin-8-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate From Intermediate 1.66 (0.47 g, 1.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.66 g, 1.9 mmol, CAS: 138662-63-2), triethylamine (0.77 mL, 5.5 mmol) and T3P® (50% w / w solution in EtOAc; 3.3 mL, 5.5 mmol), following the procedure described for Intermediate 2.1, the title compound (88 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 45 g, eluting with 50 - 100% EtOAc in heptane). LCMS (Method 4): 0.93 min, 579.3 [M+H] +

[0369] Intermediate 2.67: tert-Butyl (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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) was added BTFFH (0.51 g, 1.6 mmol), and the reaction mixture was stirred at room temperature under argon for 1 hour. Intermediate 1.67 (0.22 g, 1.1 mmol) was added, and the reaction mixture was heated at 80 °C for 6 hours. The reaction mixture was diluted with water and brine and extracted 3 times into DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 100% EtOAc), then by automated reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 60 g, eluting with 0 - 80% 0.1% ammonia / MeCN in 0.1% ammonia / H2O at pH 11) to give the title compound (0.23 g). LCMS (Method 4): 0.88 min, 529.2 [M+H] +

[0370] Intermediate 2.68: tert-Butyl (S)-(1-((3-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.68 (0.56 g, 2.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.74 g, 2.2 mmol, CAS: 138662-63-2), triethylamine (0.91 mL, 6.53 mmol) and T3P® (50% w / w solution in EtOAc; 4.2 mL, 6.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.43 g) was prepared. The crude product was purified by flash column chromatography (eluting with 45% ethyl acetate in heptane). LCMS (Method 4): 1.03 min, 581.3 [M+H] +

[0371] Intermediate 2.69: tert-butyl (S)-(1-((3-fluoro-4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-7-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.69 (0.24 g, 0.96 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.35 g, 1.0 mmol, CAS: 138662-63-2), triethylamine (0.4 mL, 2.9 mmol) and T3P® (50% w / w solution in EtOAc; 1.7 mL, 2.9 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.14 g) was prepared. The crude product was purified by automated reverse phase column chromatography on a Biotage Isolera One™ (C18 column 60 g, eluting with 0 - 95% MeCN in water containing 0.1% formic acid and 0.1% formic acid). LCMS (Method 13): 2.10 min, 568.2 [M+H] +

[0372] Intermediate 2.71: tert-butyl (S)-(1-((3-fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthyridin-8-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.71 (0.19 g, 0.86 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.29 g, 0.86 mmol, CAS: 138662-63-2), triethylamine (0.36 mL, 2.6 mmol) and T3P® (50% w / w solution in EtOAc; 1.64 mL, 2.6 mmol), according to the procedure described for Intermediate 2.1, the title compound (98 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 0.94 min, 542.2 [M+H] +

[0373] Intermediate 2.72: tert-Butyl (S)-(1-((1’,2’-Dimethyl-6’-oxo-1’,6’-dihydro-[3,3’-bipyridin]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.72 (39 mg, 0.18 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-diphenylpropanoic 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 title compound (20 mg) was prepared. The crude product was purified by automated reverse phase column chromatography on Biotage Isolera One™ (C18 column 30 g, pH 11 0.1% ammonia / H2O with 0.1% ammonia / MeCN). LCMS (Method 4): 0.90 min, 539.2 [M+H] +

[0374] Intermediate 2.73: tert-Butyl (S)-(1-((3’,5’-Dimethyl-[3,4’-bipyridin]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.73 (0.23 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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 title compound (0.18 g) was prepared. The crude product was purified by automated reverse-phase column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 1.01 min, 523.2 [M+H] +

[0375] Intermediate 2.74: tert-butyl (S)-(1-((4-(1-benzyl-5-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.74 (0.57 g, 2.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.74 g, 2.2 mmol, CAS: 138662-63-2), triethylamine (0.9 mL, 6.5 mmol) and T3P® (50% w / w solution in EtOAc; 4.1 mL, 6.5 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.67 g) was prepared. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 40 - 100% EtOAc in heptane). LCMS (Method 4): 1.08 min, 587.3 [M+H] +

