IL-17A modulators

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 preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders associated with IL-17A activity. [Background technology]

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

[0003] IL-17A is a 34-38 kDa variably glycosylated, disulfide-linked homodimeric glycoprotein that shares approximately 50% homology with its closest family member, IL-17F, both of which are secreted as either homodimers or heterodimers, 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 proinflammatory mediators such as IL-17A. Furthermore, various cell types from the innate and adaptive immune systems have been identified as sources of IL-17A. These include mast cells, neutrophil granulocytes, NK cells, NKT cells, CD8+ T cells, δγT cells, macrophages, and type 3 innate lymphoid cells [Non-Patent Document 3; Non-Patent Document 4].

[0005] The cytokines IL-17A, IL-17F, and IL-17AF bind to a common heteromeric receptor complex, IL-17RA and IL-17RC, albeit with different affinities, and although various cell types have been reported to express IL-17RA subunits, the highest response to IL-17A is mediated by epithelial cells, endothelial cells, keratinocytes, and fibroblasts [Non-patent Document 5; Non-patent Document 6; Non-patent Document 7].

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

[0007] These IL-17-mediated biological processes are involved in a variety of diseases, including psoriasis, ankylosing spondylitis, axial spondyloarthritis, psoriatic arthritis, eczema, enthesitis-related arthritis, asthma (including severe asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, ulcerative colitis, Crohn's disease, atopic dermatitis, contact dermatitis, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, multiple sclerosis, Guillain-Barré syndrome, irritable bowel syndrome, inflammatory bowel disease, Castleman's disease, pelvic inflammatory disease, systemic juvenile idiopathic arthritis (JIA), and arthritis recurrence. IL-17 has been implicated in the pathology of many human diseases with immune or autoimmune components, such as rheumatoid arthritis, giant cell arteritis, graft-versus-host disease, discoid lupus erythematosus, systemic lupus erythematosus, lupus nephritis, vasculitis, insulin-dependent type 1 diabetes, autoimmune diabetes, diabetic necrobiosis lipoidica, pyoderma gangrenosum, hidradenitis suppurativa, papulopustular rosacea, lichen planus, heart disease including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria, pain (especially inflammation-related pain), and cancer (Non-Patent Document 10; Non-Patent Document 11). In addition, due to its novel role in 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 key regulatory role of IL-17A in host defense, relevant pathologies also include viral, bacterial, fungal, and parasitic infections. An association between serum levels of IL-17 and the onset of sepsis has also been observed, suggesting that increased IL-17 may increase susceptibility to septic complications and infection-related endotoxic shock [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]. More recently, IL-17 inhibition 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) are 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 are also significantly correlated with the PASI score [Non-Patent Document 22; Non-Patent Document 23; Non-Patent Document 24].

[0009] Animal model studies 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 provided the ultimate validation, with excellent efficacy 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 efficacy in 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]. Proof of concept studies using secukinumab in MS also showed encouraging 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 [42; 43].

[0013] Additionally, IL-17A has been implicated in ocular surface disorders such as dry eye syndrome (DES) [Patent Documents 2, 3, and 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 have been associated with the clinical severity of dry eye in patients with a range of systemic autoimmune or inflammatory diseases, including Sjögren's syndrome, Stevens-Johnson syndrome (SJS), SLE, filamentous keratitis, DES, meibomian gland dysfunction (MGD), and graft-versus-host disease (GVHD) [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 [47; 48; 49; 50; 51; 52; 53; 54]. Increased levels of IL-17A have been shown to correlate with poor prognosis in several cancer types, including malignant thyroid tumors, breast cancer, pancreatic cancer, gastric cancer, NSCLC, colorectal cancer, and head and neck cancer [55; 54; 56; 57; 58; 59; 60; 61].

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

[0016] US Patent Nos. 5,629,999, 5,729,963, 5,729,973, and 5,729,973 describe a class of chemical compounds that are said to modulate the activity of IL-17 and are useful in the treatment of medical conditions, including inflammatory diseases. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Publication No. 20080269467 [Patent Document 2] PCT Publication No. WO2009089036 [Patent Document 3] PCT Publication No. WO2010062858 [Patent Document 4] PCT Publication No. WO2011163452 [Patent Document 5] WO2013 / 116682 [Patent Document 6] WO2014 / 066726 [Patent Document 7] WO2018 / 229079 [Non-patent literature]

[0018] [Non-Patent Document 1] KFGeoghegan 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] DJ Cua and CM 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] TAMoseley et al. / Cytokine Growth Factor Reviews.2003, 14, 155~174 [Non-patent document 6] SLGaffen / Nature Rev Immunol 2009, 9, 556~567

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[0019] Nevertheless, there is a continuing need for compounds that can attenuate IL-17A activity. [Means for solving the problem]

[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 invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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

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

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

[0025] In another aspect, the present invention relates to a method of treating a disease or disorder associated with IL-17A activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the 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 with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer, and neurodegenerative disorders.

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

[0028] In another aspect, the invention provides the use of a compound or a pharmaceutically acceptable salt in the manufacture of a medicament for use in the treatment of diseases with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer, and neurodegenerative disorders.

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

[0030] The present invention further provides a method of 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 obtainable by or obtained or directly obtained by a synthetic method as defined herein.

[0032] In another aspect, the present invention provides novel intermediates, as defined herein, suitable for use in any one of the synthetic methods set out herein.

[0033] The preferred, preferred and optional features of any one particular embodiment of the present invention are also preferred, preferred and optional features of any other embodiment. DETAILED DESCRIPTION OF THE INVENTION

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

[0035] References to "treating" or "treatment" should be understood to include prevention and alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition occurring in a person who may be afflicted with or predisposed to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the occurrence of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

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

[0037] The term "alkyl" refers to an aliphatic hydrocarbon group. As used herein, the term "alkyl" 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" is C 1~4 Alkyl, C 1~3 This includes alkyl, propyl, isopropyl, and t-butyl. The same rule applies to other radicals, e.g., "phenyl C 1~6 "Alkyl" is a phenyl C 1~4 Includes alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

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

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

[0041] "Cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, 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 a halogen (e.g., fluorine) atom. Examples of haloalkyl and haloalkoxy groups include fluoroalkyl and fluoroalkoxy groups such as -CHF, -CHCF, or perfluoroalkyl / alkoxy groups such as -CF, -CFCF, or -OCF.

[0044] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a non-aromatic saturated or partially unsaturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocyclic rings contain about 3 to 12 (preferably 3 to 7) ring atoms, with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include oxidized sulfur heterocycles containing SO or SO groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclyl groups bearing one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 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 through any suitable atom, such as a carbon or nitrogen atom. Suitably, the terms "heterocyclyl", "heterocyclic" or "heterocycle" will refer to a 4-, 5-, 6- or 7-membered monocyclic ring as defined above.

[0045] "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, pp. 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.

[0046] "Spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., a heterocyclic ring is linked to an additional carbocyclic or heterocyclic ring 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.

[0047] The term "heteroaryl" or "heteroaromatic" refers to 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 5 to 12 ring members, and more usually 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as fused 5- and 6-membered rings or a bicyclic structure formed from two fused 6-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more usually up to two, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in heteroaryl rings can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be less than five. Heteroaryl groups containing nitrogen atoms can exist as the corresponding N-oxides. A specific example of such a heteroaryl group is pyridine N-oxide. Preferably, the term "heteroaryl" or "heteroaromatic" refers to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0048] 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, and isoaryl. These include quinolyl, 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]-o-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.

[0049] 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.

[0050] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl groups.

[0051] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms It may be a group selected from:

[0052] Specific non-limiting examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0053] Specific non-limiting examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0054] The term "aryl" refers to 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, and the like. In some embodiments, aryl is phenyl or naphthyl, especially phenyl.

[0055] This specification also utilizes some compound terms to describe groups that contain more than one functional group. Such terms will be understood by those skilled in the art. For example, heterocyclyl C 1~4 Alkyl is substituted by heterocyclyl C 1~4 Contains alkyl.

[0056] The term "optionally substituted" refers to either groups, structures or molecules that are substituted as well as those that are not substituted.

[0057] Where optional substituents are selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. When there are multiple substituents, it is understood that the selected substituents can be the same or different.

[0058] Where numerical ranges are given, it is understood that the ranges are inclusive of the endpoints.

[0059] The phrase "compounds of the invention" means both generically and specifically the compounds disclosed herein.

[0060] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I [ka] [In formula: X 1 , X 2 , X 3 and X 4 are each independently 5 or N; Y is aryl or heteroaryl, each of which is 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 and optionally substituted by one or more substituents independently selected from haloalkyl; where, when Y is a 5- or 6-membered heteroaryl ring, said ring is optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is 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 optionally substituted by one or more substituents independently selected from haloalkyl; R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 10 membered cycloalkyl ring, wherein the cycloalkyl ring is: a.Halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4optionally substituted with one or more substituents independently selected from haloalkoxy; and b. One or more independently selected C 3~6 optionally spiro-linked to a cycloalkyl group; R 3 is hydrogen, fluoro or C 1~4 is alkyl; R 4 teeth: (A) 5- to 10-membered heteroaryl, C 3~7 cycloalkyl or 3- to 12-membered heterocyclyl rings, each of which is selected from the group consisting of 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 Optionally substituted by one or more substituents independently selected from cycloalkyl and heterocyclyl, wherein said C 3~7 Cycloalkyl and heterocyclyl substituents include 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 optionally substituted with one or more substituents independently selected from: (B) Hydroxy, Halo, C 1~4 Alkoxy, Cyano, NR 6 R 7 , C(O)NR 8 R 9 or CO2R 10 optionally substituted with C 1~6 Is it alkyl? (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 selected from the group consisting of 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 by 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 which may be selected from the group consisting of 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 by one or more substituents independently selected from cycloalkyl and heterocyclyl; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, and 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 3~7a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; R 5 is hydrogen, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 haloalkyl or cyano; R 11 are hydroxy, halo, C 1~4 Alkoxy, Cyano, NR 12 R 13 , C(O)R 14 , aryl or heteroaryl; R 14 is hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy or NR 15 R 16 and; R 6 , R 7 , R 8 , R 9 , R 10 , R 12 and R 13 is hydrogen and C 1~4 independently selected from alkyl; R 15 and R 16 is hydrogen and C 1~4 independently selected from alkyl; or R 15 and R 16 taken together 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 and N, C 1~4 optionally substituted with alkyl]; or a pharmaceutically acceptable salt thereof.

[0061] Compounds according to formula (I) may exist as a mixture of stereoisomers. Conveniently, compounds according to formula (I) have the following structure: [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , Y, R 1 , R 2 , R 3 and R 4 are as defined above or below] It has.

[0062] Certain compounds of the present invention include, for example, 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 and n is 0 or 1. Each of these has any of the meanings defined above or in any of paragraphs (1) to (72) below, or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, the present invention includes combinations of two or more substituent definitions as set out in paragraphs (1) to (72): (1)X 1 , X 2 , X 3 and X 4 are each independently CH or N; (2)X 1 , X 2 , X 3 and X 4 Two of them are CR 5 and two are N; (3)X 2 and X 4 is N and X 1 and X 3 is CR 5 is; (4)X 2 and X 4 is N and X 1 and X 3 is CH; (5)X1 , X 2 , X 3 and X 4 Three of them are CR 5 and others are N; (6)X 1 is N and X 2 , X 3 and X 4 is CR 5 is; (7)X 1 is N and X 2 , X 3 and X 4 is CH; (8)X 2 is N and X 1 , X 3 and X 4 is CR 5 is; (9)X 2 is N and X 1 , X 3 and X 4 is CH; (10)X 1 , X 2 , X 3 and X 4 are all CR 5 is; (11)X 1 , X 2 , X 3 and X 4 are all CH; (12) Y is aryl or heteroaryl, each of which is 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 optionally substituted by one or more substituents independently selected from haloalkyl; (13) Y is halo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Alkylene-C 1~2Alkoxy and C 1~2 phenyl, optionally substituted by one or more substituents independently selected from haloalkyl; (14) Y is halo, C 1~3 Alkyl, C 1~2 Alkoxy, C 1~2 Alkylene-C 1~2 Alkoxy and C 1~2 is a heteroaryl ring optionally substituted with one or more substituents independently selected from haloalkyl; (15) Y is a 5- to 6-membered heteroaryl ring optionally substituted with 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 by methyl or ethyl in the ortho position relative to the NHC(O)-moiety; (17) Y is a 5- or 6-membered heteroaryl ring fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is selected from the group consisting of 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 1~2 optionally substituted by one or more substituents independently selected from haloalkyl; (18) Y is a 5-membered heteroaryl ring fused to a 5- or 6-membered heterocyclyl ring, each of which is selected from the group consisting of halo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Alkylene-C 1~2 Alkoxy and C 1~2 optionally substituted by one or more substituents independently selected from haloalkyl; (19) Y is pyrazolyl, pyrrolyl, isoxazolyl, oxadiazolyl, or triazolyl substituted by one or more substituents independently selected from chloro, fluoro, methyl, and difluoromethyl;

[0063] (20) Y is: [ka] [In the formula, [ka] is the point of attachment to the remainder of the compound of Formula I; Y is halo, C 1~3 Alkyl, C 1~2 Alkoxy, C 1~2 Alkylene-C 1~2 Alkoxy, C 1~2 Alkylene-N(C 1~3 alkyl)2 and C 1~2 optionally substituted by one or more substituents independently selected from haloalkyl; (21) Y is pyrazolyl substituted by one or more substituents independently selected from chloro, fluoro, methyl, ethyl, isopropyl, and difluoromethyl;

[0064] (22) Y is: [ka] [In the formula, [ka] is the point of attachment to the remainder of the compound of Formula I; (23)R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 10 membered cycloalkyl ring, wherein the cycloalkyl ring is: a.Halo, C 1~2 Alkyl, C 1~2 Alkoxy and C 1~2optionally substituted with one or more substituents independently selected from haloalkyl; and b. One or more independently selected C 3~5 optionally spiro-bonded to a cycloalkyl group; (24)R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 8 membered cycloalkyl ring, wherein the cycloalkyl ring is: c.Halo, C 1~2 Alkyl, C 1~2 Alkoxy and C 1~2 optionally substituted with one or more substituents independently selected from haloalkyl; and d. One or more independently selected C 3~5 optionally spiro-bonded to a cycloalkyl group; (25)R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 8 membered cycloalkyl ring, wherein the cycloalkyl ring is: a. optionally substituted with one or more substituents independently selected from fluoro, methyl, trifluoromethyl, and methoxy; and b. optionally spiro-linked to one or more (such as one or two) cyclopropyl groups; (26)R 1 and R 2 taken together with the carbon atom to which they are attached form a cyclohexyl ring, wherein the cyclohexyl ring is substituted with one or more substituents independently selected from fluoro, trifluoromethyl and methyl; C 3~5 optionally spiro-bonded to a cycloalkyl group; (27)R 1 and R 2taken together with the carbon atom to which they are attached form a cyclohexyl ring, wherein the cyclohexyl ring is substituted with one or more substituents independently selected from fluoro, trifluoromethyl, and methyl; and is optionally spiro-bonded to a cyclopropyl group;

[0065] (28)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 is bonded. 17 Each occurrence of halo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Haloalkyl and C 1~2 haloalkoxy, and m is 0 to 6;

[0066] (29)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 is bonded. 17 each occurrence of is independently selected from fluoro, methyl, trifluoromethyl, and methoxy, and m is 0 to 6;

[0067] (30)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 is bonded. 17 each occurrence of is independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;

[0068] (31)R 1 and R 2 together with the carbon atoms to which they are attached, form: [ka] Forming In the formula, * represents R 1 and R 2 is the carbon atom to which each R 17 are independently selected from hydrogen, fluoro, trifluoromethyl and methyl; (32)R 3 is hydrogen, fluoro or methyl; (33)R 3 is hydrogen; (34)R 3 is methyl; (35)R 4 teeth: (A) 5- to 10-membered heteroaryl or C 3~7 cycloalkyl rings, each of which may be selected from the group consisting of 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 Optionally substituted by one or more substituents independently selected from cycloalkyl and heterocyclyl, wherein said C 3~7 Cycloalkyl and heterocyclyl substituents include hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4Haloalkyl, Cyano, NR 6 R 7 , C(O)NR 8 R 9 and CO2R 10 optionally substituted with one or more substituents independently selected from: (B) Hydroxy, Halo, C 1~4 Alkoxy, Cyano, NR 6 R 7 or CO2R 10 optionally substituted with C 1~6 Is it alkyl? (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 selected from the group consisting of 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 by 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 which may be selected from the group consisting of 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 by one or more substituents independently selected from cycloalkyl and heterocyclyl; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, and 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 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; (36)R 4 teeth: (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; (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 selected from the group consisting of 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 by 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 which may be selected from the group consisting of 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 by one or more substituents independently selected from cycloalkyl and heterocyclyl; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, and 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 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; (37)R 4 teeth: (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 3~7 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 selected from the group consisting of 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 (E) optionally fused to a 5- to 6-membered heteroaryl ring, and 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 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from: (38)R 4 teeth: (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 3~7 a 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from cycloalkyl; or (E) optionally fused to a 5- to 6-membered heteroaryl ring, and 1~4Alkyl, 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 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from: (39)R 4 is a 5- to 10-membered heteroaryl, C 3~7 cycloalkyl or 3- to 12-membered heterocyclyl rings, each of which is selected from the group consisting of 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 (40)R 4 is a 6- to 10-membered heteroaryl, C 3~7 cycloalkyl or 3- to 7-membered heterocyclyl rings, each of which is selected from the group consisting of 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 (41)R 4 Ha, Halo, C 1~4 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl, cyano, NR 6 R 7 , C 1~3Alkylene-R 11 and C 3~7 is a 5- to 10-membered heteroaryl ring optionally substituted with one or more substituents independently selected from cycloalkyl; (42)R 4 is fluoro, chloro, methyl, methoxy, trifluoromethoxy, cyano, NR 6 R 7 , CH2-R 11 and a 5- to 6-membered monocyclic heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring optionally substituted with one or more substituents independently selected from cyclopropyl; (43)R 4 Ha, 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 is a 6- to 10-membered heteroaryl ring optionally substituted with one or more substituents independently selected from: (44)R 4 are hydroxy, halo, C 1~2 Alkyl, C 1~2 Alkoxy, Cyano, NR 6 R 7 , C(O)NR 8 R 9 and C 1~3 Alkylene-R 11 C optionally substituted with one or more substituents independently selected from 3~7 is a cycloalkyl ring; (45)R 4 is hydroxy, fluoro, methyl, methoxy, cyano, NR 6 R 7 and C(O)NR 8 R 9 C optionally substituted with one or more substituents independently selected from 3~5 is a cycloalkyl ring; (46)R4 are 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 is a 3- to 7-membered heterocyclyl ring optionally substituted by one or more substituents independently selected from: (47)R 4 is hydroxy, methyl, methoxy, cyano, NR 6 R 7 and C(O)NR 8 R 9 is a 3- to 7-membered heterocyclyl ring optionally substituted by one or more substituents independently selected from: (48)R 4 are 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 is alkyl; (49)R 4 is hydroxy, fluoro, NR 6 R 7 or CO2R 10 optionally substituted with C 2~5 is alkyl; (50)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 selected from the group consisting of halo, oxo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 optionally substituted with one or more substituents independently selected from haloalkyl and cyano; (51)R 4is 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 with one or more substituents independently selected from chloro, fluoro, methyl, methoxy, and cyano; (52)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 which may be selected from halo, oxo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 optionally substituted with one or more substituents independently selected from haloalkyl and cyano; (53)R 4 is optionally fused to a 5- to 6-membered heteroaryl ring, and is selected from the group consisting of hydroxy, halo, oxo, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from haloalkyl and cyano; (54)R 4 Fluoro, oxo and C 1~2 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl; (55)R 4 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from oxo and methyl; (56)R 4 is a partially unsaturated 6-membered N-containing heterocyclic ring substituted with one or more substituents independently selected from oxo and methyl; (57)R 4 is fused to a 5- to 6-membered heteroaryl ring and is selected from fluoro, oxo, and C 1~2 is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl; (58)R 4 is a partially unsaturated heterocyclic ring fused to a 5- to 6-membered heteroaryl ring and optionally substituted with one or more substituents independently selected from oxo and methyl; (59)R 4 is a partially unsaturated 6-membered N-containing heterocyclic ring fused to a 5-membered N-containing heteroaryl ring and optionally substituted with one or more substituents independently selected from oxo and methyl;

[0069] (60)R 4 is the group: [ka] [In formula: [ka] is the point of attachment to the remainder of the compound of Formula I; R 18 are 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 independently selected from cycloalkyl; R 19 is hydrogen, C 1~4 Alkyl, C 1~3 Alkylene-R 11 and C 3~7 independently selected from cycloalkyl; p is 0, 1, or 2. is selected from one of where R 4 When is a bicyclic group and p is 1 or 2, each R 18 Substituents may be present on either ring of a bicyclic group;

[0070] (61)R 4 is the group: [ka] [In formula: [ka] is the point of attachment to the remainder of the compound of Formula I; R 18 are 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 independently selected from cycloalkyl; R 19 is hydrogen, C 1~4 Alkyl, C 1~3 Alkylene-R 11 and C 3~7 independently selected from cycloalkyl; p is 0, 1, or 2. is selected from one of where R 4 When is a bicyclic group and p is 1 or 2, each R 18 Substituents may be present on either ring of a bicyclic group;

[0071] (62)R 4 is the group: [ka] [In formula: [ka] is the point of attachment to the remainder of the compound of Formula I; R 18 is hydroxy, fluoro, chloro, methyl, methoxy, CF3, NR 6 R 7 , C 1~3 Alkylene-R 11 and cyclopropyl; R 19are independently selected from hydrogen, methyl and cyclopropyl; p is 0, 1, or 2. is selected from one of where R 4 When is a bicyclic group and p is 1 or 2, each R 18 Substituents may be present on either ring of a bicyclic group; (63)R 5 is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl or cyano; (64)R 5 is hydrogen, fluoro, chloro or methyl; (65)R 5 is hydrogen; (66)R 5 is fluoro; (67)R 11 is hydroxy, halo, methoxy, cyano, NR 12 R 13 , C(O)R 14 or aryl; (68)R 11 is hydroxy, methoxy, cyano, NR 12 R 13 , C(O)R 14 or phenyl; (69)R 14 is hydroxy, methoxy or NR 15 R 16 is; (70)R 14 is NR 15 R 16 is; (71)R 15 and R 16 together 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, and C 1~4 optionally substituted with alkyl; (72)R 15 and R 16taken 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.