[0376] Intermediate 2.75: tert-butyl (S)-(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-diphenylpropan-2-yl)carbamate Intermediate 1.75 (0.1 g, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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), following the procedure described for Intermediate 2.19 except using DMF as the solvent, the title compound (83 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 25 g, eluting with 50-100% EtOAc in heptane). LCMS (Method 4): 0.92 min, 582.3 [M+H] +

[0377] Intermediate 2.76: tert-butyl (S)-(1-((4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.76 (0.21 g, 0.84 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.29 g, 0.84 mmol, CAS: 138662-63-2), triethylamine (0.35 mL, 2.5 mmol) and T3P® (50% w / w solution in EtOAc; 1.6 mL, 2.5 mmol), following the procedure described for Intermediate 2.1, the title compound (0.2 g) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 25 g, eluting with 40-100% EtOAc in heptane). LCMS (Method 4): 1.01 min, 563.3 [M+H] +

[0378] Intermediate 2.77: tert-butyl (S)-(1-((4-(1-benzyl-6-oxo-1,6-dihydropyridin-2-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.77 (0.18 g, 0.57 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.19 g, 0.57 mmol, CAS: 138662-63-2), triethylamine (0.24 mL, 1.7 mmol) and T3P® (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol), according to the procedure described for Intermediate 2.1, the title compound (86 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 30 g, eluting with 30 - 100% EtOAc in heptane). LCMS (Method 20): 1.01 min, 618.3 [M+H] +

[0379] Intermediate 2.78: tert-butyl (S)-(1-oxo-1-((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.78 (89 mg, 0.32 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid (0.11 g, 0.33 mmol, CAS: 138662-63-2), triethylamine (0.13 mL, 0.95 mmol) and T3P® (50% w / w solution in EtOAc; 0.6 mL, 0.95 mmol), according to the procedure described for Intermediate 2.1, the title compound (61 mg) was prepared. The crude product was purified by flash column chromatography on Biotage Isolera One™ (ZIP spherical silica column 12 g, eluting with 0 - 20% MeOH in EtOAc). LCMS (Method 4): 1.18 min, 605.4 [M+H] +

[0380] Intermediate 2.80: tert-butyl (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate Intermediate 1.80 (80 mg, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic 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 title compound (75 mg) was prepared. The crude product was purified by automated reverse-phase column chromatography on Biotage Isolera One™ (C18 column 30 g, eluting with 10 - 50% 0.1% ammonia / MeCN in 0.1% ammonia / H2O at pH 11). LCMS (Method 3): 1.65 min, 529.2 [M+H] +

[0381] Intermediate 2.81: tert-butyl (S)-(1-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamate 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-diphenylpropanoic acid (0.2 g, 0.57 mmol, CAS: 138662-63-2), triethylamine (0.24 mL, 1.7 mmol) and T3P® (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol), according to the procedure described for Intermediate 2.1, the title compound (0.23 g) was prepared. The crude product was used directly without further purification. LCMS (Method 4): 1.04 min, 399.3 [M - Boc + H] +

[0382] Intermediate 2.83: tert-butyl ((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (71 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 2.5 mL, 3.9 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by automated reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 60 g, 0.1% ammonia in pH 11 0.1% ammonia / H2O / MeCN). LCMS (Method 4): 1.06 min, 486.2 [M+H] +

[0383] Intermediate 2.84: tert-butyl ((S)-2-((4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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 purified by flash column chromatography on a Biotage Isolera One™ (ZIP spherical silica column 20 g, eluting with 20 - 100% EtOAc in heptane). LCMS (Method 16): 3.12 min, 561.2 [M+H] +

[0384] Intermediate 2.85: tert-Butyl ((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)carbamate 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 that it was in DMF as the solvent. The crude product was purified by flash column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 3): 2.39 min, 479.3 [M+H] +

[0385] Intermediate 2.86: tert-Butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)carbamate The title compound (98 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by flash column chromatography (eluting with 10 - 20% MeOH in EtOAc). LCMS (Method 4): 0.97 min, 535.3 [M+H] +

[0386] Intermediate 2.87: tert-Butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)ethyl)carbamate 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 that it was in DMF as the solvent. The crude product was purified by flash column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 3): 2.26 min, 440.3 [M+H] +

[0387] Intermediate 2.88: tert-Butyl ((S)-2-((4-(imidazo[1,2-a]pyridin-5-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (49 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (Silicycle silica column 25 g, eluting with 30 - 100% EtOAc in heptane). LCMS (Method 4): 1.03 min, 463.3 [M+H] +

[0388] Intermediate 2.89: tert-Butyl ((S)-2-((1’,2’-dimethyl-6’-oxo-1’,6’-dihydro-[3,3’-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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 purified by automated reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 5–85% MeCN 0.1% ammonia / MeCN in 0.1% ammonia / H2O at pH 11). LCMS (Method 4): 0.95 min, 469.3 [M+H] +

[0389] Intermediate 2.90: tert-Butyl ((S)-2-((3’,5’-dimethyl-[3,4’-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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] +

[0390] Intermediate 2.93: tert-Butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)carbamate 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 that it was 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] +

[0391] Intermediate 2.94: tert-Butyl ((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (93 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 0.5 mL, 0.79 mmol) 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] +

[0392] Intermediate 2.95: tert-Butyl ((S)-2-((4-(3,6-Dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (65 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (Silicycle silica column 25 g, eluting with 10 - 100% EtOAc in heptane). LCMS (Method 4): 1.10 min, 329.2 [M - Boc + H] +

[0393] Intermediate 2.96: tert-Butyl ((S)-2-((4-(3,5-Dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (84 mg) was prepared 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 T3P® (50% w / w solution in EtOAc; 0.5 mL, 0.84 mmol) according to the procedure described for Intermediate 2.1. The crude product was purified by flash column chromatography (silica column 4 g, eluting with 0 - 25% EtOAc in heptane) on a Biotage Isolera One™. 11H NMR (400 MHz, 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).

[0394] Intermediate 2.97: tert-Butyl ((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate To a solution of 5-(3,5-dimethylisoxazol-4-yl)pyridin-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), EEDQ (84 mg, 0.35 mmol) was added under an argon atmosphere. The mixture was stirred for 64 h, concentrated in vacuo, and then partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica column 5 g, eluting with 0% - 50% EtOAc in heptane) to give the title compound (23 mg). LCMS (Method 14): 2.02 min, 443.3 [M+H] +

[0395] Intermediate 2.99: tert-Butyl ((S)-2-((5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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. An additional portion of EEDQ (60 mg, 0.24 mmol) was added and the mixture was stirred for an additional 24 hours before workup. The crude product was purified by flash column chromatography (4 g silica column, eluting with 0 - 25% EtOAc in heptane). LCMS (Method 14): 2.09 min, 562.2 [M+H] +

[0396] Intermediate 2.106: tert-butyl ((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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 flash column chromatography (5 g silica column, eluting with 20 - 80% EtOAc in heptane). LCMS (Method 14): 1.99 min, 442.2 [M+H] +

[0397] Intermediate 2.108: tert-butyl (S)-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate 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) according to the procedure described for Intermediate 2.97, except that IIDQ (0.35 g, 1.2 mmol) and DIPEA (0.41 mL, 2.3 mmol) were used while heating at 90 °C for 16 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 12 g, eluting with 0 - 100% EtOAc in heptane). LCMS (Method 14): 1.99 min, 429.2 [M+H] +

[0398] Intermediate 2.115: tert-butyl (S)-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate 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 purified by flash column chromatography on a Biotage Isolera One™ (silica column 40 g, eluting with 0 - 3% MeOH in DCM). LCMS (Method 14): 2.00 min, 443.2 [M+H] +

[0399] Intermediate 2.119: tert-butyl (S)-(1-cyclohexyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)carbamate 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 that the solvent was DMF. The crude product was used directly. LCMS: (Method 14) 1.75 min, 454.2 [M+H] +

[0400] Intermediate 2.125: tert-butyl ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate To a stirred solution of 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 DIPEA (0.15 g, 1.1 mmol) and HATU (0.3 g, 0.79 mmol) under an argon atmosphere. The mixture was heated at 50 °C for 44 h. The reaction mixture was diluted with MeOH (1 mL) and then purified by reverse-phase column chromatography on a Biotage Isolera One™ (KP-C18_HS Biotage SNAP cartridge 30 g, eluting with 5–100% MeCN in aqueous buffer with 0.005 M NH4OH) to afford the title compound (35 mg). LCMS: (Method 14) 1.83 min, 443.3 [M+H] + .