[0072] 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.

[0073] Suitably, Y is as defined in any one of paragraphs (12) to (22) above. In certain embodiments, Y is as defined in any one of paragraphs (19) to (22) above. In further embodiments, Y is as defined in paragraph (22) above.

[0074] Preferably, R 1 and R 2 is as defined in any one of paragraphs (23) to (31) above. In some embodiments, R 1 and R 2 is as defined in any one of paragraphs (26) to (31) above. Conveniently, R 1 and R 2 is as defined in item (28) above.

[0075] Preferably, R 3 is as defined in any one of paragraphs (32) to (34) above. Conveniently, R 3 is as defined in item (33) above.

[0076] Preferably, R 4 is as defined in any one of paragraphs (35) to (62) above. In certain embodiments, R 4 is as defined in any one of paragraphs (61) to (62) above. Conveniently, R 4 is as defined above in item (62).

[0077] Preferably, R 5 is as defined in any one of paragraphs (63) to (66) above. Conveniently, R 5 is as defined above in item (65).

[0078] Preferably, R 11 is as defined in any one of paragraphs (67) to (68) above. Conveniently, R 11 is as defined above in item (68).

[0079] Preferably, R 14 is as defined in any one of paragraphs (69) to (70) above. Conveniently, R 14 is as defined above in item (70).

[0080] Preferably, R 15 and R 16 is as defined in any one of paragraphs (71) to (72) above. Conveniently, R 15 and R 16 is as defined above in item (72).

[0081] In a further group of compounds, the compounds have the structural formula IA, IB, IC or ID shown below: [ka] [In the formula, X 1 From X 4 and R 4 is as defined above; each R 17 Ha, Halo, C1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 haloalkoxy; n is 0 to 4. It has one of the following.

[0082] In a further group of compounds, the compounds have one of the structural formulas IA, IB, IC or ID above, wherein X 1 From X 4 is as defined in any one of paragraphs (1) to (11) above; R 4 is as defined in any one of paragraphs (35) to (62) above; each R 17 Ha, Halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 haloalkoxy; n is 0 to 4.

[0083] In a further group of compounds, the compounds have one of the structural formulas IA, IB, IC or ID above, wherein X 1 From X 4 is as defined in any one of paragraphs (6)-(7) or (10)-(11) above; R 4 is as defined in any one of paragraphs (61) to (62) above; R 20 and R 21is independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy; and n is 0 to 4. In a further group of compounds, the compounds have one of the structural formulas IA, IB, IC, or ID above, wherein X 1 From X 4 is as defined in section (11) above; R 20 and R 21 is independently selected from hydrogen, fluoro, trifluoromethyl, and methyl; and n is 0 to 3. In still a further group of compounds, the compounds have one of the structural formulas IA, IB, IC, or ID above, wherein X 1 From X 4 is as defined in section (11) above; R 20 and R 21 are both hydrogen; and n is 0. In still a further group of compounds, the compounds have one of the structural formulas IA, IB, IC or ID above, wherein X 1 From X 4 is as defined in section (11) above; R 20 and R 21 are both methyl; and n is 0. In still a further group of compounds, the compounds have one of the structural formulas IA, IB, IC, or ID above, wherein X 1 From X 4 is as defined in section (11) above; R 20 is methyl and R 21 is hydrogen; and n is 0.

[0084] In a further group of compounds, the compounds have the structural formula IE, IF, IG, IH, IJ, IK, IL or IM as shown below: [ka] [In the formula, Y, R 1 , R 2 , R 3 , R 4 and R 5 is as defined above; each R 17 Ha, Halo, C 1~4 Alkyl, C 1~4Alkoxy, C 1~4 Haloalkyl and C 1~4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 haloalkoxy; n is 0 to 4. It has one of the following.

[0085] In a further group of compounds, the compounds have one of the structural formulas IE, IF, IG, IH, IJ, IK, IL, or IM, where Y is as defined in any one of paragraphs (12) to (22) above; R 1 and R 2 is as defined in any one of paragraphs (23) to (31) above; R 3 is as defined in any one of paragraphs (32) to (34) above; R 4 is as defined in any one of paragraphs (35) to (62) above; each R 5 are independently as defined in any one of paragraphs (63) to (66) above; each R 17 Ha, Halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 haloalkoxy; n is 0 to 4.

[0086] In a further group of compounds, the compounds have the structural formula IE, IF, IG or IH shown above, where Y is as defined in any one of paragraphs (19) to (22) above; R 1 and R 2is as defined in any one of paragraphs (26) to (31) above; R 3 is as defined in any one of paragraphs (32) to (34) above; R 4 is as defined in any one of paragraphs (61) to (62) above; each R 5 are independently as defined in any one of paragraphs (64) to (65) above. In a further group of compounds, the compounds have the structural formula IE, IF, IG, or IH shown above, where Y is as defined in paragraph (22) above; R 1 and R 2 is as defined in section (31) above; R 3 is as defined in section (33) above; R 4 is as defined in item (62) above; each R 5 is as defined above in item (65).

[0087] In a further group of compounds, the compounds have the structural formula IJ, IK, IL or IM shown above, wherein Y is as defined in any one of paragraphs (19) to (22) above; R 4 is as defined in any one of paragraphs (61) to (62) above; each R 5 are independently as defined in any one of paragraphs (64) to (65) above; each R 17 is fluoro, methyl, methoxy and C 1~2 haloalkyl; R 20 and R 21 is hydrogen, fluoro, methyl, ethyl, methoxy, C 1~2 Haloalkyl and C 1~2 haloalkoxy; n is 0 to 4. In a further group of compounds, the compounds have the structural formula IJ, IK, IL, or IM shown above, where Y is as defined in item (22) above; R 4 is as defined in item (62) above; each R 5is as defined in item (65) above; each R 17 is fluoro, methyl, methoxy and C 1~2 haloalkyl; R 20 and R 21 is hydrogen, fluoro, methyl, ethyl, methoxy and C 1~2 haloalkyl (such as trifluoromethyl); n is 0 to 3.

[0088] Particular compounds of the present invention are: N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 1); N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 2); 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 3); 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 4); 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 5); 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 6); 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 7); 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 8); 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 9); 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 10); 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 11); 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 12); N-((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 13); N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 14); N-((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 15); N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 16); N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 17); 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 18); N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 19); N-(1-(4,4-difluorocyclohexyl)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 20); N-(2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-(4,4-dimethylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 21); N-(1-cyclooctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 22); N-(1-cyclooctyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 23); N-(1-cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 24); 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 25); N-(1-cyclooctyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 26); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 27); N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 28); N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 29); 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 30); 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 31); 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 32); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 33); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 34); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 35); (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 36); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 37); (S)—N-(1-cyclohexyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 38); N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 39); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 40); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 41); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 42); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 43); N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 44); 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 45); N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 46); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 47); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 48); (S)—N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 49); N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 50); (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 51); (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 52); (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 53); N-((S)-2-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 54); (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 55); (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(methoxymethyl)isoxazole-4-carboxamide (Example 56); N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 57); 6-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3',5'-dimethyl-[3,4'-bipyridine]1'-oxide (Example 58); 3-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-4-carboxamide (Example 59); (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 60); N-((S)-2-((5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 61); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 62); (S)—N-(1-(4,4-difluorocyclohexyl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 63); 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 64); 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 65); 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 66); (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 67); (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 68); (S)—N-(1-cycloheptyl-2-((5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 69); 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 70); 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 71); 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 72); 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 73); N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 74); 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 75); (S)—N-(1-cycloheptyl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 76); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 77); N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 78); N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 79); (S)—N-(1-cycloheptyl-2-((5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 80); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 81); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 82); (S)—N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 83); (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 84); (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 85); 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 86); 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 87); (S)—N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 88); (S)—N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 89); (S)—N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 90); (S)—N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 91); (S)—N-(1-cycloheptyl-2-((5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 92); (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 93); (S)—N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 94); (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 95); (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 96); (S)—N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 97); 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 98); N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 99); (S)—N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 100); (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 101); (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 102); 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 103); 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 104); 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 105); N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-3-ethylisoxazole-4-carboxamide (Example 106); N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 107); 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 108); (S)—N-(1-cycloheptyl-2-((5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 109); N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-isopropylisoxazole-4-carboxamide (Example 110); 3-(tert-butyl)-N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide (Example 111); 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 112); N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-(trifluoromethyl)isoxazole-4-carboxamide (Example 113); (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 114); 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 115); 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 116); (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 117); 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 118); 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 119); N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 120); (S)—N-(1-cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 121); 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 122); 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 123); 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 124); N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 125); (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 126); (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 127); (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 128); (S)—N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 129); 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 130); 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 131); N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 132); (S)—N-(1-cycloheptyl-2-oxo-2-((1′,2′,4′-trimethyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-6-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 133); 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 134); (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 135); 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 136); (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 137); 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 138); 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 139); or a pharmaceutically acceptable salt thereof.

[0089] The various functional groups and substituents comprising the compounds of the invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, e.g., less than 700, or less than 650, or less than 600.

[0090] A suitable or preferred feature of any compound of the invention may also be a suitable feature of any other embodiment.

[0091] 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, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. 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, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0092] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, 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 Cahn and Prelog R- and S-sequencing rules or by the way the molecule rotates plane-polarized light, designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0093] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th Edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereomeric and geometric isomers, and mixtures thereof.

[0094] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be any isotopic form, including 1H, 2H (D) and 3H (T); C can be any isotopic form, including 12C, 13C and 14C; O can be any isotopic form, including 16O and 18O; etc.

[0095] It should also be understood that certain compounds of the present invention can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, and the present invention should be understood to encompass all such solvated forms.

[0096] It is also understood that certain compounds of the present invention may exhibit polymorphism, and that the present invention encompasses all such forms.

[0097] 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. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by the compound of the present invention. Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0098] [ka]

[0099] Compounds of the present invention containing an amine functional group can also form N-oxides. Reference herein to a compound of Formula I containing an amine functional group also includes 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 or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0100] 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. Prodrugs can be used to change the physical properties 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 can be attached. Examples of prodrugs include in vivo cleavable ester derivatives formed at a carboxy or hydroxy group in the compounds of the present invention and in vivo cleavable amide derivatives formed at a carboxy or amino group in the compounds of the present invention.

[0101] Thus, the present invention includes 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. Thus, the present invention also includes compounds of formula I produced by organic synthetic means and such compounds produced in the human or animal body by means of metabolism of precursor compounds, i.e., compounds of formula I may be synthetically produced compounds or metabolically produced compounds.

[0102] synthesis In the descriptions of synthetic methods which follow and in the reference synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, will be selected by one of ordinary skill in the art.

[0103] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0104] Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying Examples, along with the following representative process variants. Alternatively, necessary starting materials can be obtained by analogous procedures to those exemplified, which are within the ordinary skill of an organic chemist.

[0105] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reactions. The skilled chemist will know when such protection is required and how such protecting groups can be introduced and subsequently removed.

[0106] For examples of protecting groups, see one of the many general textbooks on the subject, e.g., "Protecting groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999)" by T. Greene and P. Wuts. Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as being appropriate for the removal of the protecting group in question, with such method being chosen to accomplish removal of the protecting group with minimal disturbance to groups elsewhere in the molecule.

[0107] Thus, where reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0108] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups (e.g., alkanoyl or alkoxycarbonyl groups), or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium or sodium hydroxide). Alternatively, acyl groups (e.g., tert-butoxycarbonyl groups) can be removed by treatment with a suitable acid (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid), and arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl groups) can be removed by hydrogenation with a catalyst (e.g., palladium on carbon) or by treatment with a Lewis acid (e.g., BF3.OEt2). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0109] Those skilled in the art will recognize that the compounds of the present invention can be prepared in a variety of ways in a known manner. Compounds of Formula I can be prepared by the methods described below, by the methods described in the experimental section, or by similar methods. The described routes only exemplify some of the methods used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to those described. The assignment of nucleophiles and electrophiles is not limited to those described herein, and it will also be understood that in some cases, it may be appropriate to reverse the assignment. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach," 2nd Edition, S. Warren and P. Wyatt (2008).

[0110] 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 defined above] can be reacted with a carboxylic acid or a suitably reactive derivative of a carboxylic acid of formula III, 1 , R 2 , R 3 and Y are as defined above in formula I] with an amine of formula II [wherein R 4 , X 1 , X 2 , X 3 and X 4 is as defined above in Formula I] with (Scheme A, Step i).

[0111] 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 defined above] is reacted with an amine of formula IV, 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 is as defined above in Formula I] with a carboxylic acid of Formula V or a suitably reactive derivative of a carboxylic acid, where Y is as defined above in Formula I (Scheme A, Step ii).

[0112] [ka]

[0113] Compounds of formula III can be prepared by reacting a suitably protected amine of formula VI, 1 , R 2 and R 3 is as defined above in Formula I] with a carboxylic acid of Formula V or a suitably reactive derivative of a carboxylic acid, where Y is as defined above in Formula I (Scheme B, Step i).

[0114] Compounds of formula IV can be prepared by reacting a suitably protected carboxylic acid or a suitably protected reactive derivative of a carboxylic acid of formula VI, 1 , R 2 and R 3 is as defined above in formula I] with an amine of formula II [wherein R 4 , X 1 , X 2 , X 3 and X 4 is as defined above in Formula I] with (Scheme B, Step ii).

[0115] [ka]

[0116] Suitable reactive derivatives of the carboxylic acids of formula III, V, and VI include, for example, acyl halides formed by the reaction of the acid with an inorganic acid chloride such as thionyl chloride; mixed anhydrides formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate; esters formed by the reaction of an alcohol in the presence of an acid or base; activated esters formed by the reaction of the acid with a phenol such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; or the product of the reaction of the acid with an amide coupling agent such as dicyclohexylcarbodiimide. When the carboxylic acids of formula III and V are converted to esters, for example, by the reaction of the acyl chloride with an organic alcohol such as methanol, these may be reacted with a suitable amine in the presence of an organometallic activator, for example, a Grignard reagent such as isopropylmagnesium bromide. Typically, a carboxylic acid of formula III and an amine of formula II, or a carboxylic acid of formula V and an amine of formula IV, or a suitably protected carboxylic acid of formula VI and an amine of formula II, is 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.

[0117] Those skilled in the art will recognize that the conversion of amino acids of Formula VI to compounds of Formula III and Formula IV will require a suitable synthetic strategy, which may require multiple steps, and will be able to identify such a synthetic strategy, which may include the selection, preparation, and removal of suitable protecting groups.

[0118] Natural and unnatural amino acids and derivatives thereof of formula VI, wherein R 1 , R 2 and R 3is as defined in Formula I] are either commercially available or can be prepared by methods known to those skilled in the art. For reviews of amino acid synthesis, see (a) C. Najera and JM Sansano, Chem Rev, 2007, 107, 4584; (b) R.M. Williams and J.A. Hendrix, Chem Rev, 1992, 92, 889; (c) R.O. Duthaler, Tetrahedron, 1994, 50, 1539.

[0119] 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. Compounds of formula V can be prepared by: acid- or base-catalyzed hydrolysis of esters, amides, or nitriles, such as hydrolysis of methyl esters with sodium hydroxide; transition metal-catalyzed oxidation of aldehydes or alcohols; treatment with organolithium or Grignard reagents with carbon dioxide; or transition metal-catalyzed carbonylation of aryl halides in the presence of water. Compounds of formula III or formula I can be formed directly by transition metal-catalyzed carbonylation of aryl halides in the presence of amines of formula VI or formula IV.

[0120] [ka]

[0121] An amine of formula II, wherein R 4 , X 1 , X 2 , X 3 and X 4 is as defined above in Formula I] are either commercially available or can be prepared by methods known to those skilled in the art.

[0122] Compounds of formula II can be represented by formula VII, wherein R 4 is as defined in formula I] and formula VIII [wherein X 1 , X 2 , X3 and X 4 is as defined in formula I, 1 and Z 2 is R 4 and the phenyl / heteroaryl ring and is replaced / eliminated during the bond-forming reaction (Scheme C, Step i). 1 and Z 2 Functional groups are known to those skilled in the art. For example, R 4 When is heteroaryl, the preferred bond-forming reaction may be a Suzuki reaction, and Z 1 or Z 2 One of Z is a boronic acid or boronic ester, and the other is a halide. 1 or Z 2 Compounds of formula VII and formula VIII, one of which is a boronic acid or boronic ester and the other a halide, 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.

[0123] The amine of formula II can be prepared by reacting a compound of formula IX, 4 , X 1 , X 2 , X 3 and X 4 is as defined above in formula I, and Z 3 is a functional group that can be converted to an amine via known methods (Scheme C, step ii). Examples of known methods include: 3 is, for example, azido or nitro; 3 is, for example, a primary amide (Hofmann rearrangement), a carboxylic acid (Schmidt rearrangement), an acyl azide (Curtius rearrangement); or 3is H or a halide, including C-N bond formation, e.g., nitration followed by reduction or amination (e.g., Buchwald-Hartwig reaction).

[0124] A compound of formula IX, wherein R 4 , X 1 , X 2 , X 3 and X 4 is as defined above in Formula I] are as described herein, are either commercially available, or are prepared by methods known to those skilled in the art.

[0125] Pharmaceutical Composition The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Thus, according to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0126] The pharmaceutical composition of the present invention is prepared and packaged in bulk form, such as powder or syrup, which can be extracted with a safe and effective amount of the compound of the present invention and then given to patients.Alternatively, the pharmaceutical composition of the present invention is prepared and packaged in unit dosage form, and each physically discrete unit contains a safe and effective amount of the compound of the present invention.When prepared in unit dosage form, the pharmaceutical composition of the present invention typically contains 1mg to 1000mg.

[0127] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and wafers), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration (e.g., via a transdermal patch), administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0128] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle that contributes to providing form or viscosity to a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed together to avoid interactions that would substantially reduce the efficacy of the compound of the present invention when administered to a patient and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each excipient must, of course, be of sufficiently high purity to make it pharmaceutically acceptable.

[0129] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art, some of which are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0130] An effective amount of a compound of the invention for use in therapy of a proliferative disease is an amount sufficient to symptomatically alleviate the symptoms of, slow the progression of, or reduce the risk of exacerbation of a proliferative disease in a warm-blooded animal, particularly a human.

[0131] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.5 mg to 0.5 g of active agent (more preferably from 0.5 to 100 mg, e.g., 1 to 30 mg), combined with an appropriate and convenient amount of excipient, which may vary, for example, from about 5 to about 98 weight percent of the total composition.

[0132] The size of a dose of a compound of formula I for therapeutic or protective purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles.

[0133] When using the compounds of the present invention for therapeutic or protective purposes, the compounds will generally be administered so that a daily dose of, for example, 0.1 mg to 75 mg per kg of body weight is received, assuming that divided doses are required. Generally, when parenteral routes are used, lower doses will be administered. Thus, for example, for intravenous or intraperitoneal administration, a dose of, for example, 0.1 mg to 30 mg per kg of body weight will generally be used. Similarly, for administration by inhalation, a dose of, for example, 0.05 mg to 25 mg per kg of body weight will be used. Oral administration may also be suitable, especially in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[0134] Administration route The compounds of the invention, or pharmaceutical compositions containing the active compounds, are administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0135] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by gums, films, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosols, e.g., via the mouth or nose); rectal (e.g., by suppository or enema); intravaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0136] 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 therefore useful as therapeutic compounds in the treatment or prevention of human diseases that occur as a result of IL-17A activity.

[0137] The compounds of the present invention are high-affinity binders for human IL-17A and potent modulators of human IL-17A activity, and may be useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of the present invention may be useful as radioligands in assays for detecting pharmacologically active compounds.

[0138] Thus, in one aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0139] In another aspect, the invention relates to a compound of the 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.

[0140] In another aspect, the invention relates to the use of a compound of the 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.

[0141] In another aspect, the present invention relates to a method of treating a disease or disorder in which IL-17A activity is implicated, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0142] Examples of specific diseases or disorders which can be treated using the compounds of formula (I) and their pharmaceutically acceptable salts include: 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, in particular acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-associated arthritis, endotoxic shock associated with infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, and the like. Heart disease including ischemic diseases such as inflammation, graft-versus-host disease, myocardial infarction and atherosclerosis, immune-mediated inflammatory disorders of the central and peripheral nervous system such as hepatoblastoma, hypochlorhydria, multiple sclerosis and Guillain-Barré syndrome, infections (viral, bacterial, fungal and parasitic), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, hepatic fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic These conditions include, but are not limited to, any one of inflammatory diseases, pain (especially pain associated with inflammation), periodontitis, peritonitis, Peyronie's disease, pilonidal disease, 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 1 diabetes, ulcerative colitis, uveitis, and vasculitis.

[0143] Modulators of IL-17 activity are administered to inhibit or reduce the severity of ocular inflammatory disorders ( WO 2009 / 089036 ), such as corneal ocular surface inflammatory disorders, including dry eye syndrome (DES). Consequently, compounds according to the present invention are useful in treating or preventing 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 grafting, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjögren's syndrome, Sjögren's syndrome-associated keratoconjunctivitis sicca, non-Sjögren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss.

[0144] 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 the one or more additional therapeutic agents will, of course, vary depending on the disease or condition being treated and its severity.

[0145] It is common to use combination therapies to treat certain medical conditions.