[0401] Alternative route to Intermediate 2.125: tert-butyl ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate Intermediate 2.125a: tert-Butyl ((S)-2-amino-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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) was added DIPEA (3.2 mL, 18.4 mmol), 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 organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated in DCM to afford the title compound (0.85 g). 1 1H NMR (400 MHz, 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).

[0402] Intermediate 2.125: tert-Butyl ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate A suspension of Intermediate 1.125a (0.3 g, 1.5 mmol) and Intermediate 2.125a (0.27 g, 1.0 mmol) in degassed anhydrous 1,4-dioxane (14 mL) was added with Xantphos (58 mg, 0.1 mmol) and Cs2CO3 (0.98 g, 3 mmol). After the mixture was degassed with argon for 5 minutes, tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) was added and degassed for 5 minutes. The vial was sealed and the reaction mixture was heated at 100 °C for 18 hours. 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 in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica 20 g, 30 - 100% EtOAc in heptane) to afford the title compound (0.12 g). 1 H NMR (400 MHz, MeOD) δ: 8.39 (dd, 1H), 8.32 (dd, 1H), 7.88 (dd, 1H), 4.09 (d, 1H), 3.98 (s, 3H), 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).

[0403] Intermediate 2.132: tert-Butyl (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate A solution of Intermediate 1.106 (0.62 g, 3.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.4 g, 1.6 mmol, CAS: 1228542-19-5) and DIPEA (0.4 g, 3.1 mmol) in anhydrous DMF (2.6 mL) was added with HATU (0.83 mg, 2.2 mmol) 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 phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 40 g, eluting with 0 - 50% EtOAc in heptane) to give the title compound (0.28 g). LCMS: (Method 14): 1.85 min, 442.2 [M+H] +

[0404] Intermediate 2.135: tert-butyl ((S)-2-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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 purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 30% EtOAc in heptane). LCMS (Method 14): 1.88 min, 444.2 [M+H] +

[0405] Intermediate 2.138: tert-Butyl ((S)-2-((6-(3,5-Dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate 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 purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 30% EtOAc in heptane). LCMS (Method 14): 1.93 min, 443.2 [M+H] +

[0406] Intermediate 2.140: tert-Butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate 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 (0.33 g, 0.87 mmol) according to the procedure described for Intermediate 2.132. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 20 g, eluting with 0 - 3% MeOH in DCM). LCMS (Method 14): 1.88 min, 440.2 [M+H] +

[0407] Intermediate 2.142: tert-Butyl ((S)-2-((5-(3-(Methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.12 g) was prepared from Intermediate 1.142 (0.2 g, 0.9 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.16 g, 0.6 mmol, CAS: 1187224-06-1), DIPEA (0.17 g, 1.2 mmol), and HATU (0.32 g, 0.84 mmol) according to the procedure described for Intermediate 2.132. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 20 g, eluting with 0 - 50% EtOAc in heptane). LCMS (Method 14): 1.99 min, 473.2 [M+H] +

[0408] Intermediate 2.143a: tert-Butyl (S)-(2-amino-1-cycloheptyl-2-oxoethyl)carbamate To a solution of (2S)-2-(tert-Butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.25 g, 0.92 mmol, CAS: 1228542-19-5) in anhydrous THF (11 mL) was added DIPEA (0.36 g, 2.76 mmol) at 0 °C, followed by dropwise addition of isobutyl chloroformate (0.18 g, 1.3 mmol). The mixture was stirred at 0 °C for 30 minutes, then ammonium hydroxide solution (30%, 0.22 g, 1.8 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated in diethyl ether to afford the title compound (75 mg). 11H NMR (400 MHz, DMSO-d6) δ: 7.25 (s, 1H), 6.97 (s, 1H), 6.48 (d, 1H), 3.78 - 3.69 (m, 1H), 1.74 - 1.46 (m, 20H).

[0409] Intermediate 2.143: tert-Butyl (S)-(1-cycloheptyl-2-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate To a suspension of Intermediate 1.143 (35 mg, 0.17 mmol) and Intermediate 2.143a (30 mg, 0.11 mmol) in degassed anhydrous 1,4-dioxane (1.4 mL) were added Xantphos (6.4 mg, 11 μmol) and Cs2CO3 (109 mg, 0.33 mmol). The mixture was degassed with argon for 5 minutes, then tris(dibenzylideneacetone)dipalladium(0) (5.1 mg, 6 μmol) was added and the mixture was degassed for 5 minutes. The vial was sealed and the reaction mixture was heated at 100 °C for 18 hours. 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 in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 4 g, eluting with 0 - 10% MeOH in DCM) to give the title compound (40 mg). LCMS (Method 19): 2.36 min, 443.2 [M+H] +

[0410] Intermediate 2.144: tert-Butyl (S)-(1-(4,4-difluorocyclohexyl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (0.29 g) was prepared from Intermediate 1.106 (0.39 g, 2.1 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (0.17 g, 0.62 mmol, CAS: 394735-65-0), DIPEA (0.26 g, 2.1 mmol), and HATU (0.55 g, 1.4 mmol) according to the procedure described for Intermediate 2.132. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 0-2% MeOH in DCM), then by SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 14): 2.56 min, 464.2 [M+H] +

[0411] Intermediate 2.145: tert-butyl ((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.34 g) was prepared from Intermediate 1.145 (0.31 g, 1.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.22 g, 0.81 mmol, CAS: 1187224-06-1), DIPEA (0.21 g, 1.6 mmol), and HATU (0.46 g, 1.2 mmol) according to the procedure described for Intermediate 2.132. The crude product was purified by flash column chromatography on Biotage Isolera One™ (silica column 10 g, eluting with 100% EtOAc in heptane). LCMS (Method 19): 2.73 min, 442.2 [M+H] +

[0412] Intermediate 2.146: tert-butyl ((S)-2-((4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.23 g) was prepared from Intermediate 1.146 (0.21 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.2 g, 0.74 mmol, CAS: 1187224-06-1), DIPEA (0.19 g, 1.5 mmol), and HATU (0.39 g, 1.0 mmol) according to the procedure described for Intermediate 2.132. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 12 g, eluting with 0 - 12% MeOH in DCM). LCMS (Method 14): 1.92 min, 442.2 [M+H] +

[0413] Intermediate 2.147: tert-butyl ((S)-2-((2-(1,4-dimethyl-1H-pyrazol-...