[0146] According to a particular aspect of the present invention, there is provided a combination suitable for use in the treatment of a disease or condition in which IL-17 activity is implicated, said combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0147] According to this aspect of the invention, the therapeutic effects of the present invention on 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, pulmonary arthritis, pulmonary edema, pulmonary fibrosis ... Pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-related arthritis, infection-related endotoxic shock, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, heart disease including giant cell arteritis, graft-versus-host disease, myocardial infarction and ischemic diseases such as atherosclerosis, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barré syndrome, infections (viral, bacterial, fungal and parasitic), inflammatory bowel disease, intravascular coagulation , irritable bowel syndrome, hepatic fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic inflammatory disease, pain (especially pain related to inflammation), periodontitis, peritonitis, Peyronie's disease, pilonidal disease, 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 1 diabetes, ulcerative colitis, uveitis, vasculitis, dry eye syndrome, penetrating keratoplasty In accordance with the present invention, there is provided a combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, which combination is suitable for use in the prophylaxis or treatment of corneal surgery, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal and ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis.

[0148] Examples of these additional therapeutic agents are 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), and fluconazole. These may include, but are not limited to, thioguanine, hydroxyurea, dimethyl fumarate, JAK inhibitors including TYK2 inhibitors (such as ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, celdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, BMS-986165), and NSAIDs (such as naproxen and indomethacin).

[0149] In a further aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0150] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration.In one aspect of the present invention, "combination" refers to simultaneous administration.In another aspect of the present invention, "combination" refers to separate administration.In a further aspect of the present invention, "combination" refers to sequential administration.When administration is sequential or separate, the delay in administering the second component should not be such that the beneficial effect of the combination is lost.

[0151] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, in association with a pharmaceutically acceptable excipient or carrier.

[0152] The one or more additional therapeutic agents can include additional compounds of the invention. Thus, in one embodiment, 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.

[0153] The above-mentioned combinations are advantageously presented for use in the form of pharmaceutical formulations, and thus pharmaceutical formulations comprising a combination as defined above together with pharmaceutically acceptable excipients or carriers represent a further aspect of the present invention.

[0154] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0155] Such combination therapy employs the compounds of this invention within the dosage ranges described herein and the other pharmaceutically active agent within its approved dosage range or dosage as described in the relevant published literature.

[0156] General steps: Methods for preparing the compounds of the present invention are illustrated in the following examples. 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. If no reaction temperature is included, the reactions were carried out at ambient temperature (or room temperature), which is typically 17-27°C.

[0157] Those skilled in the art will recognize that reaction temperatures, reaction times, and amounts of reagents may vary from those described herein.

[0158] Compound names were generated using ChemDraw Professional version 20.0.0.41.

[0159] The compounds described in this invention 1When characterized by H NMR spectroscopy, spectra were recorded on a JEOL ECX300 (300 MHz), JEOL ECX400 (400 MHz), or Bruker Avance III Ultrashield 400 (400 MHz) instrument. Unless temperature is included, spectra were recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). The following abbreviations are used for NMR signal multiplicities: s = singlet, b = broadband, t = triplet, q = quartet, m = multiplet, and d = doublet.

[0160] Where the compounds described in this invention are characterized by LCMS data, retention times and molecular weights were determined using the conditions listed below.

[0161] 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 x 50 mm (Flow rate 0.8 mL / min). Run time: 1.30 min. Conditions: 10 mM ammonium bicarbonate pH 10 [Eluent C], MeCN [Eluent B]. Gradient: 2 to 98% B at 0.80 min, hold at 98% B until 1.30 min.

[0162] 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 x 50 mm (Flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: 10 mM ammonium bicarbonate pH 10 [Eluent C], MeCN [Eluent B]. Gradient: 2 to 98% B in 1.20 min, hold at 98% B until 1.40 min.

[0163] Method 3: Waters Acquity UPLC H-Class system (Quaternary pump with PDA (210-350 nm) and QDa mass detector). Column: BEHC18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: Water [Eluent A], MeCN [Eluent B], 2% ammonia in water [Eluent C; 5% throughout]. Gradient: 2 to 95% B and 5% C with A at 4.0 min, hold at 95% B 5% C until 4.60 min, column temperature 40 °C.

[0164] Method 4: Waters Acquity UPLC H-Class system (Quaternary pump with PDA (210-350 nm) and QDa mass detector). Column: BEHC18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: Water [Eluent A], MeCN [Eluent B], 2% ammonia in water [Eluent C; 5% throughout]. Gradient: 2 to 95% B and 5% C with A in 1.2 min, hold at 95% B 5% C until 1.40 min, column temperature 40 °C.

[0165] 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 x 50 mm (Flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: 10 mM ammonium bicarbonate pH 10 [Eluent C], MeCN [Eluent B]. Gradient: 2 to 98% B in 4.0 min, hold at 98% B until 4.60 min.

[0166] 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 x 50 mm (flow rate 0.8 mL / min). Run time: 4.6 min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2 to 98% B in 4.0 min, hold at 98% B until 4.60 min. Column temperature: 40 °C.

[0167] 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 x 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 at 4.50 min, hold at 95% C until 5.00 min, column temperature 40 °C.

[0168] 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 to 98% B in 1.2 min, hold at 98% B until 1.40 min. Column temperature: 40 °C.

[0169] 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 x 50 mm (Flow rate 0.7 mL / min). Run time: 5.00 min. Conditions: Water + 0.1% formic acid [Eluent A], MeCN + 0.1% formic acid [Eluent B]. Gradient: 2 to 95% B at 4.50 min, hold at 95% B until 5.00 min.

[0170] 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 x 50 mm (flow rate 0.8 mL / min). Run time: 4.80 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2 to 98% B in 4.0 min, hold at 98% B until 4.70 min.

[0171] 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 at 4.50 min, hold at 95% B until 5.00 min, column temperature 40 °C.

[0172] 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 to 95% B in 4.0 min, hold at 95% B until 4.60 min, column temperature 40 °C.

[0173] 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 to 95% B in 4.0 min, hold at 95% B until 4.60 min, column temperature 40 °C.

[0174] Method 14: Agilent 6140 Series Quadrupole Mass Spectrometer with Multimode Source (Monitoring 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 to 100% B in 3.75 min.

[0175] Method 15: Agilent 6140 Series Quadrupole Mass Spectrometer with Multimode Source (Monitoring 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 to 100% B in 5.5 min.

[0176] Method 16: Agilent 6140 Series Quadrupole Mass Spectrometer with Multimode Source (Monitoring 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 to 100% B in 3.5 min.

[0177] 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 to 95% B in 4.0 min, hold at 95% B until 4.60 min. Column temperature: 40 °C.

[0178] 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 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [Eluent A], MeCN [Eluent B], 2% ammonia in water [Eluent C; 5% throughout]. 2 to 95% B over 4.5 min, hold at 95% B until 5.00 min, column temperature 40 °C.

[0179] Method 19: Agilent 6140 Series Quadrupole Mass Spectrometer with Multimode Source (Monitoring 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 to 95% B in 5 min.

[0180] 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 x 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: 50-95% B and 5% C with A in 1.2 min, hold at 95% B 5% C until 1.40 min, column temperature 40 °C.

[0181] 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 min, 95% B at 4.0 min, hold at 95% B until 4.60 min, column temperature 40 °C.

[0182] 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 x 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 to 50% B and 5% C with A at 1.0 min, 95% B at 1.8 min, hold at 95% B 5% C until 2.0 min, column temperature 40 °C.

[0183] 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.

[0184] 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 at 1.00 min, hold at 98% B until 1.80 min, column temperature 40 °C.

[0185] Method 25: Agilent 1260. Column: Exselect 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.

[0186] Method 26: Agilent 1260 (binary 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% NH3 in water [eluent A], MeCN [eluent B] (flow rate 1.35 mL / min). Gradient: 5 to 100% B in 2.5 min, hold at 100% B for 3 min. Column temperature: 40 °C.

[0187] 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% HCl in water.acid [Eluent A], MeCN [Eluent B] (flow rate 1.35 mL / min). Gradient: 5 to 100% B in 2.5 min, held at 100% B for 3 min. Column temperature 40°C.

[0188] 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.

[0189] Method 29: Agilent 1260 (Agilent VWD or DAD detector and Agilent MSD detector at 254 nm). 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.

[0190] Preparative HPLC was performed using various preparative or mass-directed automated preparative (MDAP) systems with variable wavelength UV detection as listed below:

[0191] Method 1: Waters Fraction Lynx Preparative HPLC System (2545 Pump, 2998 UV / VIS Detector, 2767 Liquid Handler) with Waters 3100 Mass Detector. Column: Waters Crossbridge OBD C18 Column, Exselect 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 hydroxide (0.1%) as specified. Gradient as specified.

[0192] 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 Crossbridge Preparative OBD C18, 5 μm, 19 mm ID x 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. Fractions from the HPLC were collected using UV detection, e.g., 254 nM.

[0193] Method 3: Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515ACD Pump, Waters 2998 Photodiode Array Detector) using a Waters Crossbridge Preparative OBD C18, 5 μm, 19 mm ID x 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. Fractions from the HPLC were collected using UV detection, e.g., 254 nM.

[0194] Method 4: Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluid Organizer, Waters 515ACD Pump, Waters 2998 Photodiode Array Detector) using a Waters Crossbridge Preparative OBD C18, 5 μm, 19 mm ID x 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. Fractions from the HPLC were collected using UV detection, e.g., 254 nM.

[0195] Method 5: A Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidic Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) was used, using a Waters Ecselect CSH C18 ODB Preparative Column, 130 Å, 5 μm, 30 mm x 100 mm, eluting with a 0.1% formic acid-MeCN gradient in water over 12.5 min at a flow rate of 40 mL / min. The at-column dilution pump provided 2 mL / min MeCN throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0–0.5 min, 25% MeCN; 0.5–10.5 min, ramp from 25% MeCN to 55% MeCN; 10.5–10.6 min, ramp from 55% MeCN to 100% MeCN; 10.6–12.5 min, hold at 100% MeCN. UV detection across all wavelengths using PDA as well as QDA and ELS detectors.

[0196] Method 6: A Waters HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidic Organizer, Waters 515 ACD Pump, Waters 2998 Photodiode Array Detector) was used, using a Waters Crossbridge BEH C18 ODB Preparative Column, 130 Å, 5 μm, 30 mm x 100 mm, eluting with a 0.3% ammonia-MeCN gradient in water over 12.5 min at a flow rate of 40 mL / min. The at-column dilution pump provided 2 mL / min MeCN throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0–0.5 min, 30% MeCN; 0.5–10.5 min, ramp from 30% MeCN to 60% MeCN; 10.5–10.6 min, ramp from 60% MeCN to 100% MeCN; 10.6–12.5 min, hold at 100% MeCN. UV detection across all wavelengths using PDA as well as QDA and ELS detectors.

[0197] Preparative supercritical fluid chromatography (SFC) was performed using a Waters 05962 fluid delivery module, a Waters 07419 autosampler, and a Waters 2489 UV / Vis detector. 、 The experiments were performed on a Waters Investigator SFC, consisting of a Waters 08005 column oven, a Waters 279002192 heat exchanger, a Waters ABPR-20A backpressure regulator, and a Waters 08127 fraction collection module. The general method used liquid CO2 (Airproducts) and appropriate modifiers as specified. UV detection was at 254 nM.

[0198] Abbreviation: [Table 1-1] [Table 1-2]

[0199] Intermediate 1: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15.6 g, 71.3 mmol, CAS: 214360-73-3), 5-bromo-1,6-dimethyl-pyridin-2-one (12.0 g, 59.4 mmol, CAS: 889865-54-7) and 2 M potassium carbonate (99 mL, 178 mmol) in degassed ethanol (300 mL) was added XPhos Pd G2 (0.47 g, 0.59 mmol) at room temperature. The reaction mixture was heated at 85 °C for 1 hour, then diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography (eluting with 60-100% EtOAc in heptane followed by 0-15% MeOH in EtOAc) to give the title compound (10 g). LCMS (Method 4): 0.46 min, 215.0 [M+H] +

[0200] Intermediate 1.1: 5-(4-amino-2-fluorophenyl)-1,6-dimethylpyridin-2(1H)-one A suspension of 5-bromo-1,6-dimethyl-pyridin-2-one (1.2 g, 5.8 mmol, CAS: 889865-54-7), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.4 g, 5.8 mmol, CAS: 819057-45-9), sodium carbonate (1.5 g, 14.6 mmol) and Pd(dppf)Cl (0.47 g, 0.58 mmol) in degassed water (10 mL) / 1,4-dioxane (40 mL) was heated at 80 °C for 4 hours. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude product was purified by flash column chromatography (eluted with 100% EtOAc) to give the title compound (0.43 g). LCMS (method 3): 1.07 min, 233.1[M+H] +

[0201] Intermediate 1.2: 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 potassium phosphate tripotassium (1.8 M in water, 1.5 mL, 2.7 mmol) was added XPhos (85 mg, 0.18 mmol) and XPhos Pd G2 (70 mg, 0.09 mmol), 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] +

[0202] Intermediate 1.3: 4-(4-aminophenyl)pyridin-2(1H)-one The title compound (80 mg) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (277 mg, 1.26 mmol, CAS: 214360-73-3), 4-bromo-1H-pyridin-2-one (0.2 g, 1.2 mmol, CAS: 36953-37-4), sodium carbonate (0.30 g, 2.9 mmol), and Pd(dppf)Cl (84 mg, 0.11 mmol) in degassed water (8 mL) / 1,4-dioxane (14 mL) according to the procedure described for Intermediate 1.1 at 80° C. for 2 h. 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] +

[0203] Intermediate 1.4: 4-(imidazo[1,2-a]pyridin-5-yl)aniline The title compound (61 mg) was prepared from 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), a 1.8 M aqueous solution of potassium phosphate tribasic (2.1 mL, 3.8 mmol) in degassed ethanol (7.6 mL), and XPhos Pd G2 (20 mg, 0.03 mmol) by microwave irradiation at 85 °C for 1 h according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (25 g silicycle silica column, eluting with 40 to 100% EtOAc in heptane). LCMS (method 4): 0.56 min, 210.1[M+H] +

[0204] Intermediate 1.6: 4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)aniline The title compound (1.1 g) was prepared from 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 (240 mg, 0.31 mmol), potassium phosphate tripotassium (4.2 g, 31 mmol) in ethanol (44 ml) by microwave irradiation at 80° C. for 1 hour according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (100 g silica column, eluting with 0-100% EtOAc in heptane). 1 H 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).

[0205] Intermediate 1.7: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethan-1-one Intermediate 1.7a: 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 hours, 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] +

[0206] Intermediate 1.7: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethan-1-one The title compound (0.2 g) was prepared from Intermediate 1.7a (0.34 g, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-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, 3.1 mL, 6.3 mmol) by heating at 100 °C for 2 h according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g Silicycle silica column, eluted with 0-20% MeOH in EtOAc). LCMS (Method 22): 0.66 min, 282.1 [M+H] +

[0207] Intermediate 1.8: 6'-amino-1,2-dimethyl-[3,3'-bipyridin]-6(1H)-one The title compound (0.23 g) was prepared from 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 potassium phosphate tribasic (1.8 M in water, 1.9 mL, 3.3 mmol) by microwave irradiation at 85° C. for 1 h according to the procedure described for Intermediate 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 1-40% MeCN / 0.1% ammonia in HO / 0.1% ammonia solution). LCMS (Method 4): 0.36 min, 216.1 [M+H] +

[0208] Intermediate 1.9: 3',5'-dimethyl-[3,4'-bipyridine]-6-amine The title compound (0.22 g) was prepared from 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 in water, 1.9 mL, 3.4 mmol) by microwave irradiation at 85° C. for 2 hours according to the procedure described for Intermediate 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 10-70% MeCN / 0.1% ammonia in HO / 0.1% ammonia solution). LCMS (Method 4): 0.49 min, 200.1 [M+H] +

[0209] Intermediate 1.17: 4-(3,5-dimethylpyridin-4-yl)aniline To a mixture of 4-chloro-3,5-dimethyl-pyridine (0.93 g, 6.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.4 g, 6.6 mmol), XPhos Pd G2 (52 mg, 0.07 mmol), and K2CO3 (2.7 g, 19.7 mmol), water (8.4 mL) and ethanol (17 mL) were added. The reaction mixture was degassed with argon and then stirred at 85 °C for 1 h. The mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera™ (4 g silica cartridge, eluted with 0-10% MeOH in DCM) to give the title compound (1.3 g). 1 H NMR (400 MHz, CDCl3) δ: 8.34 - 8.19 (m, 2H), 6.92 - 6.80 (m, 2H), 6.80 - 6.67 (m, 2H), 2.03 (t, 6H), NHs not observed.

[0210] Intermediate 1.18: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine Intermediate 1.18a: 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 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and brine. The organics were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluting with 0-30% EtOAc in heptane) to give the title compound (0.53 g).1 H 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).

[0211] Intermediate 1.18b: 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 from Intermediate 1.18a (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 potassium phosphate tribasic (1.8 M in water, 2.8 mL, 5.0 mmol) by heating at reflux for 19 hours according to the procedure described for Intermediate 1. 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] +

[0212] Intermediate 1.18: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine To a solution of intermediate 1.18b (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 an additional 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 to 100% EtOAc in heptane) to give the title compound (0.27 g). 1 H 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).

[0213] Intermediate 1.23: tert-butyl 4-(4-aminophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate To a mixture of 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), K2CO3 (0.4 g, 2.9 mmol) and Xphos Pd G2 (57 mg, 0.07 mmol) was added ethanol (2 mL) and water (0.5 mL). The reaction mixture was degassed with argon and then stirred at 85 °C for 1 hour. The mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera™ (40 g silica cartridge, eluting with 0-10% MeOH in DCM) to give the title compound (70 mg).1 H 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).

[0214] Intermediate 1.25: 5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.35 g) was prepared from 5-iodopyridin-2-amine (1.1 g, 5 mmol, CAS: 20511-12-0), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-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 potassium phosphate tribasic (1.8 M in water, 8.3 mL, 15 mmol) by heating to reflux for 20 hours according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluted with 0-10% MeOH in DCM). LCMS (Method 14): 1.06 min, 189.2 [M+H] +

[0215] Intermediate 1.44: 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) was 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 minutes, then tetrakis(triphenylphosphine)palladium(0) (0.33 g, 0.28 mmol) was added, and the reaction was heated at 120° C. for 20 hours. The reaction was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organics were washed with brine, then dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (100 g silica column, 0-100% EtOAc in heptane) to give the title compound (0.3 g). 1 H 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).

[0216] Intermediate 1.44a: 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), KCO (6.6 g, 48 mmol), and PEPPSI™-IPr catalyst (0.33 g, 0.28 mmol). The mixture was heated at 120° C. for 20 hours. The reaction was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The aqueous was extracted with EtOAc, and the combined organics were then washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 340 g, 0-70% EtOAc in heptane) to give the title compound (1.6 g). 1 H 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).

[0217] Intermediate 1.57: 6-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine The title compound (0.18 g) was prepared from 2-chloropyridin-5-amine (1 g, 7.8 mmol, CAS: 5350-93-6), (3,5-dimethylisoxazol-4-yl)boronic acid (3.8 mg, 27 mmol, CAS: 16114-47-9), Pd(dppf)Cl (0.57 g, 0.78 mmol), and sodium carbonate (3.3 g, 31 mmol) according to the procedure described for Intermediate 1.1, heated at 145 °C for 3 h by microwave irradiation. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 50 g, eluted with 5-100% MeCN in water buffer with 0.005 M NHOH). LCMS (Method 14): 1.21 min, 190.2 [M+H] +

[0218] Intermediate 1.59: 5-(5-methylpyrimidin-4-yl)pyridin-2-amine The title compound (0.24 g) was prepared from 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)Cl (0.14 g, 0.19 mmol) and sodium carbonate (0.62 mg, 5.8 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 3 hours. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 0-7% MeOH in DCM) and by flash column chromatography on a Biotage Isolera One™ (4 g silica column, 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).

[0219] Intermediate 1.61: 5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-amine The title compound (0.2 g) was prepared from 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)Cl (0.23 g, 0.28 mmol), and potassium carbonate (1.1 g, 8.3 mmol) according to the procedure described for Intermediate 1.1, heating at 120 °C for 1 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluting with 0-100% EtOAc in heptane). LCMS (Method 14): 1.18 min, 220.2 [M+H] +

[0220] Intermediate 1.62: 2-chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine Intermediate 1.62a: 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), acetohydrazide (0.98 g, 13.3 mmol, CAS: 1068-57-1) in acetonitrile (5 mL) was heated to 50° C. for 30 minutes, after which 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 to 120° C. for 20 hours and then concentrated in vacuo. The crude product was triturated with diethyl ether to give the title compound (0.72 g). LCMS (Method 14): 1.24 min, 205.2 [M+H] +

[0221] Intermediate 1.62b: 5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one To a solution of intermediate 1.62a (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 to 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 give 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).

[0222] Intermediate 1.62: 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 1.62b (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 / HO (1:1) was slowly added. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 0-10% MeOH in DCM) to give the title compound (0.41 g). LCMS (Method 14): 1.22 min, 209.2 [M+H] +

[0223] Intermediate 1.64: 6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-amine The title compound (0.91 g) was prepared 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 potassium phosphate tribasic (2.5 M aqueous solution; 6.6 mL, 16.6 mmol) by heating to reflux for 24 hours according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 10% MeOH in DCM). LCMS (Method 14): 1.22 min, 189.2 [M+H] +

[0224] Intermediate 1.65: 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.85 g) was prepared 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)Cl (0.19 mg, 0.27 mmol), and sodium carbonate (2.3 g, 21 mmol) according to the procedure described for Intermediate 1.1, heating at 120 °C for 16 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluting with 0-10% MeOH in DCM). LCMS (Method 19): 0.52 min, 189.2 [M+H]. +

[0225] Intermediate 1.66: 2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-amine The title compound (0.66 g) was prepared from 2-chloropyrimidin-5-amine (603 mg, 4.66 mmol, CAS: 56621-90-0), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.0 g, 4.7 mmol, CAS: 1047644-76-7), XPhos Pd G2 (73 mg, 0.09 mmol), and potassium phosphate tripotassium (2.5 M aqueous solution; 5.6 mL, 16.6 mmol) by heating to reflux for 24 hours according to the procedure described for Intermediate 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 10% MeOH in DCM). LCMS (Method 19): 1.25 min, 190.2 [M+H] +

[0226] Intermediate 1.69: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-amine Intermediate 1.69a: 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. under argon for 20 hours. The reaction was cooled to room temperature and then diluted with diethyl ether and washed with water and brine. The organics were dried over NaSO, 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).

[0227] Intermediate 1.69: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-amine The title compound (0.22 g) was prepared from Intermediate 1.69a (1.6 g, 7.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.9 g, 8.5 mmol, CAS: 827614-64-2), Pd(dppf)Cl (0.63 g, 0.78 mmol), and potassium carbonate (3.2 g, 23 mmol) according to the procedure described for Intermediate 1.1, heating at 120 °C for 1 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, 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)

[0228] Intermediate 1.70: 3'-Methoxy-2'-methyl-[3,4'-bipyridine]-6-amine The title compound (0.2 g) was prepared from 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)Cl (0.23 g, 0.32 mmol), and sodium carbonate (1.0 g, 9.5 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 3 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, 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).

[0229] Intermediate 1.71: 2',3'-dimethyl-[3,4'-bipyridine]-6-amine The title compound (0.5 g) was prepared from 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)Cl (0.2 g, 0.27 mmol), and sodium carbonate (0.85 g, 8.1 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 3 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, 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).

[0230] Intermediate 1.72: 2',5'-dimethyl-[3,4'-bipyridine]-6-amine The title compound (0.17 g) was prepared from 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)Cl (0.26 g, 0.35 mmol), and sodium carbonate (1.1 g, 10.6 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 20 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted 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).

[0231] Intermediate 1.76: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine Intermediate 1.76a: 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 EtN (1.3 mL, 9.3 mmol) were added, and the mixture was heated by microwave irradiation at 140 °C for 5 minutes. The mixture was concentrated in vacuo, and the residue was dissolved in DCM and HO. The phases were separated, and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over NaSO, 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).

[0232] Intermediate 1.76: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine The title compound (0.27 g) was prepared from Intermediate 1.76a (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) according to the procedure described for Intermediate 1.44a, heated at 130° C. for 2 hours. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-70% EtOAc in heptane) and reverse-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H] +

[0233] Intermediate 1.77: 4-(5-chloropyrazin-2-yl)-3,5-dimethylisoxazole The title compound (0.52 g) was prepared from 2-bromo-5-chloro-pyrazine (1 g, 5.2 mmol, CAS: 912773-21-8), (3,5-dimethylisoxazol-4-yl)boronic acid (1.1 g, 7.8 mmol, CAS: 16114-47-9), Pd(dppf)Cl (0.19 mg, 0.26 mmol), and sodium carbonate (2.2 g, 21 mmol) according to the procedure described for Intermediate 1.1, heating at 120 °C for 16 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluting with 0-10% MeOH in DCM). LCMS (Method 19): 2.09 min, 210.2 [M+H] +

[0234] Intermediate 1.80: 2-chloro-5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine The title compound (0.26 g) was prepared from 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) according to the procedure described for Intermediate 1.44a, heating at 130° C. for 2 hours. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluting with 0-70% EtOAc in heptane) and reverse-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6[M+H] +

[0235] Intermediate 1.81: 5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-amine The title compound (0.56 g) was prepared from 5-bromo-3-fluoro-pyridin-2-amine (1.0 g, 5.2 mmol, CAS: 748812-37-5), (3,5-dimethylisoxazol-4-yl)boronic acid (0.89 g, 6.3 mmol, CAS: 16114-47-9), Pd(dppf)Cl (0.19 g, 0.26 mmol), and sodium carbonate (0.22 g, 21 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 16 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (25 g silica column, eluting with 0-2% MeOH in DCM). LCMS (Method 14): 1.26 min, 208.2 [M+H] +

[0236] Intermediate 1.84: 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 1.44. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluted with 0-2% MeOH in DCM). LCMS (Method 14): 1.51 min, 209.2 [M+H] +

[0237] Intermediate 1.92: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine Intermediate 1.92a: 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 slowly added, and the mixture was stirred at −78° C. for 3 hours. 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 give 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).

[0238] Intermediate 1.92b: 4-cyclopropyl-1-methyl-1H-1,2,3-triazole To a stirred solution of intermediate 1.92a (2 g, 11.6 mmol) in MeOH (25 mL), 4-methylbenzenesulfonohydrazide (2.8 g, 15.1 mmol, CAS: 1576-35-8) was added, and the mixture was stirred at room temperature for 1 hour. An additional portion of 4-methylbenzenesulfonohydrazide (0.64 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, methanamine (1.3 mL, 15.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) were added, and the mixture was stirred at room temperature for 5 minutes and then heated at 140° C. for 5 minutes 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 a Biotage Isolera One™ (40 g silica column, 2-65% EtOAc in heptane) to give the title product (0.66 g). 1H 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).

[0239] Intermediate 1.92: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine To a solution of intermediate 1.92b (0.3 g, 2.4 mmol) in toluene (6.1 mL), 5-bromo-2-chloro-pyridine (1.4 g, 7.3 mmol, CAS: 53939-30-3), palladium(II) acetate (55 mg, 0.24 mmol), potassium carbonate (0.67 g, 4.9 mmol), and triphenylphosphine (0.13 g, 0.49 mmol) were added under argon. The reaction mixture was stirred at 120° C. for 40 hours. An additional portion 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-chloro-pyridine (0.47 g, 2.4 mmol) was added, and the reaction mixture was stirred at 120° C. for 72 hours. 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 a Biotage Isolera One™ (12 g silica column, 2-80% EtOAc in heptane) to give the title compound (0.22 g). 1 H 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).

[0240] Intermediate 1.93: 5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-amine The title compound (1.1 g) was prepared from 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 potassium phosphate tribasic (0.5 M aqueous solution; 25 mL, 13 mmol) by heating to 60 °C for 18 h according to the procedure described for Intermediate 1. 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).

[0241] Intermediate 1.98: 6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-amine The title compound (1g) was prepared from 6-bromo-5-fluoro-pyridin-3-amine (1g, 5.2mmol, CAS: 1256276-41-1), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.7g, 7.9mmol, CAS: 1047644-76-7), Pd(dppf)Cl (0.38g, 0.52mmol), and sodium carbonate (2.2g, 21mmol) according to the procedure described for Intermediate 1.1 and heated by microwave irradiation at 120°C for 1 hour. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20g silica column, 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).

[0242] Intermediate 1.109: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide Intermediate 1.109a: 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 hours and then concentrated in vacuo. The residue was diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, and the combined organics were washed with water, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluting with 0-10% MeOH in DCM) to give the title compound (0.7 g). LCMS (Method 14): 1.01 min, 169.2[M+H] +

[0243] Intermediate 1.109: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide A solution of intermediate 1.109a (0.64 g, 3.1 mmol), 5-bromo-2-chloro-pyridine (0.59 g, 3.1 mmol, CAS: 53939-30-3), 2,2-dimethylpropanoic acid (94 mg, 0.92 mmol), palladium(II) acetate (69 mg, 0.31 mmol) and potassium carbonate (0.85 g, 6.1 mmol) in DMA (12 mL) was heated at 120 °C for 1 h by microwave irradiation. The reaction mixture was cooled to room temperature, diluted with EtOAc and quenched with 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 a Biotage Isolera One™ (20 g silica column, 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).

[0244] Intermediate 1.112: 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)Cl (0.12 g, 0.16 mmol), and sodium carbonate (0.68 g, 6.5 mmol) according to the procedure described for Intermediate 1.1 and heated by microwave irradiation at 120 °C for 1 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 0-100% EtOAc in heptane, then 0-10% MeOH in DCM). LCMS (Method 14): 0.78 min, 200.2[M+H] +

[0245] Intermediate 1.114: 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, and 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)Cl (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]+

[0246] Intermediate 1.115: 5-(3,5-dimethylisothiazol-4-yl)pyridin-2-amine The title compound (0.14 g) was prepared from 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)Cl (59 mg, 0.08 mmol), and potassium carbonate (0.34 g, 2.5 mmol) according to the procedure described for Intermediate 1.1, heating at 100 °C for 18 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, 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).

[0247] Intermediate 1.126: 6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-amine To a stirred solution of 6-chloropyridin-3-amine (0.1 g, 0.8 mmol, CAS: 5350-93-6) and 2-[[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-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), water (1 mL), Pd-170 (26 mg, 0.04 mmol), and potassium carbonate (0.24 g, 1.7 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. 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 a Teledyne ISCO CombiFlash® (12 g silica column, eluting with 0-100% 3:1 EtOAc:EtOH in isohexane) to give the title compound as a brown oil (0.21 g). LCMS (Method 28): 1.42 min, 319.5 [M+H] +

[0248] Intermediate 1.133: 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 1.126. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluted with 0-10% MeOH in DCM). LCMS (Method 29): 0.44 min, 230.2 [M+H] +

[0249] Intermediate 1.135: 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 1.126. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluted with 0-10% MeOH in DCM). LCMS (Method 26): 0.53 min, 203.2 [M+H] +

[0250] Intermediate 1.138: 5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-amine The title compound (0.45 g) was prepared from 5-iodo-1-methyl-4-(trifluoromethyl)-1H-pyrazole (0.75 g, 2.7 mmol, CAS: 2137730-49-3), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.82 g, 3.3 mmol, CAS: 827614-64-2), Pd(dppf)Cl (0.2 g, 0.27 mmol) and potassium carbonate (1.1 g, 8.2 mmol) according to the procedure described for Intermediate 1.1, heating at 80 °C for 18 hours. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (50 g silica column, eluting with 2-4% MeOH in DCM) followed by an SCX cartridge (10 g, washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 14): 1.18 min, 243.2 [M+H] +

[0251] Intermediate 2: 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 To a solution of Intermediate 1 (79 mg, 0.37 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (50 mg, 0.18 mmol, CAS: 1187224-06-1, prepared according to the method described in WO2020011731) and triethylamine (0.1 mL, 0.55 mmol) in EtOAc (0.74 mL) and acetonitrile (0.49 mL) was added a 50% w / w T3P® solution in EtOAc (0.33 mL, 0.55 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred for 4 hours, then diluted with saturated aqueous NaHCO and extracted into EtOAc (×2). The combined organics were dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 10% MeOH in EtOAc) to give the title compound (55 mg). LCMS (Method 4): 0.97 min, 468.3 [M+H] +

[0252] Intermediate 2.1: 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 1.1 (0.4 g, 1.7 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.27 g, 0.98 mmol, CAS: 1187224-06-1), triethylamine (0.54 mL, 3.9 mmol), and T3P® (50% w / w solution in EtOAc; 2.5 mL, 3.9 mmol) according to the procedure described for Intermediate 2. The crude product was purified by automated reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 60 g, pH 11 0.1% ammonia / MeCN in 0.1% ammonia / H2O). LCMS (Method 4): 1.06 min, 486.2 [M+H] +

[0253] Intermediate 2.2: 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 To a stirred solution of intermediate 1.2 (86 mg, 0.38 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.1 g, 0.38 mmol, CAS: 1187224-06-1) and triethylamine (0.48 mL, 3.4 mmol) in DMF (4.3 mL) at room temperature, HATU (0.52 g, 1.4 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 5% MeOH in DCM) to give the title compound (0.12 g). LCMS (Method 3): 2.39 min, 479.3 [M+H] +

[0254] Intermediate 2.3: 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 1.3 (60 mg, 0.32 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (87 mg, 0.32 mmol, CAS: 1187224-06-1), HATU (0.14 g, 0.35 mmol) and triethylamine (0.09 mL, 0.64 mmol) according to the procedure described for Intermediate 2.2. The crude product was purified by flash column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 3): 2.26 min, 440.3 [M+H] +

[0255] Intermediate 2.4: 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 1.4 (56 mg, 0.24 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (64 mg, 0.24 mmol, CAS: 1187224-06-1), triethylamine (0.12 mL, 0.89 mmol), and T3P® (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol) according to the procedure described for intermediate 2. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (25 g Silacycle silica column, eluting with 30-100% EtOAc in heptane). LCMS (Method 4): 1.03 min, 463.3 [M+H] +

[0256] Intermediate 2.6: 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 1.6 (0.35 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.31 g, 1.1 mmol, CAS: 1187224-06-1), HATU (0.52 mg, 1.4 mmol), and triethylamine (0.48 mL, 3.4 mmol) according to the procedure described for Intermediate 2.2, except in an EtOAc / MeCN (2:1) solvent mixture. The crude product was 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] +

[0257] Intermediate 2.7: 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. 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] +

[0258] Intermediate 2.8: 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 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.13 g, 0.47 mmol, CAS: 1187224-06-1) and DIPEA (0.28 mL, 1.6 mmol) in 1,2-dichloroethane (4.2 mL) was added BTFFH (0.17 g, 0.54 mmol) and the reaction mixture was stirred at room temperature under argon for 1 hour. Intermediate 1.8 (78 mg, 0.36 mmol) was added and the reaction mixture was heated at 80° C. in a microwave for 2 hours. The reaction mixture was diluted with water and brine and extracted three times into DCM. The combined organics were dried over NaSO, filtered and concentrated in vacuo. 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 / H2O pH 11 0.1% ammonia / MeCN) to give the title compound (18 mg). LCMS (Method 4): 0.95 min, 469.3 [M+H] +

[0259] Intermediate 2.9: 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 1.9 (0.11 g, 0.55 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.18 g, 0.66 mmol, CAS: 1187224-06-1), DIPEA (0.43 mL, 2.5 mmol), and BTFFH (0.21 g, 0.66 mmol) according to the procedure described for Intermediate 2.8. The crude product was purified by MDAP (Method 1: 20-90% MeCN in 0.1% NH4OH). LCMS (Method 4): 1.07 min, 453.3 [M+H] +

[0260] Intermediate 2.12: 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 2.2, except in an EtOAc / MeCN (2:1) solvent mixture. The crude product was used directly. LCMS (Method 12) 2.83 min, 331.2 [M-Boc+H] +

[0261] Intermediate 2.13: 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. The crude product was used directly without further purification. LCMS (Method 4): 0.94 min, 347.0 [M-Boc+H] +

[0262] Intermediate 2.14: 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 4-(3,6-dihydro-2H-pyran-4-yl)aniline (0.1 g, 0.57 mmol, CAS: 1039053-21-8) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.16 g, 0.57 mmol, CAS: 1187224-06-1), triethylamine (0.24 mL, 1.7 mmol), and 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™ (25 g Siliacycle silica column, eluting with 10 to 100% EtOAc in heptane). LCMS (method 4): 1.10 min, 329.2 [M-Boc+H] +

[0263] Intermediate 2.15: 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. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluting with 0-25% EtOAc in heptane). 1 H 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).

[0264] Intermediate 2.16: 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) was added EEDQ (84 mg, 0.35 mmol) under an argon atmosphere. The mixture was stirred for 64 h, concentrated in vacuo, and then partitioned between EtOAc and saturated NaHCO. The organics were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (5 g silica column, eluted with 0% to 50% EtOAc in heptane) to give the title compound (23 mg). LCMS (Method 14): 2.02 min, 443.3[M+H] +

[0265] Intermediate 2.18: 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 1.18 (50 mg, 0.16 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (53 mg, 0.19 mmol, CAS: 1187224-06-1) and EEDQ (60 mg, 0.24 mmol) according to the procedure described for Intermediate 2.16. An additional portion of EEDQ (60 mg, 0.24 mmol) was added and the mixture was stirred for an additional 24 h before workup. The crude product was purified by flash column chromatography (4 g silica column, eluted with 0-25% EtOAc in heptane). LCMS (Method 14): 2.09 min, 562.2 [M+H] +

[0266] Intermediate 2.25: 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 1.25 (65 mg, 0.35 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.11 g, 0.41 mmol, CAS: 1187224-06-1) and EEDQ (0.13 g, 0.52 mmol) according to the procedure described for intermediate 2.16. The crude product was purified by flash column chromatography (5 g silica column, eluted with 20-80% EtOAc in heptane). LCMS (Method 14): 1.99 min, 442.2 [M+H] +

[0267] Intermediate 2.27: 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 (110 mg, 0.58 mmol, CAS: 1177269-12-3), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (150 mg, 0.58 mmol, CAS: 109183-71-3), IIDQ (354 mg, 1.17 mmol), and DIPEA (0.41 mL, 2.3 mmol) according to the procedure described for Intermediate 2.16, except that IIDQ (0.35 g, 1.2 mmol) was used with heating at 90° C. for 16 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluting with 0 to 100% EtOAc in heptane). LCMS (Method 14): 1.99 min, 429.2 [M+H] +

[0268] Intermediate 2.34: 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 2.16. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluted with 0-3% MeOH in DCM). LCMS (Method 14): 2.00 min, 443.2 [M+H] +

[0269] Intermediate 2.38: 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 (0.18 g, 0.86 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.2 g, 0.78 mmol, CAS: 109183-71-3), DIPEA (0.2 g, 1.6 mmol) and HATU (0.4 g, 1.1 mmol) according to the procedure described for Intermediate 2.2. The crude product was used directly. LCMS: (Method 14) 1.75 min, 454.2 [M+H] +

[0270] Intermediate 2.44: 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 1.44 (0.12 g, 0.62 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 g, 0.56 mmol, CAS: 1187224-06-1) in anhydrous DMF (0.77 mL), DIPEA (0.15 g, 1.1 mmol) and HATU (0.3 g, 0.79 mmol) were added under an argon atmosphere. The mixture was heated at 50° C. for 44 hours. The reaction mixture was diluted with MeOH (1 mL) and then purified by reverse-phase column chromatography on a Biotage Isolera One™ (30 g KP-C18_HS Biotage SNAP cartridge, eluting with 5-100% MeCN in water buffer with 0.005 M NH4OH) to give the title compound (35 mg). LCMS: (Method 14) 1.83 min, 443.3 [M+H] + .

[0271] Alternative route to intermediate 2.44: 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 2.44a: 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 hours. 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 give the title compound (0.85 g). 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).

[0272] Intermediate 2.44: 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 suspension of Intermediate 1.44a (0.3 g, 1.5 mmol) and Intermediate 2.44a (0.27 g, 1.0 mmol) in degassed anhydrous 1,4-dioxane (14 mL) was added Xantphos (58 mg, 0.1 mmol) and CsCO (0.98 g, 3 mmol). The mixture was degassed with argon for 5 minutes, after which 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 to 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 NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica, 30-100% EtOAc in heptane) to give 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).

[0273] Intermediate 2.51: tert-butyl (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate To a solution of intermediate 1.25 (0.62 g, 3.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.4 g, 1.6 mmol, CAS: 1228542-19-5) and DIPEA (0.4 g, 3.1 mmol) in anhydrous DMF (2.6 mL) was added HATU (0.83 mg, 2.2 mmol) under an argon atmosphere. The mixture was heated at 50 °C for 24 hours. The mixture was partitioned between EtOAc and water, and the aqueous 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 a Biotage Isolera One™ (40 g silica column, eluted with 0 to 50% EtOAc in heptane) to give the title compound (0.28 g). LCMS: (Method 14): 1.85 min, 442.2 [M+H] +

[0274] Intermediate 2.54: 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 2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-amine (0.18 g, 0.95 mmol, CAS: 1094246-50-0), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 mg, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.14 g, 1.1 mmol) and HATU (0.29 g, 0.77 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 30% EtOAc in heptane). LCMS (Method 14): 1.93 min, 443.2 [M+H] +

[0275] Intermediate 2.57: 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 1.57 (0.18 g, 0.95 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 mg, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.14 g, 1.1 mmol) and HATU (0.29 g, 0.77 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 30% EtOAc in heptane). LCMS (Method 14): 1.93 min, 443.2 [M+H] +

[0276] Intermediate 2.59: 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 1.59 (0.24 g, 1.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.17 g, 0.62 mmol, CAS: 1187224-06-1), DIPEA (0.16 g, 1.2 mmol) and HATU (0.33 g, 0.87 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 0-3% MeOH in DCM). LCMS (Method 14): 1.88 min, 440.2 [M+H] +

[0277] Intermediate 2.61: 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 1.61 (0.2 g, 0.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.16 g, 0.6 mmol, CAS: 1187224-06-1), DIPEA (0.17 mg, 1.2 mmol) and HATU (0.32 g, 0.84 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 0-50% EtOAc in heptane). LCMS (Method 14): 1.99 min, 473.2 [M+H] +

[0278] Intermediate 2.62a: 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, 2.8 mmol) at 0° C., followed by the dropwise addition of isobutyl chloroformate (176 mg, 1.29 mmol). The mixture was stirred at 0° C. for 30 minutes, and 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, and the combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude product was triturated with diethyl ether to give the title compound (75 mg). 1 H 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).