Claims

1. A compound of formula I 【Chemical 1】 [wherein: Two of X1, X2, X3 and X4 are CR5 and two are N; or three of X1, X2, X3 and X4 are CR5 and the other is N; Y is aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from halo, C 1 ~ 4 alkyl, C 1 ~ 4 alkoxy and C 1 ~ 4 haloalkyl; R 1 and R 2 are: (A) In each case, halo, C 1 to 4 alkyl, C 1 to 4 alkoxy and C 1 to 4 phenyl optionally substituted with one or more substituents independently selected from haloalkyl, wherein the phenyl group is bonded or C 1 to 2 optionally linked by an alkylene moiety; or (B) Together with the carbon atom to which they are attached, form a 4- to 10-membered cycloalkyl or 4- to 10-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl ring is: a. Halo, C 1 to 4 Alkyl, C 1 to 4 Alkoxy, C 1 to 4 Haloalkyl and C 1 to 4 optionally substituted with one or more substituents independently selected from haloalkyl and haloalkoxy; b. Optionally contain one or two C═C double bonds; c. C connecting two carbon atoms of the ring 1 to 3 optionally bridged by an alkylene group; and d. C 3 to 5 is optionally spiro - bonded to a cycloalkyl group; R 3 is hydrogen, fluoro or C 1 to 4 alkyl; R 4 is: is a 5- to 10-membered heteroaryl and is optionally substituted by one or more substituents independently selected from hydroxy, halo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO 2 R 10 and is optionally substituted by one or more substituents independently selected from C1-3 alkylene-R11; (B) is a 5- to 6-membered heteroaryl ring, which is fused with a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is hydroxy, halo, oxo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO 2 R 10 and is optionally substituted by one or more substituents independently selected from C1-3 alkylene-R11; (C)a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclyl ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl ring, each of said rings being optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO 2 R 10 and optionally substituted by one or more substituents independently selected from C1-3 alkylene-R11; or is optionally fused with a 5- to 6-membered heteroaryl ring and is hydroxy, halo, oxo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO 2 R 10 ; and is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from C1-3 alkylene-R11; R 5 is hydrogen, fluoro, chloro, methyl, methoxy, or trifluoromethyl; R 11 is hydroxy, halo, C 1 to 4 alkoxy, cyano, NR 12 R 13 , C(O)R 14 is aryl or heteroaryl; R 14 is hydroxy, C 1 to 4 alkyl, C 1 to 4 alkoxy or NR 15 R 16 ; R 6 、 R 7 、 R 8 、 R 9 、 R 10 、 R 12 and R 13 are independently selected from hydrogen and C 1 to 4 alkyl; R 15 and R 16 are each independently selected from hydrogen and C 1 to 4 alkyl; or R 15 and R 16 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl ring, which ring optionally contains a further heteroatom selected from O, S and N and is optionally substituted with C 1 to 4 alkyl]; Or a pharmaceutically acceptable salt thereof.

2. X 1 is N, and X 2 , X 3 and X 4 is CH, the compound according to claim 1.

3. Y is heteroaryl optionally substituted by one or more substituents independently selected from halo, C 1 to 4 alkyl, C 1 to 4 alkoxy and C 1 to 4 haloalkyl, the compound according to claim 1 or claim 2

4. Y is a 5- or 6-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from halo, C 1 to 4 alkyl, C 1 to 4 alkoxy, and C 1 to 4 haloalkyl, the compound according to claim 3.

5. Y is a heteroaryl optionally substituted by one or more substituents independently selected from halo, C 1 ~ 3 alkyl, C 1 ~ 2 alkoxy and C 1 ~ 2 haloalkyl The compound according to claim 3, which is a -r ring.

6. The compound according to claim 3, wherein Y is a 5- to 6-membered heteroaryl optionally substituted by one or more substituents independently selected from halo and methyl.

7. The compound according to claim 3, wherein Y is a 5- to 6-membered heteroaryl ring substituted at the ortho position to the NHC(O)- moiety by methyl or ethyl.

8. Y is: 【Chemical Formula 2】 [wherein, 【Chemical Formula 3】 is a bonding point with the remainder of the compound of formula I], and Y is halo, C 1 to 3 alkyl, C 1 to 2 alkoxy and C 1 to 2 The compound according to claim 1 or 2, optionally substituted by one or more substituents independently selected from haloalkyl.

9. R 1 and R 2 The compound according to any one of claims 1 to 8, wherein each of R and R is phenyl optionally substituted with one or more substituents independently selected from fluoro and methyl.

10. R 1 and R 2 together with the carbon atoms to which they are attached form a 5- to 8-membered cycloalkyl ring, where the cycloalkyl ring is: a. Halo, C 1 to 2 alkyl, C 1 to 2 alkoxy and C 1 to 2 optionally substituted with one or more substituents independently selected from haloalkyl; b. Optionally contain one or two C═C double bonds; c. C connecting two carbon atoms of the ring 1 to 3 optionally crosslinked by an alkylene group; and d.C 3 to 5 A compound according to any one of claims 1 to 8, wherein the cycloalkyl group is optionally spiro-bonded.