[0279] Intermediate 2.62: 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 1.62 (35 mg, 0.17 mmol), Intermediate 2.62a (30 mg, 0.11 mmol) in degassed anhydrous 1,4-dioxane (1.4 mL) was added Xantphos (6.4 mg, 11 μmol) and CsCO (109 mg, 0.33 mmol). The mixture was degassed with argon for 5 minutes, after which tris(dibenzylideneacetone)dipalladium(0) (5.1 mg, 6 μmol) 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 NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluting with 0-10% MeOH in DCM) to give the title compound (40 mg). LCMS (Method 19): 2.36 min, 443.2 [M+H] +

[0280] Intermediate 2.63: 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 1.25 (0.39 g, 2.1 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (0.17 g, 0.62 mmol, CAS: 394735-65-0), DIPEA (0.26 g, 2.1 mmol), and HATU (0.55 g, 1.4 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-2% MeOH in DCM) followed by an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 14): 2.56 min, 464.2 [M+H] +

[0281] Intermediate 2.64: 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 1.64 (0.31 g, 1.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.22 g, 0.81 mmol, CAS: 1187224-06-1), DIPEA (0.21 g, 1.6 mmol) and HATU (0.46 g, 1.2 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 100% EtOAc in heptane). LCMS (Method 19): 2.73 min, 442.2 [M+H] +

[0282] Intermediate 2.65: 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 1.65 (0.21 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.2 g, 0.74 mmol, CAS: 1187224-06-1), DIPEA (0.19 g, 1.5 mmol) and HATU (0.39 g, 1.0 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluted with 0-12% MeOH in DCM). LCMS (Method 14): 1.92 min, 442.2 [M+H] +

[0283] Intermediate 2.66: tert-butyl ((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.50 g) was prepared from intermediate 1.66 (0.49 g, 2.6 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.35 g, 1.3 mmol, CAS: 1187224-06-1), DIPEA (0.45 mL, 2.6 mmol) and HATU (0.69 g, 1.8 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluted with 100% EtOAc in heptane). LCMS (Method 19): 2.82 min, 443.2 [M+H] +

[0284] Intermediate 2.67: tert-butyl (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (0.18 g) was prepared from Intermediate 1.44a (0.3 g, 1.5 mmol), Intermediate 2.62a (0.27 g, 1.0 mmol), Xantphos (58 mg, 0.10 mmol), CsCO (976 mg, 3.00 mmol), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) in a similar procedure to Intermediate 2.62a. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica 20 g, 50-100% EtOAc in heptane). LCMS (Method 19): 1.62 min, 443.2 [M+H] +

[0285] Intermediate 2.69: tert-butyl (S)-(1-cycloheptyl-2-((5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (90 mg) was prepared from Intermediate 1.69 (0.13 g, 0.61 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.11 g, 0.41 mmol, CAS: 1228542-19-5), DIPEA (0.14 mL, 0.81 mmol), and HATU (0.21 g, 0.57 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, eluted with 0-60% EtOAc in heptane). LCMS (Method 19): 2.89 min, 473.2 [M+H] +

[0286] Intermediate 2.70: tert-butyl ((S)-2-((3'-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.11 g) was prepared from Intermediate 1.70 (0.18 g, 0.83 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 g, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.19 mL, 1.1 mmol) and HATU (0.29 g, 0.77 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-2% MeOH in DCM) followed by an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 19): 2.40 min, 469.2 [M+H] +

[0287] Intermediate 2.71: tert-butyl ((S)-2-((2',3'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.19 g) was prepared from Intermediate 1.71 (0.26 g, 1.3 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.18 g, 0.65 mmol, CAS: 1187224-06-1), DIPEA (0.17 g, 1.3 mmol) and HATU (0.34 g, 0.9 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-2% MeOH in DCM) followed by an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). LCMS (Method 14): 1.54 min, 453.2 [M+H] +

[0288] Intermediate 2.72: tert-butyl ((S)-2-((2',5'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (102 mg) was prepared from intermediate 1.72 (171 mg, 0.86 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (155 mg, 0.57 mmol, CAS: 1187224-06-1), DIPEA (0.3 mL, 1.71 mmol) and HATU (304 mg, 0.80 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluting with 0-10% MeOH in DCM) followed by ion exchange (SCX elution with MeOH followed by 2 M ammonia in MeOH). LCMS (Method 14): 1.57 min, 453.2 [M+H] +

[0289] Intermediate 2.76: tert-butyl (S)-(1-cycloheptyl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (31 mg) was prepared from Intermediate 1.76 (0.27 g, 1.2 mmol), Intermediate 2.62a (0.22 g, 0.81 mmol), Xantphos Pd G3 (39 mg, 0.04 mmol), and Cs2CO3 (0.8 g, 2.4 mmol) in a procedure similar to Intermediate 2.62. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 0-100% EtOAc in heptane). LCMS (Method 14): 1.87 min, 457.2 [M+H] +

[0290] Intermediate 2.77: tert-butyl (S)-(1-cycloheptyl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (31 mg) was prepared from Intermediate 1.7 (0.2 g, 0.96 mmol), Intermediate 2.62a (0.2 g, 0.74 mmol), Xantphos Pd G3 (70 mg, 0.07 mmol) and Cs2CO3 (0.72 g, 2.2 mmol) in a procedure similar to Intermediate 2.62. The crude product was used directly. LCMS (Method 14): 1.87 min, 457.2 [M+H] +

[0291] Intermediate 2.80: tert-butyl (S)-(1-cycloheptyl-2-((5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (18 mg) was prepared from Intermediate 1.80 (0.15 g, 0.67 mmol), Intermediate 2.62a (0.14 g, 0.52 mmol), Xantphos Pd G3 (49 mg, 0.05 mmol), and Cs2CO3 (0.5 g, 1.5 mmol) in a procedure similar to Intermediate 2.62. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica, 0-100% EtOAc in heptane). LCMS (Method 14): 1.98 min, 469.2 [M+H] +

[0292] Intermediate 2.81: tert-butyl (S)-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (23 mg) was prepared from Intermediate 1.81 (0.34 g, 1.7 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), DIPEA (0.39 mL, 2.2 mmol), and HATU (0.5 g, 1.3 mmol) according to the procedure described for Intermediate 2.51. An additional portion of (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), HATU (0.5 g, 1.3 mmol), and DIPEA (0.39 mL, 2.2 mmol) was added, and the reaction was stirred at 50° C. for an additional 24 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluting with 0-30% EtOAc in heptane). LCMS (Method 14): 1.97 min, 461.2 [M+H] +

[0293] Intermediate 2.84: tert-butyl (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino)-2-oxoethyl)carbamate The title compound (59 mg) was prepared from Intermediate 1.84 (0.14 g, 0.67 mmol), Intermediate 2.62a (0.12 g, 0.44 mmol), Xantphos (26 mg, 0.044 mmol), CsCO (0.43 g, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol) according to the procedure described for Intermediate 2.62. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica 12 g, 0-3% MeOH in DCM). LCMS (Method 14): 1.86 min, 443.2 [M+H] +

[0294] Intermediate 2.85: tert-butyl (S)-(1-cycloheptyl-2-((5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (30 mg) was prepared from 5-(4-benzyloxy-2-methyl-pyrazol-3-yl)pyridin-2-amine (35 mg, 0.12 mmol, CAS: 2151907-63-8), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (50 mg, 0.18 mmol, CAS: 1228542-19-5), DIPEA (0.06 mL, 0.37 mmol), and HATU (77 mg, 0.2 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluted with 0-50% EtOAc in heptane). LCMS (Method 14): 2.13 min, 534.2 [M+H] +

[0295] Intermediate 2.88: tert-butyl (S)-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate The title compound (0.48 g) was prepared from Intermediate 1.57 (0.42 g, 2.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), DIPEA (0.39 mL, 2.2 mmol), and HATU (0.63 g, 1.7 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 0-100% EtOAc in heptane). LCMS (Method 14): 2.00 min, 443.2 [M+H] +

[0296] Intermediate 2.92: tert-butyl (S)-(1-cycloheptyl-2-((5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (51 mg) was prepared from Intermediate 1.92 (88 mg, 0.33 mmol), Intermediate 2.62a (80 mg, 0.3 mmol), Xantphos (17 mg, 0.03 mmol), CsCO (0.29 g, 0.89 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol) according to the procedure described for Intermediate 2.62. An additional portion of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol), Xantphos (17 mg, 0.03 mmol), and CsCO (0.29 g, 0.89 mmol) was added, and the mixture was stirred at 100 °C for 18 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 2-80% EtOAc in heptane). LCMS (Method 19): 2.81 min, 469.2 [M+H] +

[0297] Intermediate 2.93: tert-butyl (S)-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)carbamate The title compound (0.72 g) was prepared from Intermediate 1.93 (1.1 g, 5.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.8 g, 2.9 mmol, CAS: 1228542-19-5), DIPEA (1.0 mL, 5.9 mmol), and HATU (1.6 g, 4.2 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (100 g silica column, eluted with 0-100% EtOAc in heptane). LCMS (Method 19): 2.96 min, 462.2 [M+H] +

[0298] Intermediate 2.96: tert-butyl (S)-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (0.5 g) was prepared from intermediate 1.25 (0.79 g, 4.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.54 g, 2.1 mmol, CAS: 109183-71-3), DIPEA (0.73 mL, 4.2 mmol), and HATU (1.1 g, 2.9 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (100 g silica column, eluted with 100% EtOAc). 1H NMR (400 MHz, CDCl3) δ: 8.65 (s, 1H), 8.37 (dd, 1H), 8.25 (dd, 1H), 7.67 (dd, 1H), 7.40 (d, 1H), 5.08 (s, 1H), 4.12 (m, 1H), 3.77 (s, 3H), 2.01 (d, 3H), 1.77 (s, 3H), 1.66 (s, 2H), 1.47 (s, 9H), 1.26 - 1.18 (m, 3H), 1.18 - 1.01 (m, 3H).

[0299] Intermediate 2.98: tert-butyl ((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.49 g) was prepared from intermediate 1.98 (0.79 g, 3.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.5 g, 1.8 mmol, CAS: 1187224-06-1), DIPEA (0.64 mL, 3.7 mmol), and HATU (1.1 g, 2.8 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 0-100% EtOAc in heptane). LCMS (Method 14): 2.02 min, 460.2 [M+H] +

[0300] Intermediate 2.101: tert-butyl (S)-(2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)carbamate Intermediate 2.101a: tert-butyl (S)-(1-cycloheptyl-2-oxo-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)ethyl)carbamate The title compound (0.59 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.81 g, 3.7 mmol, CAS: 827614-64-2), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.5 g, 1.8 mmol, CAS: 1228542-19-5), DIPEA (0.64 mL, 3.7 mmol), and HATU (2 g, 2.6 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluted with 2-80% EtOAc in heptane). LCMS (Method 15): 2.36 min, 392.2 [M-C6H 14 +H] +

[0301] Intermediate 2.101b: 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole To a solution of (5-bromo-1-methyl-1H-pyrazol-4-yl)methanol (0.38 g, 2 mmol, CAS: 1415638-13-9) in DMF (15 mL) was added tert-butyldimethylsilyl chloride (0.36 g, 2.4 mmol), followed by imidazole (0.34 g, 5 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 2-40% EtOAc in heptane) to give the title compound (0.54 g). 1H NMR (400 MHz, CDCl3) δ: 7.50 (s, 1H), 4.52 (s, 2H), 3.86 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H)

[0302] Intermediate 2.101: tert-butyl (S)-(2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)carbamate The title compound (0.11 g) was prepared from Intermediate 2.101a (0.12 mg, 0.24 mmol), Intermediate 2.101b (89 mg, 0.29 mmol), Pd(dppf)Cl (20 mg, 0.02 mmol), and potassium carbonate (0.1 g, 0.73 mmol) according to the procedure described for Intermediate 1.1, heating at 100 °C for 18 h. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluting with 2-70% EtOAc in heptane). LCMS (Method 15): 3.47 min, 572.2 [M+H] +

[0303] Intermediate 2.102: tert-butyl (S)-(1-cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (48 mg) was prepared from Intermediate 1.25 (0.1 g, 0.53 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclopentyl-acetic acid (0.14 g, 0.56 mmol, CAS: 109183-72-4), DIPEA (0.19 mL, 1.1 mmol), and HATU (0.3 g, 0.8 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluting with 0-100% EtOAc in isohexane). LCMS (Method 25): 2.26 min, 414.3 [M+H] +

[0304] Intermediate 2.103: tert-butyl (1-(bicyclo[2.2.1]heptan-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (60 mg) was prepared from Intermediate 1.25 (77 mg, 0.41 mmol), 2-(tert-butoxycarbonylamino)-2-norbornan-2-yl-acetic acid (0.1 g, 0.37 mmol, CAS: 182292-11-1), DIPEA (0.13 mL, 0.74 mmol), and HATU (0.21 g, 0.56 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluting with 0-100% EtOAc in isohexane). LCMS (Method 26): 1.50 min, 440.20 [M+H] +

[0305] Intermediate 2.104: tert-butyl (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)carbamate Intermediate 2.104a: 5-((1r,4r)-4-(trifluoromethyl)cyclohexyl)imidazolidine-2,4-dione A solution of trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (0.93 g, 5.2 mmol, CAS: 133261-34-4), sodium cyanide (0.51 g, 10.3 mmol), and ammonium carbonate (1.5 g, 15.5 mmol) in MeOH (3 mL) and then water (3 mL) was degassed with argon and heated at 60 °C for 48 h. The reaction mixture was cooled to room temperature and carefully quenched with HCl (1 M aqueous solution; 8 mL). HCl (5 M aqueous solution) was carefully added until the pH was approximately 4-5. The mixture was filtered, and the solid was washed with water to give the title compound (0.73 g). LCMS (Method 19): 1.82 min, 249.2 [MH] -

[0306] Intermediate 2.104b: 2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-2-ureidoacetic acid A solution of intermediate 2.104a (0.73 g, 2.9 mmol) in sodium hydroxide (5 M aqueous solution; 3.8 mL, 18.9 mmol) was heated to reflux for 18 hours. The reaction was cooled to room temperature and the pH was adjusted to approximately 5-6 by dropwise addition of HCl (5 M aqueous solution). The mixture was filtered and the solid was triturated with diethyl ether to give the title compound (0.3 g). LCMS (Method 14): 1.46 min, 269.2 [M+H] +

[0307] Intermediate 2.104c: 2-((tert-butoxycarbonyl)amino)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)acetic acid To a suspension of intermediate 2.104b (0.3 g, 1.1 mmol) in water (3.4 mL) was added sodium hydroxide (6 M aqueous solution; 0.56 mL, 3.4 mmol). The mixture was heated at 110° C. for 48 h. An additional portion of sodium hydroxide (134 mg, 3.4 mmol) was added, and the mixture was heated at 110° C. for an additional 72 h. The reaction was acidified to pH 6 by the dropwise addition of HCl (5 M aqueous solution). To the mixture was added sodium carbonate (0.36 g, 3.4 mmol), followed by THF (4 mL) and Boc anhydride (0.37 g, 1.7 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was adjusted to pH 5 with HCl (1 M aqueous solution), diluted with water, and then extracted with EtOAc. The aqueous phase was acidified to pH 1 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with heptane to give the title compound (0.22 g). LCMS (Method 14): 1.83 min, 324.0 [MH] -

[0308] Intermediate 2.104: tert-butyl (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)carbamate The title compound (0.22 g) was prepared from Intermediate 1.25 (0.25 g, 1.3 mmol), Intermediate 2.104c (0.22 g, 0.66 mmol), DIPEA (72 mg, 1.3 mmol), and HATU (0.35 g, 0.93 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluted with 0-1.5% MeOH in DCM). LCMS (Method 14): 1.96 min, 496.2 [M+H] +

[0309] Intermediate 2.109: tert-butyl (S)-(1-cycloheptyl-2-((5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamate The title compound (55 mg) was prepared from Intermediate 1.109 (0.11 g, 0.38 mmol), Intermediate 2.62a (68 mg, 0.25 mmol), Xantphos (15 mg, 0.03 mmol), CsCO (0.25 g, 0.75 mmol), and tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.01 mmol) according to the procedure described for Intermediate 2.62. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica 10 g, 0-100% EtOAc in heptane). 1 H NMR (400 MHz, CDCl3) δ: 8.87 (s, 1H), 8.37 (dd, 1H), 8.30 (dd, 1H), 7.80 (dd, 1H), 5.03 (s, 2H), 4.21 (s, 1H), 3.05 (s, 3H), 2.96 (s, 4H), 2.32 (s, 3H), 2.17 (d, 1H), 1.83 - 1.65 (m, 4H), 1.60 (d, 2H), 1.47 (s, 15H).

[0310] Intermediate 2.112: tert-butyl ((S)-2-((5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (70 mg) was prepared from Intermediate 1.112 (0.21 g, 1.0 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.14 g, 0.51 mmol, CAS: 1187224-06-1), DIPEA (0.18 mL, 1.0 mmol), and HATU (0.29 g, 0.77 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 0-100% EtOAc in heptane). LCMS (Method 14): 1.99 min, 453.2 [M+H] +

[0311] Intermediate 2.114: tert-butyl (S)-(1-cycloheptyl-2-oxo-2-((5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)ethyl)carbamate The title compound (70 mg) was prepared from Intermediate 1.114 (0.85 g, 4.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.67 g, 2.5 mmol, CAS: 1228542-19-5), DIPEA (0.86 mL, 4.9 mmol) and HATU (0.32 g, 3.5 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography (eluting with 20-100% EtOAc in heptane). LCMS (Method 14): 2.07 min, 456.2 [M+H] +

[0312] Intermediate 2.115: tert-butyl ((S)-2-((5-(3,5-dimethylisothiazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.11 g) was prepared from intermediate 1.115 (0.14 g, 0.66 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.1 g, 0.37 mmol, CAS: 1187224-06-1), DIPEA (0.13 mL, 0.74 mmol) and HATU (0.2 g, 0.52 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (20 g silica column, eluted with 20-100% EtOAc in heptane). LCMS (Method 15): 3.09 min, 459.2 [M+H] +

[0313] Intermediate 2.118: tert-butyl ((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.48 g) was prepared from Intermediate 1.93 (0.46 g, 2.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.4 g, 1.4 mmol, CAS: 1187224-06-1), DIPEA (0.49 mL, 2.8 mmol), and HATU (0.75 g, 2.0 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluting with 10-50% EtOAc in heptane). LCMS (Method 15): 3.04 min, 462.2 [M+H] +

[0314] Intermediate 2.124: tert-butyl ((S)-2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate Intermediate 2.124a: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)ethyl)carbamate The title compound (0.69 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.8 g, 3.7 mmol, CAS: 827614-64-2), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.5 g, 1.8 mmol, CAS: 1187224-06-1), DIPEA (0.64 mL, 3.7 mmol), and HATU (0.98 g, 2.6 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (25 g silica column, eluting with 2 to 100% EtOAc in heptane). LCMS (Method 15): 2.41 min, 392.2 [M+H] for boronic acid +

[0315] Intermediate 2.124: tert-butyl ((S)-2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.27 g) was prepared from Intermediate 2.124a (0.32 g, 0.67 mmol), Intermediate 2.101b (0.27 g, 0.87 mmol), Pd(dppf)Cl (49 mg, 0.07 mmol), and potassium carbonate (0.28 g, 2.0 mmol) according to the procedure described for Intermediate 1.1, heating at 110 °C for 18 hours. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (50 g silica column, eluting with 2-70% EtOAc in heptane). LCMS (Method 15): 3.49 min, 572.2 [M+H] +

[0316] Intermediate 2.126: tert-butyl (S)-(1-cyclohexyl-2-((6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate The title compound (37 mg) was prepared from Intermediate 1.126 (0.15 g, 0.43 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.14 g, 0.52 mmol, CAS: 109183-71-3), DIPEA (0.24 mL, 1.4 mmol), and HATU (0.2 g, 0.51 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluting with 0-100% 3:1 EtOAc:EtOH in isohexane). LCMS (Method 28): 2.04 min, 558.5 [M+H] +

[0317] Intermediate 2.127: tert-butyl (S)-(1-cycloheptyl-2-((6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate The title compound (0.9 g) was prepared from Intermediate 1.126 (0.55 g, 1.5 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.57 g, 2.1 mmol, CAS: 1228542-19-5), DIPEA (0.8 mL, 4.6 mmol), and HATU (0.8 g, 2.1 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (24 g silica column, eluting with 0-100% 3:1 EtOAc:EtOH in isohexane). LCMS (Method 28): 2.14 min, 572.4 [M+H] +

[0318] Intermediate 2.130: tert-butyl ((S)-2-((6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.36 g) was prepared from intermediate 1.126 (0.22 g, 0.59 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.2 g, 0.74 mmol, CAS: 1187224-06-1), DIPEA (0.32 mL, 1.8 mmol) and HATU (0.29 g, 0.76 mmol) according to the procedure described for intermediate 2.51. An additional portion of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (40 mg, 0.15 mmol, CAS: 1187224-06-1) and HATU (56 mg, 0.15 mmol) was added and the mixture was stirred at 50° C. for a further 3 h. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (24 g silica column, eluting with 0-100% 3:1 EtOAc:EtOH in isohexane). LCMS (Method 26): 1.95 min, 572.4 [M+H] +

[0319] Intermediate 2.133: tert-butyl (S)-(1-cycloheptyl-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)ethyl)carbamate The title compound (0.36 g) was prepared from intermediate 1.133 (30 mg, 0.13 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.12 g, 0.43 mmol, CAS: 1228542-19-5), DIPEA (0.14 mL, 0.8 mmol), and HATU (0.22 g, 0.59 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluted with 0-100% EtOAc in isohexane). LCMS (Method 28): 1.63 min, 483.3 [M+H] +

[0320] Intermediate 2.134: tert-butyl ((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)carbamate The title compound (30 mg) was prepared from intermediate 1.133 (90 mg, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (32 mg, 0.12 mmol, CAS: 1187224-06-1), DIPEA (0.04 mL, 0.23 mmol) and HATU (68 mg, 0.18 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluting with 0-100% EtOAc in isohexane). LCMS (Method 28): 1.64 min, 483.3 [M+H] +

[0321] Intermediate 2.135: tert-butyl (S)-(1-cycloheptyl-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)carbamate The title compound (30 mg) was prepared from intermediate 1.135 (79 mg, 0.38 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.1 g, 0.38 mmol, CAS: 1228542-19-5), DIPEA (0.13 mL, 0.75 mmol), and HATU (0.17 g, 0.46 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (12 g silica column, eluted with 0-100% EtOAc in isohexane). LCMS (Method 27): 1.54 min, 456.2 [M+H] +

[0322] Intermediate 2.136: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)carbamate The title compound (30 mg) was prepared from intermediate 1.135 (46 mg, 0.23 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (62 mg, 0.23 mmol, CAS: 1187224-06-1), DIPEA (0.08 mL, 0.46 mmol) and HATU (95 mg, 0.25 mmol) according to the procedure described for intermediate 2.51. The crude product was used without further purification. LCMS (Method 27): 1.55 min, 456.2 [M+H] +

[0323] Intermediate 2.138: tert-butyl ((S)-2-((5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate The title compound (0.22 g) was prepared from intermediate 1.138 (0.46 g, 1.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.26 g, 0.94 mmol, CAS: 1187224-06-1), DIPEA (0.33 mL, 1.9 mmol), and HATU (0.54 g, 1.4 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (50 g silica column, eluting with 0-3% MeOH in DCM) and by flash column chromatography on a Biotage Isolera One™ (50 g silica column, eluting with 0-30% EtOAc in heptane). LCMS (Method 14): 2.11 min, 496.2[M+H] +

[0324] Intermediate 2.139: tert-Butyl(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)carbamate Intermediate 2.139a: 4-(methoxymethylene)dispiro[2.1.2 5 .2 3 ] Nonan To a solution of (methoxymethyl)triphenylphosphonium chloride (1.9 g, 5.5 mmol) in THF (6 mL) at 0° C. was slowly added n-butyllithium (2.5 M in hexane; 2.2 mL, 5.5 mmol). The mixture was stirred for 20 min, and then the dispiro[2.1.2] in tetrahydrofuran (4 mL) was added. 5 .2 3]nonan-4-one (0.5 g, 3.7 mmol, CAS: 1004-54-2) was added. The mixture was heated at 60° C. for 20 hours, then cooled to room temperature and quenched with water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were passed through a phase separation cartridge and then concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (silica column 10 g, eluted with 100% DCM) to give the title compound as an impure mixture, which was subjected to the same reaction conditions as described below.