11. R 1 and R 2 together with the carbon atoms to which they are attached, [Chemical Formula 4] Form a group selected from In the formula, * is a carbon atom to which R 1 and R 2 are bonded, and each occurrence of R 17 is halo, C 1 to 2 alkyl, C 1 to 2 alkoxy and C 1 to 2 The compound according to any one of claims 1 to 8, which is independently selected from haloalkyl, and m is 0, 1, 2 or 3.

12. R 1 and R 2 together with the carbon atoms to which they are attached form the following group: 【Chemical Formula 5】 Form In the formula, * is a carbon atom to which R 1 and R 2 are bonded, and each R 17 is independently selected from hydrogen, fluoro, methyl and trifluoromethyl, the compound according to any one of claims 1 to 8.

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

14. R 4 is a 5- to 10-membered heteroaryl, optionally substituted by one or more substituents independently selected from hydroxy, halo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 2 fluoroalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 and C 1 to 3 alkylene-R 11 The compound according to any one of claims 1 to 13, optionally substituted by one or more substituents independently selected therefrom.

15. R 4 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 fluoro, chloro, methyl, methoxy, cyano, NR 6 R7 and CH 2 -R 11 The compound according to any one of claims 1 to 13, which is optionally substituted by one or more substituents independently selected from the group consisting of

16. R 4 is optionally fused with a 5- to 6-membered heteroaryl ring and is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1 to 2 alkyl, C 1 to 2 alkoxy, C 1 to 2 haloalkyl and cyano, and is a partially unsaturated heterocyclic ring, a compound according to any one of claims 1 to 13.

17. R 4 is the following basis: [Chemical Formula 6] [wherein: [Chemical Formula 7] Is the point of attachment with the rest of the compound of formula I; R 18 is independently selected from hydroxy, halo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl, cyano, NR6R7 and C1-3 alkylene-R11; R 19 is independently selected from hydrogen, C 1 to 4 alkyl and C1 to 3 alkylene-R11; p is 0, 1 or 2] Selected from one of Here, R 4 is a bicyclic group, and when p is 1 or 2, each R 18 substituent may be present in any ring of the bicyclic group The compound according to any one of claims 1 to 13.

18. R 18 is independently selected from hydroxy, fluoro, chloro, methyl, methoxy, CF 3 , NR6R7 and C1-3 alkylene-R11; R 19 is independently selected from hydrogen and methyl, the compound according to claim 17.

19. The following structural formulae IA, IB, IC or ID: 【Chemical 8】 [wherein, X 1 from X 4 to X, Y, and R 4 are as defined in claim 1; Each R 17 is independently selected from hydrogen, halo, C 1 to 2 alkyl, C 1 to 2 alkoxy and C 1 to 2 haloalkyl; n is 1, 2, 3 or 4] The compound according to claim 1, having one of them.

20. The following structural formulae IE, IF, IG, IH, IJ, IK, IL or IM: 【Chemical Formula 9】 [wherein, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1; Each R 17 is selected independently from halo, C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 haloalkyl and C 1 to 4 haloalkoxy; R 20 and R 21 are independently selected from hydrogen, halo, C 1 ~ 4 -alkyl, C 1 ~ 4 -alkoxy, C 1 ~ 4 -haloalkyl and C 1 ~ 4 -haloalkoxy; m is from 0 to 4] The compound according to claim 1, having one of them.

21. R 20 and R 21 are hydrogen, fluoro, methyl, trifluoromethyl and methoxy Independently selected from; m is 0, the compound according to claim 20.

22. Each R 5 is hydrogen, and the compound according to claim 20 or 21.

23. The following compound: (S)-N-(1-((4-(2,3-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-chloropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-(((4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-oxo-3,3-diphenyl-1-(((4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)amino)propan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-(((4-(3-(methylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-(dimethylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,5-dimethoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-(((4-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(3,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((3-fluoro-4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-((2S)-1-((3-fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1,1-bis(4-fluorophenyl)-3-((4-(3-methoxypyridin-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((4-(3-methoxypyridin-4-yl)-3-methylphenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((2-fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-3-methoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamide)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide; (S)-3,5-dimethyl-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamide)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide; (S)-3,5-dimethoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamide)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide; (S)-3-fluoro-5-methoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamide)-3,3-diphenylpropanamido)phenyl)pyridine 1-oxide; (S)-N-(1-(((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3,5-difluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3,5-difluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-(((4-(1,2-dimethyl-6-oxo-1,6-dihydropyr idin-3-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-ethyl-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-fluoropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(2,5-dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(2,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(imidazo[1,2-a]pyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(imidazo[1,2-a]pyrimidin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-(hydroxymethyl)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-cyanopyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-(((3-methyl-4-(pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-1-(difluoromethyl)-N-(1-(((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-methoxy-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-oxo-1-(((4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-1-Methyl-N-(1-(((4-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-1-Methyl-N-(1-(((4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (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-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-chloro-4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(2,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(2,3-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-Ethyl-N-(1-(((3-fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(5-oxo-5,6-dihydro-1,6 -naphthyridin-8-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-Ethyl-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-(((4-(5-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (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-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-1-methyl-N-(1-oxo-1-(((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)-3,3-diphenylpropan-2-yl)-1H-pyrazole-5-carboxamide; (S)-4-(4-(2-(1-methyl-1H-pyrazole-5-carboxamido)-3,3-diphenylpropanamido)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridine 1-oxide; (S)-N-(1-(((3-fluoro-4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(1-(9H-fluoren-9-yl)-2-(((4-(3-methoxypyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; 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; N-((S)-2-(((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; 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; 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide; 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; 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; 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-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridin]-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'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; 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; 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; 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; N-((S)-2-((4-(3,5-Dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-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-(1-(4,4-Difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-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-pyrazole-5-carboxamide; N-(1-(4,4-Dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; 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; 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; N-(1-Cyclooctyl-2-(((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-(1-Cyclooctyl-2-(((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-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-pyrazole-5-carboxamide; 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; (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-ethylisoxazole-4-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide; N-(1-cyclooctyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyra zole-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-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-methylisoxazole-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-triazole-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; (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; 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-methylisoxazole-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-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)-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-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-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- N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-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-pyrazole-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-triazole-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)acetamido)-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-triazole-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-pyrazole-5-carboxamide; 1-Methyl-N-((S)-2-((4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclo ohexyl)-2-oxoethyl)-1H-pyrazole-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-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-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-(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'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-(((2',3'-Dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-(((2',5'-Dimethyl-[3,4'-bipyridin]-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-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)-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-pyrazole-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-methylisoxazole-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-ethylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-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-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-1,2,3-triazole-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-triazole-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-methylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-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-pyrazole-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-pyrazole-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-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-pyrazole-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-pyrazole-5-carboxamide; (S)-N-(1-cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-(1-(Bicyclo[2.2.1]heptan-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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-isopropylisoxazole-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-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-(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-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisothiazol-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-dimethylisothiazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazole-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-pyrazole-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-pyrazole-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-triazole-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-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-isopropyl-1H-pyrazole-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-pyrazole-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-pyrazole-5-carboxamide; (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-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-triazole-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-pyrazole-5-carboxamide; N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyr idin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-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'-bipyridin]-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-pyrazole-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-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-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-pyrazole-5-carboxamide; and N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro 5 .2 3 nonan-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; a compound selected from one of or a pharmaceutically acceptable salt thereof.

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

25. The pharmaceutical composition according to Claim 24 for use in therapy.

26. Acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors and hematological malignancies such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, particularly acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-related arthritis, endotoxin shock associated with infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypochlorhydria, central and peripheral nervous system immune-mediated inflammatory disorders such as multiple sclerosis and Guillain-Barré syndrome, infectious diseases (viruses, bacteria, fungi and parasites), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, liver fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic inflammatory disease, pain (particularly pain related to inflammation), periodontitis, peritonitis, Peyronie's disease, folliculitis, psoriasis, psoriatic arthritis (PsA), The pharmaceutical composition according to claim 24 for use in the treatment of renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), transplant rejection, type I diabetes, ulcerative colitis, uveitis or vasculitis.

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