[0325] To a solution of (methoxymethyl)triphenylphosphonium chloride (1.3 g, 3.7 mmol) in THF (4 mL) at 0° C. was slowly added n-butyllithium (2.5 M in hexanes; 1.5 mL, 3.7 mmol). The mixture was stirred for 20 minutes, after which the crude mixture was added as a solution in tetrahydrofuran (2 mL). The mixture was heated at 60° C. for 20 hours, then cooled to room temperature and quenched with water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were passed through a phase separation cartridge and then concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 100% DCM) to give the title compound (0.56 g). 1 H NMR (400 MHz, CDCl3) δ: 5.32 (s, 1H), 3.40 (s, 3H), 1.74 (d, 4H), 1.38 (q, 2H), 0.76 - 0.68 (m, 2H), 0.65 (q, 2H), 0.62 - 0.56 (m, 2H).

[0326] Intermediate 2.139b: dispiro[2.1.2 5 .2 3 ]nonane-4-carbaldehyde To a solution of intermediate 2.139a (70 mg, 0.43 mmol) in THF (0.5 mL) was added HCl (5 M aqueous solution; 0.5 mL, 2.5 mmol) in water (0.5 mL), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM, passed through a phase separation cartridge, and concentrated in vacuo to give the title compound (67 mg), which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 9.45 (d, 1H), 3.51 (t, 2H), 2.60 (tt, 2H), 2.39 (ddt, 2H), 1.88 - 1.79 (m, 3H), 0.78 - 0.70 (m, 2H), 0.48 - 0.44 (m, 2H).

[0327] Intermediate 2.139c: 5-(dispiro[2.1.2 5 .2 3 ]nonan-4-yl)imidazolidine-2,4-dione A mixture of intermediate 2.139b (0.2 g, 1.3 mmol), ammonium carbonate (0.37 mg, 3.9 mmol), sodium cyanide (95 mg, 1.9 mmol) in MeOH (5 mL) and water (5 mL) was added to a microwave vial. The vial was sealed and the mixture was heated to 60° C. for 2 days. The mixture was cooled to room temperature and then acidified to pH 3 with HCl (1 M aqueous solution). The volatiles were concentrated in vacuo and the aqueous residue was extracted with DCM. The organics were passed through a phase separation cartridge and concentrated in vacuo. The crude product was triturated with DCM to give the title compound (35 mg). LCMS (Method 14): 1.50 min, 221.2 [M+H] +

[0328] Intermediate 2.139d: 2-((tert-butoxycarbonyl)amino)-2-(dispiro[2.1.2 5 .2 3 ]nonan-4-yl)acetic acid A solution of intermediate 2.139c (0.5 g, 2.3 mmol) in NaOH (5 M aqueous solution; 25 mL, 125 mmol) and water (25 mL) was heated to reflux for 3 days. The mixture was cooled to room temperature and then acidified to pH 3 with HCl (12 M aqueous solution). Potassium carbonate was added to adjust the pH to approximately 8, and then THF (150 mL) followed by Boc anhydride (1.4 g, 6.8 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (40 g silica column, eluting with 0-10% MeOH in DCM) to give the title compound (0.27 g). LCMS (method 14): 2.11 min, 1.89 min, 294.2[MH] -

[0329] Intermediate 2.139: tert-Butyl(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)carbamate The title compound (0.22 g) was prepared from Intermediate 1.25 (45 mg, 0.24 mmol), Intermediate 2.139d (47 mg, 0.16 mmol), DIPEA (0.06 mL, 0.32 mmol), and HATU (85 mg, 0.22 mmol) according to the procedure described for Intermediate 2.51. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-10% MeOH in DCM). LCMS (Method 14): 2.05 min, 466.2 [M+H] +

[0330] Intermediate 3: (S)-2-amino-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride A solution of intermediate 2 (73 mg, 0.16 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.11 g). LCMS (Method 4): 0.76 min, 368.2 [M+H] +

[0331] Intermediate 3.1: (S)-2-amino-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride A solution of intermediate 2.1 (60 mg, 0.12 mmol) in HCl (4 M in 1,4-dioxane; 3 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (70 mg). LCMS (Method 3): 0.86 min, 384.2 [MH] -

[0332] Intermediate 3.2: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide hydrochloride A solution of intermediate 2.2 (0.12 g, 0.25 mmol) in HCl (3 M in 1,4-dioxane; 15 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.11 g). LCMS (Method 4): 0.73 min, 379.3 [M+H] +

[0333] Intermediate 3.3: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)acetamide hydrochloride A solution of intermediate 2.3 (49 mg, 0.11 mmol) in HCl (3 M in 1,4-dioxane; 10 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the title compound (40 mg). LCMS (Method 4): 0.68 min, 340.2 [M+H]+

[0334] Intermediate 3.4: (S)-2-amino-N-(4-(imidazo[1,2-a]pyridin-5-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride A solution of intermediate 2.4 (32 mg, 0.07 mmol) in HCl (3 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to give the title compound (28 mg). LCMS (Method 4): 0.84 min, 363.2 [M+H] +

[0335] Intermediate 3.6: (S)-2-amino-N-(4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride A solution of intermediate 2.6 (0.69 g, 1.2 mmol) in HCl (4 M in 1,4-dioxane; 3.1 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified by flash column chromatography on a Biotage Isolera™ (20 g silica column, eluted with 30 to 100% EtOAc in heptane) to give the title compound (0.4 g). LCMS (Method 14): 1.57 min, 461.2 [M+H] +

[0336] Intermediate 3.6a: (S)-N-(2-((4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide To a solution of intermediate 3.6 (370 mg, 0.80 mmol) in MeCN (4 mL) and EtOAc (12 mL) was added 2-methylpyrazole-3-carboxylic acid (101 mg, 0.80 mmol, CAS: 16034-46-1), HATU (367 mg, 0.96 mmol), and triethylamine (0.34 mL, 2.41 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 and EtOAc and separated. The organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera™ (120 g silica column, 30 to 100% EtOAc in heptane) to give the title compound (400 mg). 1 H NMR (400 MHz, MeOD) δ: 7.67 - 7.60 (m, 2H), 7.47 (d, 1H), 7.22 (s, 2H), 7.12 - 7.04 (m, 2H), 6.92 - 6.84 (m, 3H), 5.22 (s, 2H), 4.44 (d, 1H), 4.08 (s, 3H), 3.77 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 1.94 (d, 1H), 1.88 - 1.84 (m, 1H), 1.77 (d, 3H), 1.35 - 1.27 (m, 2H), 1.17 (d, 1H), 0.98 (q, 2H), 0.90 (d, 3H).

[0337] Intermediate 3.7: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)acetamide dihydrochloride A solution of intermediate 2.7 (98 mg, 0.18 mmol) in HCl (4 M in 1,4-dioxane; 1.4 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound (95 mg). LCMS (Method 4): 0.77 min, 435.3 [M+H] +

[0338] Intermediate 3.8: (S)-2-amino-N-(1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.8 (18 mg, 0.04 mmol) in HCl (3 M in 1,4-dioxane; 3 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to give the title compound (16 mg). LCMS (Method 4): 0.75 min, 369.2 [M+H] +

[0339] Intermediate 3.9: (S)-2-amino-N-(3',5'-dimethyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.9 (60 mg, 0.13 mmol) in HCl (3 M in 1,4-dioxane; 3 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (57 mg). LCMS (Method 4): 0.90 min, 353.2 [M+H] +

[0340] Intermediate 3.12: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride A solution of intermediate 2.12 (0.13 g, 0.3 mmol) in HCl (4 M in 1,4-dioxane; 0.8 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was triturated with diethyl ether (5 mL) to give the title compound (75 mg). LCMS (Method 12) 2.20 min, 331 [M+H] +

[0341] Intermediate 3.13: (S)-2-amino-N-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A suspension of intermediate 2.13 (0.1 g, 0.22 mmol) in HCl (4 M in 1,4-dioxane; 0.56 mL) was stirred at room temperature for 35 minutes. The reaction mixture was diluted with water and purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 5-100% 0.1% ammonia in 0.1% ammonia / water MeCN) to give the title compound (54 mg). LCMS (Method 4): 0.70 min, 347.2 [M+H] +

[0342] Intermediate 3.14: (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A suspension of intermediate 2.14 (0.23 g, 0.54 mmol) in HCl (4 M in 1,4-dioxane; 1.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 30 g, eluting with 5-100% 0.1% ammonia in 0.1% ammonia / water MeCN) to give the title compound (0.11 g). LCMS (Method 4): 0.91 min, 329.0 [M+H] +

[0343] Intermediate 3.15: (S)-2-amino-N-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride A solution of intermediate 2.15 (81 mg, 0.18 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (70 mg). LCMS (Method 14): 1.44 min, 342.2 [M+H] +

[0344] Intermediate 3.16: (S)-2-amino-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.16 (0.28 g, 0.62 mmol) in HCl (4 M in 1,4-dioxane; 5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH (6 mL) and passed through an SCX cartridge (5 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.19 mg). LCMS (Method 14): 1.40 min, 343.2 [M+H] +

[0345] Intermediate 3.18: (S)-2-amino-N-(5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.18 (37 mg, 0.07 mmol) in HCl (4 M in 1,4-dioxane; 0.17 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (33 mg). 1 H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 8.36 - 8.24 (m, 4H), 8.12 (d, 1H), 7.78 (dd, 1H), 7.20 - 7.14 (m, 2H), 6.95 - 6.88 (m, 2H), 5.21 (s, 2H), 3.95 - 3.86 (m, 1H), 3.73 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 1.84 - 1.61 (m, 5H), 1.30 - 1.04 (m, 3H), 0.94 - 0.83 (m, 5H).

[0346] Intermediate 3.18a: N-((S)-2-((5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide To a solution of intermediate 3.18 (33 mg, 0.07 mmol) in EtOAc (0.39 mL) and MeCN (0.39 mL) at 0 °C, 2-methylpyrazole-3-carboxylic acid (9.2 mg, 0.07 mmol, CAS: 16034-46-1), HATU (28 mg, 0.07 mmol), and triethylamine (0.03 mL, 0.2 mmol) were added. The mixture was stirred at 0 °C for 20 h, and then the solvent was removed in vacuo. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting with 20-80% EtOAc in heptane) to give the title compound (24 mg). LCMS (Method B): 2.78 min, 570.2 [M+H] +

[0347] Intermediate 3.25: (S)-2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.25 (28 mg, 0.06 mmol) in HCl (4 M in 1,4-dioxane; 0.75 mL) was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo to give the title compound (24 mg). LCMS (Method 14): 1.38 min, 342.3 [M+H] +

[0348] Intermediate 3.27: (S)-2-amino-2-cyclohexyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)acetamide A solution of intermediate 2.27 (0.6 g, 1.4 mmol) in HCl (4 M in 1,4-dioxane; 6 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH (6 mL) and passed through an SCX cartridge (5 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.45 mg). LCMS (Method 14): 1.36 min, 329.2 [M+H] +

[0349] Intermediate 3.34: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)acetamide A solution of intermediate 2.34 (0.2 g, 0.38 mmol) in HCl (4 M in 1,4-dioxane; 4 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was suspended in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted twice with EtOAc, and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.15 g). LCMS (Method 14): 1.35 min, 343.2 [M+H] +

[0350] Intermediate 3.38: (S)-2-amino-2-cyclohexyl-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acetamide hydrochloride A suspension of intermediate 2.38 (0.26 g, 0.57 mmol) in HCl (4 M in 1,4-dioxane; 0.14 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.28 g). LCMS (Method 14): 1.27 min, 354.2 [M+H] +

[0351] Intermediate 3.44: (S)-2-amino-N-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.44 (35 mg, 0.08 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (32 mg). LCMS (Method 14): 1.32 min, 343.3 [M+H] +

[0352] Intermediate 3.49a: tert-butyl (S)-6-((1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate To 2-tert-butoxycarbonyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-6-carboxylic acid (61 mg, 0.23 mmol, CAS: 1363380-86-2) in anhydrous DCM (1.5 mL) was added HATU (88 mg, 0.23 mmol) and DIPEA (0.1 mL, 0.58 mmol). The mixture was stirred at room temperature for 5 minutes, and then intermediate 3.27 (70 mg, 0.19 mmol) was added. The reaction was stirred at room temperature under an argon atmosphere for an additional 20 hours before being diluted with DCM and washed with saturated aqueous NaHCO3. The organics were washed with brine, passed through a hydrophobic fritted tube, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 12 g, eluting with 0-80% EtOAc in heptane) to give the title compound (41 mg). LCMS (Method 14): 2.71 min, 577.4 [M+H] +

[0353] Intermediate 3.51: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A suspension of intermediate 2.51 (0.36 g, 0.81 mmol) in HCl (4 M in 1,4-dioxane; 7 mL) was stirred at room temperature for 1 hour. The reaction was diluted with saturated aqueous NaHCO3 and EtOAc, and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.3 g). LCMS (Method 14): 1.35 min, 342.2 [M+H] +

[0354] Intermediate 3.54: (S)-2-amino-N-(2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.54 (0.24 g, 0.54 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (97 mg). LCMS (Method 14): 1.42 min, 344.2 [M+H] +

[0355] Intermediate 3.57: (S)-2-amino-N-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.57 (0.13 g, 0.29 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (93 mg). LCMS (Method 14): 1.43 min, 343.2 [M+H] +

[0356] Intermediate 3.59: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(5-(5-methylpyrimidin-4-yl)pyridin-2-yl)acetamide A solution of intermediate 2.59 (0.13 g, 0.3 mmol) in HCl (4 M in 1,4-dioxane; 0.08 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (93 mg). LCMS (Method 14): 1.32 min, 340.2 [M+H] +

[0357] Intermediate 3.61: (S)-2-amino-N-(5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.61 (0.12 g, 0.25 mmol) in HCl (4 M in 1,4-dioxane; 0.08 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was diluted with saturated aqueous NaHCO3 and extracted into ethyl acetate. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (82 mg). LCMS (Method 14): 1.37 min, 373.2 [M+H] +

[0358] Intermediate 3.62: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2-yl)acetamide dihydrochloride A solution of intermediate 2.62 (34 mg, 0.08 mmol) in HCl (4 M in 1,4-dioxane; 0.19 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified by flash column chromatography (eluting with 2-100% MeOH in DCM) to give the title compound (23 mg). 1 H NMR (400 MHz, MeOD) δ: 8.60 (s, 1H), 8.49 (d, 1H), 8.18 - 8.04 (m, 1H), 4.13 - 4.07 (m, 1H), 2.52 (d, 6H), 2.25 (s, 1H), 1.94 - 1.39 (m, 12H).

[0359] Intermediate 3.63: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.63 (0.29 g, 0.6 mmol) in HCl (4 M in 1,4-dioxane; 1.6 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.19 g). LCMS (Method 19): 1.63 min, 364.2 [M+H] +

[0360] Intermediate 3.64: (S)-2-amino-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.64 (0.34 g, 0.77 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (239 mg). LCMS (Method 19): 1.68 min, 342.2 [M+H] +

[0361] Intermediate 3.65: (S)-2-amino-N-(4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.65 (0.23 g, 0.51 mmol) in HCl (4 M in 1,4-dioxane; 1.3 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (0.5 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.12 g). LCMS (Method 14): 1.29 min, 342.2 [M+H] +

[0362] Intermediate 3.66: (S)-2-amino-N-(2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.66 (0.5 g, 0.89 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.27 g). LCMS (Method 14): 1.41 min, 343.2 [M+H] +

[0363] Intermediate 3.67: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.67 (0.14 g, 0.31 mmol) in HCl (4 M in 1,4-dioxane; 2.5 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (2 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.1 g). 1 H NMR (400 MHz, MeOD) δ: 8.41 - 8.33 (m, 2H), 7.89 (dd, 1H), 3.99 (s, 3H), 3.44 (d, 1H), 2.29 (s, 3H), 2.10 - 1.97 (m, 1H), 1.81 - 1.34 (m, 12H)

[0364] Intermediate 3.69: (S)-2-amino-2-cycloheptyl-N-(5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-yl)acetamide dihydrochloride A solution of intermediate 2.69 (90 mg, 0.19 mmol) in HCl (4 M in 1,4-dioxane; 0.48 mL) and 1,4-dioxane (3 mL) was stirred at room temperature for 40 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.1 g). LCMS (Method 19): 1.810 min, 373.2 [M+H] +

[0365] Intermediate 3.70: (S)-2-amino-N-(3'-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.70 (0.11 g, 0.24 mmol) in HCl (4 M in 1,4-dioxane; 0.6 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (86 mg). LCMS: (Method 19): 1.50 min, 369.2 [M+H] +

[0366] Intermediate 3.71: (S)-2-amino-N-(2',3'-dimethyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.71 (0.19 g, 0.43 mmol) in HCl (4 M in 1,4-dioxane; 1.1 mL) and 1,4-dioxane (3 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.13 g). 1H NMR (400 MHz, CDCl3) δ: 10.05 (s, 1H), 8.42 - 8.32 (m, 2H), 8.25 (dd, 1H), 7.66 (dd, 1H), 6.99 (d, 1H), 3.45 (d, 1H), 2.59 (s, 3H), 2.21 (s, 3H), 2.06 - 1.95 (m, 1H), 1.78 - 1.71 (m, 3H), 1.60 (m, 1H), 1.35 - 1.22 (m, 2H), 1.16 (m, 1H), 1.09 - 0.91 (m, 2H), 0.88 (d, 3H)

[0367] Intermediate 3.72: (S)-2-amino-N-(2',5'-dimethyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.72 (0.1 g, 0.23 mmol) in HCl (4 M in 1,4-dioxane; 0.56 mL) and 1,4-dioxane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (77 mg). LCMS (Method 14): 1.24 min, 353.2 [M+H] +

[0368] Intermediate 3.76: (S)-2-amino-2-cycloheptyl-N-(5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.76 (31 mg, 0.068 mmol) in HCl (4 M in 1,4-dioxane; 0.17 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (0.5 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (19 mg). LCMS (Method 19): 1.67 min, 357.2 [M+H] +

[0369] Intermediate 3.77: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)acetamide A solution of intermediate 2.77 (20 mg, 0.05 mmol) in HCl (4 M in 1,4-dioxane; 0.17 mL), 1,4-dioxane (5 mL) and MeOH (5 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (0.1 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (16 mg). LCMS (Method 14): 1.36 min, 344.2 [M+H] +

[0370] Intermediate 3.80: (S)-2-amino-2-cycloheptyl-N-(5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.80 (18 mg, 0.04 mmol) in HCl (4 M in 1,4-dioxane; 0.05 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (0.1 g, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (16 mg). LCMS (Method 14): 1.35 min, 369.2 [M+H] +

[0371] Intermediate 3.81: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)acetamide A solution of intermediate 2.81 (0.22 g, 0.49 mmol) in HCl (4 M in 1,4-dioxane; 1.2 mL) and 1,4-dioxane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (99 mg). LCMS (Method 14): 1.36 min, 361.2 [M+H] +

[0372] Intermediate 3.84: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)acetamide A solution of intermediate 2.84 (59 mg, 0.13 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (51 mg). LCMS (Method 14): 1.27 min, 343.2 [M+H] +

[0373] Intermediate 3.85: (S)-2-amino-2-cycloheptyl-N-(5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide To a solution of intermediate 2.85 (30 mg, 0.06 mmol) in DCM (10 mL) at 0° C. was added boron tribromide (1 M in DCM; 0.17 mL, 0.17 mmol). The mixture was allowed to warm to room temperature, then an additional portion of boron tribromide (0.56 mL, 0.56 mmol) was added and the mixture was stirred at room temperature for 8 hours. A further portion of boron tribromide (0.56 mL, 0.56 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water, neutralized using 1 M NaOH solution, extracted with DCM and the phases were separated using a phase separation cartridge. The organic layer was concentrated in vacuo to give the title compound (21 mg). LCMS (Method 14): 1.24 min, 344.2 [M+H] +

[0374] Intermediate 3.88: (S)-2-amino-2-cycloheptyl-N-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)acetamide A solution of intermediate 2.88 (0.44 g, 0.99 mmol) in HCl (4 M in 1,4-dioxane; 5 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.3 g). LCMS (Method 14): 1.34 min, 343.2 [M+H] +

[0375] Intermediate 3.92: (S)-2-amino-2-cycloheptyl-N-(5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.92 (53 mg, 0.09 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous NaHCO3 and EtOAc, and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (46 mg). LCMS (Method 19): 1.70 min, 369.2 [M+H] +

[0376] Intermediate 3.93: (S)-2-amino-N-(5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-cycloheptylacetamide A solution of intermediate 2.93 (0.58 g, 1.1 mmol) in HCl (4 M in 1,4-dioxane; 5.6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (10 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.38 g). LCMS (Method 19): 1.78 min, 362.2 [M+H] +

[0377] Intermediate 3.96: (S)-2-amino-2-cyclohexyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.96 (0.5 g, 1.2 mmol) in HCl (4 M in 1,4-dioxane; 2.9 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 18 hours. The reaction was diluted with saturated aqueous NaHCO3 and EtOAc, and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.38 g). 1 H NMR (400 MHz, MeOD) δ: 8.35 - 8.28 (m, 2H), 7.81 (dd, 1H), 7.38 (d, 1H), 3.74 (s, 3H), 3.36 (d, 1H), 2.01 (d, 3H), 1.81 - 1.65 (m, 6H), 1.45 - 1.11 (m, 5H).

[0378] Intermediate 3.98: (S)-2-amino-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)-2-(4-methylcyclohexyl)acetamide A solution of intermediate 2.98 (0.49 g, 1.1 mmol) in HCl (4 M in 1,4-dioxane; 5.3 mL) and 1,4-dioxane (4 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (10 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.33 g). LCMS (Method 14): 1.35 min, 360.2 [M+H] +

[0379] Intermediate 3.101: (S)-2-amino-2-cycloheptyl-N-(5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.101 (70 mg, 0.12 mmol) in HCl (4 M in 1,4-dioxane; 0.15 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 3 hours. An additional portion of HCl (4 M in 1,4-dioxane; 0.15 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (36 mg). LCMS (Method 15): 1.45 min, 358.2 [M+H] +

[0380] Intermediate 3.102: (S)-2-amino-2-cyclopentyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.102 (48 mg, 0.12 mmol) in HCl (4 M in 1,4-dioxane; 0.3 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated and the aqueous layer was extracted with DCM. The combined organics were washed with water and brine, separated using a phase separation cartridge and concentrated in vacuo to give the title compound (34 mg). LCMS (Method 26): 1.02 min, 314.2 [M+H] +

[0381] Intermediate 3.103: 2-amino-2-(bicyclo[2.2.1]heptan-2-yl)-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.103 (60 mg, 0.13 mmol) in HCl (4 M in 1,4-dioxane; 0.33 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (30 mg). LCMS (Method 26): 1.30 min, 340.3 [M+H] +

[0382] Intermediate 3.104: 2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)acetamide A solution of intermediate 2.104 (0.22 g, 0.44 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.16 g). LCMS (Method 14): 1.30 min, 396.2 [M+H] +

[0383] Intermediate 3.109: (S)-2-amino-2-cycloheptyl-N-(5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.109 (55 mg, 0.1 mmol) in HCl (4 M in 1,4-dioxane; 0.48 mL) and 1,4-dioxane (1.5 mL) was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (2 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (36 mg). LCMS (Method 14): 1.25 min, 414.2 [M+H] +

[0384] Intermediate 3.112: (S)-2-amino-N-(5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.112 (71 mg, 0.14 mmol) in HCl (4 M in 1,4-dioxane; 0.71 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (2 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (44 mg). LCMS (Method 14): 1.33 min, 353.2 [M+H] +

[0385] Intermediate 3.114: (S)-2-amino-2-cycloheptyl-N-(5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)acetamide A solution of intermediate 2.114 (0.36 g, 0.78 mmol) in HCl (4 M in 1,4-dioxane; 0.98 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (10 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo to give the title compound (0.29 g). LCMS (Method 14): 1.35 min, 356.2 [M+H] +

[0386] Intermediate 3.115: (S)-2-amino-N-(5-(3,5-dimethylisothiazol-4-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.115 (0.1 g, 0.23 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (77 mg). LCMS (Method 15): 1.77 min, 359.2 [M+H] +

[0387] Intermediate 3.118: (S)-2-amino-N-(5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.118 (0.48 g, 0.93 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (10 g cartridge, washed with MeOH and eluted with 2 M methanolic ammonia). The solvent was removed in vacuo. The crude compound was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-5% 2 M methanolic ammonia in DCM) to give the title compound (0.28 g). LCMS (Method 15): 1.77 min, 362.2 [M+H] +

[0388] Intermediate 3.124: (S)-2-amino-N-(5-(4-(hydroxymethyl)-1-methyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.124 (0.27 g, 0.47 mmol) in HCl (4 M in 1,4-dioxane; 0.59 mL) and 1,4-dioxane (11.5 mL) was stirred at room temperature for 3 hours. An additional portion of HCl (4 M in 1,4-dioxane; 0.59 mL) was added, and the mixture was stirred at room temperature for another 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.17 g). LCMS (Method 15): 1.48 min, 358.2 [M+H] +

[0389] Intermediate 3.126: (S)-2-amino-2-cyclohexyl-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)acetamide dihydrochloride A solution of intermediate 2.126 (37 mg, 0.05 mmol) in HCl (4 M in 1,4-dioxane; 0.5 mL), 1,4-dioxane (0.5 mL) and MeOH (1 mL) was stirred at 40° C. for 3 hours. The mixture was concentrated in vacuo to give the title compound (30 mg). LCMS (Method 28): 1.03 min, 328.3 [M+H] +

[0390] Intermediate 3.127: (S)-2-amino-2-cycloheptyl-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)acetamide dihydrochloride A solution of intermediate 2.127 (0.9 g, 1.6 mmol) in HCl (4 M in 1,4-dioxane; 5 mL), 1,4-dioxane (5 mL) and MeOH (20 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the title compound (0.76 g). LCMS (Method 28): 1.14 min, 342.3 [M+H] +

[0391] Intermediate 3.130: (S)-2-amino-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride A solution of intermediate 2.130 (0.36 g, 0.62 mmol) in HCl (4 M in 1,4-dioxane; 2.2 mL) and MeOH (5 mL) was stirred at 40° C. for 20 hours. The mixture was concentrated in vacuo to give the title compound (0.34 g). LCMS (Method 28): 1.16 min, 342.3 [M+H] +

[0392] Intermediate 3.133: (S)-2-amino-2-cycloheptyl-N-(1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)acetamide A solution of intermediate 2.133 (30 mg, 0.06 mmol) in HCl (4 M in 1,4-dioxane; 0.16 mL) and 1,4-dioxane (0.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (1 g cartridge, washed with MeOH and eluted with 5% methanolic ammonia). The solvent was removed in vacuo to give the title compound (25 mg). LCMS (Method 29): 1.27 min, 383.3 [M+H] +

[0393] Intermediate 3.134: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)acetamide A solution of intermediate 2.134 (30 mg, 0.06 mmol) in HCl (4 M in 1,4-dioxane; 0.15 mL) and 1,4-dioxane (0.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH and passed through an SCX cartridge (1 g cartridge, washed with MeOH and eluted with 5% methanolic ammonia). The solvent was removed in vacuo to give the title compound (16 mg). LCMS (Method 28): 1.23 min, 383.4 [M+H] +

[0394] Intermediate 3.135: (S)-2-amino-2-cycloheptyl-N-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide A solution of intermediate 2.135 (71 mg, 0.16 mmol) in HCl (4 M in 1,4-dioxane; 0.39 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated with a phase separator cartridge and the organics were concentrated in vacuo to give the title compound (65 mg). LCMS (Method 26): 1.30 min, 356.3 [M+H] +

[0395] Intermediate 3.136: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide A solution of intermediate 2.136 (80 mg, 0.16 mmol) in HCl (4 M in 1,4-dioxane; 0.4 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated with a phase separator cartridge and the organics were concentrated in vacuo to give the title compound (46 mg). LCMS (Method 28): 1.37 min, 356.3 [M+H] +

[0396] Intermediate 3.138: (S)-2-amino-N-(5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide A solution of intermediate 2.138 (0.11 g, 0.21 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) and DCM (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (85 mg). LCMS (Method 14): 1.42 min, 396.2 [M+H]+

[0397] Intermediate 3.139: 2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-(dispiro[2.1.2 5 .2 3 ]nonan-4-yl)acetamide A solution of intermediate 2.139 (30 mg, 0.06 mmol) in HCl (4 M in 1,4-dioxane; 0.08 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (10 g silica column, eluted with 0-10% MeOH in DCM) to give the title compound (16 mg). LCMS (Method 14): 1.36 min, 366.2 [M+H] +

[0398] Intermediate 4.17: 4-(4,4-difluorocyclohexylidene)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one To a mixture of titanium chloride IV (1 M in DCM; 4.8 mL, 4.8 mmol) in THF (10 mL) was added a solution of 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (200 mg, 1.2 mmol, CAS: 2256070-09-2) in THF (10 mL) at −10° C. under argon, followed by a solution of 4,4-difluorocyclohexanone (179 mg, 1.3 mmol, CAS: 22515-18-0) in THF (5 mL). After stirring the mixture at −10° C. for 30 minutes, pyridine (0.59 mL, 7.3 mmol) was added dropwise, and the mixture was then stirred from −10° C. to room temperature for 16 hours. The mixture was quenched by the addition of saturated aqueous NH4Cl and then extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera™ (10 g silica column, eluted with 0-30% EtOAc in heptane) to give the title compound (240 mg). 1 H NMR (400 MHz, CDCl3) δ:7.55 (d, 1H), 6.90 (d, 1H), 4.28 (s, 3H), 3.30 - 3.19 (m, 2H), 3.08 - 2.97 (m, 2H), 2.22 - 2.05 (m, 4H)

[0399] Intermediate 4.19: 4-(4,4-dimethylcyclohexylidene)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one The title compound (0.17 g) was prepared from 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (0.19 g, 1.1 mmol, CAS: 22515-18-0) and 4,4-dimethylcyclohexanone (0.13 g, 1 mmol, CAS: 4255-62-3) according to the procedure described for Intermediate 4.17. LCMS (Method 14): 2.07 min, 274.2 [M+H] +

[0400] Intermediate 4.20: 4-(4,4-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one A mixture of intermediate 4.17 (60 mg, 0.210 mmol) in THF (10 mL) was hydrogenated in an H-Cube® using a 10% Pd / C cartridge at 50 bar and 70° C. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluting with 0-10% MeOH in DCM) to give the title compound (45 mg). 1 H NMR (400 MHz, CDCl3) δ: 7.57 (d, 1H), 6.84 (d, 1H), 4.35 (d, 1H), 4.26 (s, 3H), 2.30 - 2.00 (m, 4H), 1.91 - 1.64 (m, 4H), 1.62 - 1.58 (m, 1H).

[0401] Intermediate 4.22: 4-cyclooctylidene-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one The title compound (0.14 g) was prepared from 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (0.3 g, 0.76 mmol, CAS: 22515-18-0) and cyclooctanone (96 mg, 0.76 mmol, CAS: 696-71-9) according to the procedure described for intermediate 4.17. 1 H NMR (400 MHz, CDCl3) δ:7.53 (d, 1H), 6.86 (d, 1H), 4.29 (s, 3H), 3.02 - 2.95 (m, 2H), 2.91 - 2.83 (m, 2H), 1.92 (tdd, 4H), 1.45 - 1.31 (m, 2H), 1.26 (s, 2H), 0.85 (d, 2H).

[0402] Intermediate 5.17: N-(1-(4,4-difluorocyclohexylidene)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of intermediate 4.17 (50 mg, 0.18 mmol) and intermediate 1.17 (41 mg, 0.21 mmol) in THF (10 mL) under argon was added acetic acid (0.1 mL, 1.8 mmol). The reaction mixture was heated by microwave irradiation at 100° C. for 30 minutes. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (50% EtOAc in heptane) to give the title compound (80 mg). 1 H NMR (400 MHz, MeOD) δ: 8.28 (s, 2H), 7.78 (d, 2H), 7.52 (d, 1H), 7.20 - 7.13 (m, 2H), 6.99 (d, 1H), 4.12 (s, 3H), 2.77 (t, 2H), 2.54 (t, 2H), 2.17 - 2.10 (m, 4H), 2.08 (s, 6H).

[0403] Intermediate 5.19: (N-(1-(4,4-dimethylcyclohexylidene)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide The title compound (30 mg) was prepared from Intermediate 4.19 (51 mg, 0.19 mmol) and Intermediate 1.17 (41 mg, 0.21 mmol) according to the procedure described for Intermediate 5.17. LCMS (Method 14): 1.50 min, 472.2 [M+H] +

[0404] Intermediate 5.21: N-(2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-(4,4-dimethylcyclohexylidene)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide The title compound (75 mg) was prepared from Intermediate 4.19 (50 mg, 0.18 mmol) and Intermediate 1 (43 mg, 0.20 mmol) according to the procedure described for Intermediate 5.17. LCMS (Method 14): 1.72 min, 488.2 [M+H] +

[0405] Intermediate 5.22: N-(1-cyclooctylidene-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide The title compound (50 mg) was prepared from Intermediate 4.22 (41 mg, 0.15 mmol) and Intermediate 1.17 (30 mg, 0.15 mmol) according to the procedure described for Intermediate 5.17. LCMS (Method 14): 1.51 min, 472.2 [M+H] +

[0406] Intermediate 5.23: N-(1-cyclooctylidene-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide The title compound (14 mg) was prepared from Intermediate 4.22 (51 mg, 0.19 mmol) and Intermediate 1.23 (54 mg, 0.11 mmol) according to the procedure described for Intermediate 5.17. 1 H NMR (400 MHz, MeOD) δ: 7.66 - 7.57 (m, 2H), 7.49 (dd, 1H), 7.28 - 7.20 (m, 2H), 6.95 (d, 1H), 4.10 (d, 3H), 2.71 - 2.64 (m, 2H), 2.47 - 2.39 (m, 2H), 2.23 (s, 6H), 1.85 (s, 2H), 1.77 (s, 2H), 1.59 (s, 6H). Synthesis of Examples [Example]

[0407] 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 [ka] To a stirred solution of intermediate 3 (110 mg, 0.27 mmol), 2-methylpyrazole-3-carboxylic acid (41 mg, 0.33 mmol, CAS: 16034-46-1) and triethylamine (0.15 mL, 1.1 mmol) in EtOAc (0.9 mL) and acetonitrile (0.5 mL) at 0 °C under an argon atmosphere was added HATU (125 mg, 0.33 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, then diluted with saturated aqueous sodium bicarbonate and extracted into EtOAc (x2). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (eluting with 10% MeOH in EtOAc) followed by automated reverse-phase column chromatography on a Biotage Isolera One™ (200-400 nm diode array detector, 30 g C18 column, eluting with 10-80% MeCN (containing 0.1% aqueous NH3) in water containing 0.1% aqueous NH3). Fractions containing the desired product were combined and the solvent removed via lyophilization to give the title compound (37 mg). LCMS (Method 3): 2.05 min, 476.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.29 (s, 1H), 8.52 (d, 1H), 7.69 (d, 2H), 7.46 (d, 1H), 7.29 (d, 1H), 7.21 (d, 2H), 7.07 (d, 1H), 6.34 (d, 1H), 4.38 (t, 1H), 4.03 (s, 3H), 3.50 (s, 3H), 2.30 (s, 3H), 1.90-1.54 (m, 5H), 1.37-0.98 (m, 3H), 0.94-0.81 (m, 5H). [Example]

[0408] 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 [ka] The title compound (23 mg) was prepared from Intermediate 3.1 (52 mg, 0.12 mmol), 2-methylpyrazole-3-carboxylic acid (23 mg, 0.19 mmol, CAS: 16034-46-1), HATU (71 mg, 0.19 mmol), and triethylamine (0.1 mL, 0.74 mmol) in MeCN / DMF according to the procedure described for Example 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (25 g Silicycle silica column, eluting with 10–60% EtOAc in heptane). The compound was dissolved in a mixture of DCM / MeOH (95:5) and washed with 10% LiCl solution followed by HO. The organic layer was concentrated in vacuo, and the residue was dissolved in hot EtOAc and then washed with HO. The organic layer was filtered through a phase separation cartridge, and the organics were concentrated in vacuo. LCMS (Method 3): 2.14 min, 494.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (s, 1H), 8.57 (d, 1H), 7.72 (dd, 1H), 7.46 (d, 1H), 7.42 (dd, 1H), 7.27-7.21 (m, 2H), 7.07 (d, 1H), 6.35 (d, 1H), 4.36 (dd, 1H), 4.03 (s, 3H), 3.51 (s, 3H), 2.21 (d, 3H), 2.12-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.62-1.54 (m, 1H), 1.37-1.13 (m, 2H), 1.10-0.98 (m, 1H), 0.95-0.79 (m, 5H). [Example]

[0409] 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 [ka] The title compound (50 mg) was synthesized from Intermediate 3.2 (0.1 g, 0.22 mmol), 2-methylpyrazole-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), 、 Prepared from HATU (84 mg, 0.22 mmol) and triethylamine (0.12 mL, 0.89 mmol) in MeCN / DMF according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 25 g, eluting with 10-50% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 18) 2.19 min, 487.4 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 12.24 (s, 1H), 11.21 (d, 1H), 10.38 (s, 1H), 8.61 (d, 1H), 7.80 (d, 2H), 7.58 (d, 2H), 7.54 (d, 1H), 7.42 (dd, 1H), 7.14 (d, 1H), 7.00 (d, 1H), 6.51 (dd, 1H), 4.42 (t, 1H), 4.06 (s, 3H), 1.91-1.55 (m, 5H), 1.34-1.13 (m, 2H), 1.02 (m, 1H), 0.93-0.78 (m, 5H). [Example]

[0410] 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 [ka] The title compound (13 mg) was synthesized from Intermediate 3.3 (30 mg, 0.08 mmol), 2-methylpyrazole-3-carboxylic acid (10 mg, 0.08 mmol, CAS: 16034-46-1), 、 This was prepared from HATU (30 mg, 0.08 mmol) and triethylamine (0.03 mL, 0.24 mmol) in MeCN / DMF according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (25 g C18 column, eluting with 10-50% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO) and flash column chromatography on a Biotage Isolera One™ (5 g ZIP silica column, eluting with 0-10% MeOH in DCM). LCMS (Method 3): 1.84 min, 448.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 10.51 (s, 1H), 8.63 (d, 1H), 7.82 (d, 2H), 7.75 (d, 2H), 7.54 (d, 1H), 7.49 (d, 1H), 7.14 (d, 1H), 6.62 (d, 1H), 6.55 (d, 1H), 4.42 (t, 1H), 4.05 (s, 3H), 1.90-1.51 (m, 5H), 1.35-1.11 (m, 2H), 1.02 (m, 1H), 0.92-0.77 (m, 5H). [Example]

[0411] 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 [ka] The title compound (14 mg) was prepared from Intermediate 3.4 (28 mg, 0.07 mmol), 2-methylpyrazole-3-carboxylic acid (8.7 mg, 0.07 mmol, CAS: 16034-46-1), HATU (32 mg, 0.08 mmol), and triethylamine (0.02 mL, 0.17 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column, 30 g, eluting with 30-70% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 12): 2.23 min, 471.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.50 (d, 1H), 8.58 (dd, 1H), 7.91-7.79 (m, 3H), 7.73-7.54 (m, 4H), 7.50-7.44 (m, 1H), 7.39-7.28 (m, 1H), 7.11-7.04 (m, 1H), 6.88 (dd, 1H), 4.41 (dd, 1H), 4.08-4.00 (m, 3H), 1.96-1.52 (m, 5H), 1.38-1.18 (m, 2H), 1.13-1.01 (m, 1H), 0.93-0.80 (m, 5H). [Example]

[0412] 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 [ka] A solution of intermediate 3.6a (200 mg, 0.35 mmol) in MeOH (80 mL) was hydrogenated in an H-Cube® using a Pd(OH)2 / C cartridge at 60 bar and 60°C over 14 runs. The mixture was concentrated in vacuo and then purified by automated reverse-phase column chromatography on a Biotage Isolera One™ (200-400 nm diode array detector, 10 g C18 column, 5-100% MeCN / 0.1% ammonia in HO / 0.1% ammonia solution) to give the title compound (25 mg). LCMS (Method 15): 2.32 min, 448.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 12.20 (s, 1H), 10.21 (s, 1H), 8.51 (d, 1H), 7.70 - 7.62 (m, 2H), 7.46 (d, 1H), 7.25 - 7.17 (m, 2H), 7.07 (d, 1H), 4.38 (t, 1H), 4.03 (s, 3H), 2.17 (s, 6H), 1.90 - 1.56 (m, 5H), 1.32 - 0.79 (m, 8H). [Example]

[0413] 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 [ka] The title compound (47 mg) was prepared from Intermediate 3.7 (93 mg, 0.18 mmol), 2-methylpyrazole-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), HATU (84 mg, 0.22 mmol), and triethylamine (0.1 mL, 0.73 mmol) according to the procedure described for Example 1. The crude product was purified by flash column chromatography (eluting with 25% MeOH in EtOAc) and MDAP (Method 1: 38% MeCN in 0.1% NH4OH). LCMS (Method 3): 2.05 min, 543.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 8.55 (d, 1H), 8.46 (d, 1H), 8.43 (s, 1H), 7.72 (d, 2H), 7.46 (d, 1H), 7.28 (d, 2H), 7.22 (d, 1H), 7.07 (d, 1H), 4.38 (t, 1H), 4.03 (s, 3H), 3.58 (s, 2H), 3.26-3.17 (m, 4H), 1.91-1.54 (m, 9H), 1.37-1.15 (m, 2H), 1.04 (m, 1H), 0.94-0.81 (m, 5H). [Example]

[0414] 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 [ka] The title compound (3.2 mg) was prepared from Intermediate 3.8 (16 mg, 0.04 mmol), 2-methylpyrazole-3-carboxylic acid (16 mg, 0.04 mmol, CAS: 16034-46-1), HATU (18 mg, 0.05 mmol), and triethylamine (0.01 mL, 0.1 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 12 g, eluting with 10-70% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 12): 1.96 min, 477.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.71 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.71 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 1H), 7.04 (d, 1H), 6.38 (d, 1H), 4.53 (dd, 1H), 4.02 (s, 3H), 3.52 (s, 3H), 2.31 (s, 3H), 1.88-1.54 (m, 5H), 1.36-1.19 (m, 2H), 1.17-1.00 (m, 1H), 0.88-0.81 (m, 5H). [Example]

[0415] 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 [ka] The title compound (33 mg) was prepared from Intermediate 3.9 (57 mg, 0.13 mmol), 2-methylpyrazole-3-carboxylic acid (17 mg, 0.13 mmol, CAS: 16034-46-1), HATU (61 mg, 0.16 mmol), and triethylamine (0.05 mL, 0.33 mmol) according to the procedure described for Example 1. The crude product was purified by MDAP (Method 1: 40-70% MeCN in 0.1% NHOH). LCMS (Method 12): 2.29 min, 461.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.77 (s, 1H), 8.50 (d, 1H), 8.36 (s, 2H), 8.22-8.19 (m, 2H), 7.69 (dd, 1H), 7.47 (d, 1H), 7.04 (d, 1H), 4.54 (t, 1H), 4.02 (s, 3H), 2.03 (s, 6H), 1.90-1.75 (m, 2H), 1.75-1.55 (m, 3H), 1.37-1.19 (m, 2H), 1.08 (m, 1H), 0.95-0.80 (m, 5H). [Example]

[0416] 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 [ka] The title compound (2 mg) was prepared from Intermediate 3.8 (11 mg, 0.03 mmol), 2-ethylpyrazole-3-carboxylic acid (3.9 mg, 0.03 mmol, CAS: 400755-43-3), HATU (13 mg, 0.03 mmol), and triethylamine (0.01 mL, 0.07 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 12 g, eluting with 10-70% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 12): 2.07 min, 491.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.71 (s, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 8.14 (d, 1H), 7.71 (dd, 1H), 7.48 (d, 1H), 7.35 (d, 1H), 7.00 (d, 1H), 6.38 (d, 1H), 4.52 (dd, 1H), 4.45 (m, 2H), 3.52 (s, 3H), 2.31 (s, 3H), 1.88-1.78 (m, 2H), 1.73-1.65 (m, 2H), 1.63-1.55 (m, 1H), 1.38-1.20 (m, 5H), 1.16-1.02 (m, 1H), 0.93-0.81 (m, 5H). [Example]

[0417] 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 [ka] The title compound (25 mg) was prepared from Intermediate 3.9 (42 mg, 0.1 mmol), 2-ethylpyrazole-3-carboxylic acid (17 mg, 0.12 mmol, CAS: 400755-43-3), HATU (5.1 mg, 0.12 mmol), and triethylamine (0.05 mL, 0.35 mmol) in DCM according to the procedure described for Example 1. The crude product was purified by MDAP (Method 1: 40-80% MeCN in 0.1% NH4OH). LCMS (Method 12): 2.42 min, 475.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.76 (s, 1H), 8.50 (d, 1H), 8.36 (s, 2H), 8.23-8.18 (m, 2H), 7.69 (dd, 1H), 7.49 (d, 1H), 7.01 (d, 1H), 4.54 (t, 1H), 4.46 (m, 2H), 2.03 (s, 6H), 1.90-1.76 (m, 2H), 1.76-1.57 (m, 3H), 1.37-1.20 (m, 5H), 1.09 (m, 1H), 0.90-0.80 (m, 5H). [Example]

[0418] 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 [ka] The title compound (20 mg) was prepared from Intermediate 3.12 (65 mg, 0.18 mmol), 2-methylpyrazole-3-carboxylic acid (22 mg, 0.18 mmol, CAS: 16034-46-1), HATU (67 mg, 0.18 mmol), and triethylamine (0.05 mL, 0.35 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column, 30 g, eluted with 10-70% MeCN in pH 10 0.1 M NH4HCO3 buffer). LCMS (Method 12): 2.38 min, 439.3 [M+H] + ; 1H NMR (300 MHz, CDCl3) δ: 7.60 (s, 1H), 7.47-7.41 (m, 3H), 7.18 (d, 2H), 6.65 (d, 1H), 6.58 (d, 1H), 4.40 (t, 1H), 4.14 (s, 3H), 4.07 (m, 1H), 4.03 (m, 1H), 3.56-3.44 (m, 2H), 2.78-2.64 (m, 1H), 1.90-1.66 (m, 9H), 1.35-1.05 (m, 3H), 1.02-0.82 (m, 5H). [Example]

[0419] 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 [ka] The title compound (29 mg) was prepared from Intermediate 3.13 (54 mg, 0.16 mmol), 2-methylpyrazole-3-carboxylic acid (20 mg, 0.16 mmol, CAS: 16034-46-1), HATU (71 mg, 0.19 mmol), and triethylamine (0.07 mL, 0.47 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 25 g, eluting with 10-70% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 12): 1.90 min, 452.8 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H), 8.48 (d, 1H), 7.57 (d, 2H), 7.45 (d, 1H), 7.40 (d, 2H), 7.05 (d, 1H), 4.95 (s, 1H), 4.37 (t, 1H), 4.02 (s, 3H), 3.80-3.72 (m, 2H), 3.72-3.65 (m, 2H), 2.00-1.73 (m, 4H), 1.72-1.63 (m, 2H), 1.57 (m, 1H), 1.53-1.46 (m, 1H), 1.24-1.12 (m, 2H), 1.03 (m, 1H), 0.92-0.80 (m, 5H). [Example]

[0420] 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 [ka] The title compound (5.2 mg) was prepared from Intermediate 3.14 (0.11 g, 0.3 mmol), 2-methylpyrazole-3-carboxylic acid (38 mg, 0.3 mmol, CAS: 16034-46-1), HATU (0.14 g, 0.36 mmol), and triethylamine (0.13 mL, 0.9 mmol) according to the procedure described for Example 1. The crude product was purified by reverse-phase column chromatography on a Biotage Isolera One™ (C18 column 25 g, eluting with 5-80% 0.1% ammonia / MeCN in pH 11 0.1% ammonia / HO). LCMS (Method 3): 2.39 min, 435.2 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.52 (d, 1H), 7.62 (d, 2H), 7.46 (d, 1H), 7.40 (d, 2H), 7.07 (d, 1H), 6.19 (m, 1H), 4.37 (t, 1H), 4.21 (m, 2H), 4.02 (s, 3H), 3.81 (t, 2H), 1.90-1.53 ​​(m, 6H), 1.33-0.95 (m, 4H), 0.93-0.78 (m, 5H). [Example]

[0421] N-((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] The title compound (38 mg) was prepared from intermediate 3.15 (69 mg, 0.2 mmol), 2-methylpyrazole-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), HATU (85 mg, 0.22 mmol), and triethylamine (0.1 mL, 0.71 mmol) according to the procedure described for Example 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (12 g silica column, 0-2% MeOH in DCM) and reverse-phase preparative HPLC (Method 2). LCMS (Method 10): 2.68 min, 450.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 7.91 (s, 1H), 7.58 (d, 2H), 7.44 (d, 1H), 7.20 (d, 2H), 6.68 (d, 1H), 6.60 (d, 1H), 4.44 (t, 1H), 4.14 (s, 3H), 2.36 (s, 3H), 2.23 (s, 3H), 1.96-1.81 (m, 3H), 1.81-1.69 (m, 2H), 1.31 (m, 1H), 1.16 (m, 2H), 1.03-0.90 (m, 2H), 0.87 (d, 3H). [Example]

[0422] 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 [ka] The title compound (8.5 mg) was prepared from Intermediate 3.16 (19 g, 0.05 mmol), 2-methylpyrazole-3-carboxylic acid (7.1 mg, 0.06 mmol, CAS: 16034-46-1), HATU (22 mg, 0.06 mmol), and triethylamine (0.01 mL, 0.18 mmol) according to the procedure described for Example 1. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (4 g silica column, eluted with 0-2% MeOH in DCM) and reverse-phase preparative HPLC (Method 2). LCMS (Method 10): 2.61 min, 451.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 10.75 (s, 1H), 8.48 (d, 1H), 8.36 (m, 1H), 8.18 (m, 1H), 7.83 (m, 1H), 7.47 (d, 1H), 7.04 (d, 1H), 4.54 (t, 1H), 3.33 (s, 3H), 2.41 (s, 3H), 2.23 (s, 3H), 1.90-1.54 (m, 5H), 1.35-1.17 (m, 2H), 1.07 (m, 1H), 0.95-0.80 (m, 5H). [Example]

[0423] (S)-N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] A solution of intermediate 5.17 (80 mg, 0.17 mmol) in MeOH (10 mL) was hydrogenated at 50 bar and 60° C. in an H-Cube® using a 10% Pd / C cartridge. The mixture was concentrated in vacuo and the crude compound was purified by preparative SFC (Chiralpak® AD-H, 5 μM, 10 mm ID×250 mm column, 15 ml / min, 20% IPA+1% diethylamine and CO as eluent) to give the title compound (2.3 mg), the stereochemistry of which was assumed based on activity data. LCMS (Method 14): 1.84 min, 482.2 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ: 8.30 (s, 2H), 7.79 (d, 2H), 7.52 (d, 1H), 7.18 (d, 2H), 6.95 (d, 1H), 4.60 (d, 1H), 4.13 (s, 3H), 2.21-1.98 (m, 10H), 1.94-1.75 (m, 3H), 1.67-1.46 (m, 2H). The other inactive enantiomer was also isolated (3.7 mg). [Example]

[0424] 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 [ka] The title compound (3.9 mg) was prepared from intermediate 3.18a (20 mg, 0.04 mmol) and hydrogenated in an H-Cube® using a 10% Pd / C cartridge according to the procedure described for Example 6. The crude product was purified by reverse-phase preparative HPLC (Method 2). LCMS (Method 15): 2.31 min, 450.2 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ: 8.27 (dd, 1H), 8.19 (d, 1H), 7.75 (dd, 1H), 7.51 (d, 1H), 6.94 (d, 1H), 4.57 (d, 1H), 4.12 (s, 3H), 2.29 (s, 6H), 1.99-1.88 (m, 2H), 1.88-1.77 (m, 3H), 1.46-1.17 (m, 3H), 1.09-0.96 (m, 2H), 0.94 (d, 3H). [Example]

[0425] (S)-N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] A solution of intermediate 5.19 (30 mg, 0.06 mmol) in MeOH (5 mL) was hydrogenated at 50 bar and 60° C. in an H-Cube® using a 10% Pd / C cartridge. The mixture was concentrated in vacuo, and the crude compound was purified by flash column chromatography (eluting with 5% MeOH in DCM) and preparative SFC (Chiralpak® AD-H, 5 μM, 10 mm ID×250 mm column, 15 ml / min, 17% IPA+1% diethylamine and CO2 as eluents) to give the title compound (5.3 mg), the stereochemistry of which was assumed based on activity data. LCMS (Method 14): 1.54 min, 474.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.32 (s, 2H), 7.86 (s, 1H), 7.62 (d, 2H), 7.45 (d, 1H), 7.08 (d, 2H), 6.63 (d, 1H), 6.59 (d, 1H), 4.47 (t, 1H), 4.16 (s, 3H), 2.00 (s, 6H), 1.93-1.82 (m, 1H), 1.74-1.64 (m, 2H), 1.40-1.30 (m, 2H), 1.30-1.15 (m, 4H), 0.91 (s, 3H), 0.88 (s, 3H). The other inactive enantiomer was also isolated (3.6 mg). [Example]

[0426] (S)-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 [ka] To a mixture of intermediate 4.20 (45 mg, 0.16 mmol) and intermediate 1 (37 mg, 0.17 mmol) in THF (3 mL) under argon, acetic acid (0.09 mL, 1.6 mmol) was added and the mixture was heated by microwave irradiation at 100° C. for 1 h. The mixture was concentrated in vacuo and purified directly by flash column chromatography (0-10% MeOH in DCM) and preparative SFC (Chiralpak® AD-H, 5 μM, 10 mm ID×250 mm column, 15 ml / min, 40% IPA+1% diethylamine and CO as eluents) to give the title compound (16 mg), the stereochemistry of which was assumed based on activity data. LCMS (Method 14): 2.22 min, 498.2 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ: 7.71 (d, 2H), 7.51 (d, 1H), 7.46 (d, 1H), 7.29 (d, 2H), 6.94 (d, 1H), 6.54 (d, 1H), 4.59 (d, 1H), 4.13 (s, 3H), 3.69 (s, 3H), 2.41 (s, 3H), 2.21-1.97 (m, 4H), 1.94-1.73 (m, 3H), 1.66-1.43 (m, 2H). The other inactive enantiomer was also isolated (15 mg). [Example]

[0427] (S)-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 [ka] A solution of intermediate 5.21 (75 mg, 0.14 mmol) in MeOH (5 mL) was hydrogenated at 30 bar and 60° C. in an H-Cube® using a 10% Pd / C cartridge. The mixture was concentrated in vacuo, and the crude compound was purified by flash column chromatography (eluting with 5% MeOH in DCM) and preparative SFC (Daicel Chiralpak AS-H, 5 μM, 10 mm ID×250 mm column, 15 ml / min, 40% IPA+1% diethylamine and CO as eluents) to give the title compound (2.9 mg), the stereochemistry of which was assumed based on activity data. LCMS (Method 14): 1.79 min, 490.2 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ: 7.71 (d, 2H), 7.51 (d, 1H), 7.46 (d, 1H), 7.28 (d, 2H), 6.93 (d, 1H), 6.54 (d, 1H), 4.53 (d, 1H), 4.12 (s, 3H), 3.69 (s, 3H), 2.41 (s, 3H), 1.95-1.75 (m, 2H), 1.65-1.22 (m, 7H), 0.97 (s, 3H), 0.96 (s, 3H). The other inactive enantiomer was also isolated (3.3 mg). [Example]

[0428] N-(1-cyclooc...

Claims

1. Compounds of Formula I 【Chemistry 1】 [In the formula: X 1 , X 2 , X 3 and X 4 Two of them are CR 5 and two are N; or X 1 , X 2 , X 3 and X 4 Three of them are CR 5 and the others are N; Y is aryl or heteroaryl, each of which is selected from halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy and C 1 ~ 4 optionally substituted with one or more substituents independently selected from haloalkyl; R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 10 membered cycloalkyl ring, where the cycloalkyl ring is: a. Halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl and C 1 ~ 4 optionally substituted with one or more substituents independently selected from haloalkoxy; and b. C 3 ~ 5 optionally spiro-linked to a cycloalkyl group; R 3 is hydrogen, fluoro or C 1 ~ 4 is alkyl; R 4 teeth: (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 , CO 2 R 10 and C 1 ~ 3 Alkylene-R 11 Independence from a 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from the following: (B) optionally fused to a 5- to 6-membered heteroaryl ring, and 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl, cyano, NR 6 R 7 , C(O)NR 8 R 9 , CO 2 R 10 and C 1 ~ 3 Alkylene-R 11 one independently selected from or more optionally substituted partially unsaturated heterocyclic rings; R 5 is hydrogen, fluoro, chloro, methyl, methoxy or trifluoromethyl; R 11 is hydroxy, halo, C 1 ~ 4 Alkoxy, cyano, NR 12 R 13 , C(O)R 14 , aryl or heteroaryl; R 14 is hydroxy, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy or NR 15 R 16 and R 6 , R 7 , R 8 , R 9 , R 10 , R 12 and R 13 is hydrogen and C 1 ~ 4 independently selected from alkyl; R 15 and R 16 is hydrogen and C 1 ~ 4 alkyl; or R 15 and R 16 taken together 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 and N; C 1 ~ 4 optionally substituted with alkyl; or a pharmaceutically acceptable salt thereof.

2. X 1 is N and X 2 , X 3 and X 4 The compound of claim 1 , wherein is CH.

3. Y is halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy and C 1 ~ 4 3. The compound of claim 1 or 2, which is heteroaryl optionally substituted with one or more substituents independently selected from haloalkyl.

4. Y is halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy and C 1 ~ 4 4. The compound of claim 3, which is a 5- or 6-membered heteroaryl ring optionally substituted with one or more substituents independently selected from haloalkyl.

5. Y is halo, C 1 ~ 3 Alkyl, C 1 ~ 2 Alkoxy and C 1 ~ 2 4. The compound of claim 3, which is a heteroaryl ring optionally substituted with one or more substituents independently selected from haloalkyl.

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

7. 4. The compound of claim 3, wherein Y is a 5- to 6-membered heteroaryl ring substituted with methyl or ethyl in the ortho position relative to the NHC(O)-moiety.

8. Y is: 【Chemistry 2】 [In the formula, 【Transformation 3】 is the point of attachment to the remainder of the compound of Formula I; Y is halo, C 1 ~ 3 Alkyl, C 1 ~ 2 Alkoxy and C 1 ~ 2 one or more independently selected from haloalkyl 3. The compound of claim 1 or 2, optionally substituted by a substituent.

9. R 1 and R 2 together with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl ring, where the cycloalkyl ring is: a. Halo, C 1 ~ 2 Alkyl, C 1 ~ 2 Alkoxy and C 1 ~ 2 optionally substituted with one or more substituents independently selected from haloalkyl; and b. C 3 ~ 5 9. The compound of any one of claims 1 to 8, optionally spiro-linked to a cycloalkyl group.

10. R 1 and R 2 together with the carbon atoms to which they are attached, 【Chemistry 4】 forming a group selected from In the formula, * represents R 1 and R 2 is the carbon atom to which R is bonded, 17 Each occurrence of 1 ~ 2 Alkyl, C 1 ~ 2 Alkoxy and C 1 ~ 2 9. The compound of claim 1, wherein m is independently selected from haloalkyl and m is 0, 1, 2, or 3.

11. R 1 and R 2 together with the carbon atom to which they are attached form the following group: 【Transformation 5】 Forming In the formula, * represents R 1 and R 2 is a carbon atom to which each R 17 is independently selected from hydrogen, fluoro, methyl and trifluoromethyl.

12. R 3 12. The compound of claim 1, wherein is hydrogen.

13. R 4 is hydroxy, halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 2 Fluoroal Kill, Cyano, NR 6 R 7 , C(O)NR 8 R 9 and C 1 ~ 3 Alkylene-R 11 13. The compound of any one of claims 1 to 12, which is a 5- to 10-membered heteroaryl optionally substituted with one or more substituents independently selected from:

14. R 4 is fluoro, chloro, methyl, methoxy, cyano, NR 6 R 7 and C.H. 2 -R 11 optionally substituted by one or more substituents independently selected from The compound of any one of claims 1 to 12, which is a 5- to 6-membered monocyclic heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring.

15. R 4 is optionally fused to a 5- to 6-membered heteroaryl ring, and is , oxo, C 1 ~ 2 Alkyl, C 1 ~ 2 Alkoxy, C 1 ~ 2 13. The compound of any one of claims 1 to 12, which is a partially unsaturated heterocyclic ring optionally substituted with one or more substituents independently selected from haloalkyl and cyano.

16. R 4 is the following group: 【Transformation 6】 [In the formula: 【Transformation 7】 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 and C 1 ~ 3 Alkylene-R 11 are independently selected from R 19 is hydrogen, C 1 ~ 4 Alkyl and C 1 ~ 3 Alkylene-R 11 are independently selected from 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 substituent is a bicyclic group. can be present in any ring of 13. A compound according to any one of claims 1 to 12.

17. R 18 is hydroxy, fluoro, chloro, methyl, methoxy, CF 3 , N.R. 6 R 7 and C 1 ~ 3 Alkylene-R 11 independently selected from R 19 is independently selected from hydrogen and methyl.

18. Structural formula IA, IB, IC or ID shown below: 【Transformation 8】 [In the formula, X 1 From X 4 and R 4 is as defined in claim 1; Each R 17 Ha, Halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl and C 1 ~ 4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl and C 1 ~ 4 independently selected from haloalkoxy; n is 0 to 4.

2. The compound of claim 1, having one of:

19. Structural formula IE, IF, IG, IH, IJ, IK, IL or IM shown below: 【Chemistry 9】 [In the formula, Y, R 1 , R 2 , R 3 , R 4 and R 5 is as defined in claim 1; Each R 17 Ha, Halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl and C 1 ~ 4 independently selected from haloalkoxy; R 20 and R 21 is hydrogen, halo, C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, C 1 ~ 4 Haloalkyl and C 1 ~ 4 independently selected from haloalkoxy; n is 0 to 4.

2. The compound of claim 1, having one of:

20. R 20 and R 21 20. The compound of claim 18 or 19, wherein: is independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy; and n is 0.

21. Each R 5 21. The compound of claim 19 or 20, wherein is hydrogen.

22. The following compound: 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; 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; 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-(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-((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-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)-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 (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-pyrazole-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-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide; (S)—N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-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)pyrazole (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-methylcyclohexyl)-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)pyridin-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[2.1.2 5 .2 3 ]nonan-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

24. 24. A pharmaceutical composition according to claim 23 for use in therapy.

25. 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, especially 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-associated arthritis, infection-related endotoxic shock, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, myocardial infarction and atherosclerosis 24. The pharmaceutical composition of claim 23 for use in the treatment of heart disease including ischemic disease, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barré syndrome, infections (viral, bacterial, fungal and parasitic), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, hepatic fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis, Parkinson's disease, pelvic inflammatory disease, pain (especially pain associated with inflammation), periodontitis, peritonitis, Peyronie's disease, pilonidal disease, 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 1 diabetes, ulcerative colitis, uveitis or vasculitis.

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