Inhibitors of TYK2

Abstract

In exemplary embodiments, the invention provides inhibitors of tyrosine kinase 2 (TYK2), pharmaceutical formulations comprising these compounds, methods of using these compounds to inhibit TYK2 and treat diseases, such as autoimmune and inflammatory diseases.

Description

Cross-references to related applications

[0001] This U.S. patent application claims priority to Provisional Patent Application No. 63 / 505,969, filed June 2, 2023, and Provisional Patent Application No. 63 / 618,980, filed January 9, 2024, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] This invention belongs to the field of effective and selective small molecule inhibitors of tyrosine kinase 2 (TYK2), pharmaceutical formulations containing these compounds, and methods of using these compounds to treat or prevent diseases involving TYK2. Background Technology

[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and type I and type III interferon receptors and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncokinin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Activated TYK2 then continues to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. These cytokines are involved in the pathogenesis of a variety of autoimmune diseases, such as psoriasis, inflammatory bowel disease (IBD), and lupus.

[0004] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members are recognized: JAK1, JAK2, JAK3, and TYK2. When a cytokine binds to its receptor, JAK family members autophosphorylate and / or transphosphorylate each other, followed by STAT phosphorylation, and then migration to the nucleus to regulate transcription. JAK-STAT intracellular signal transduction is effective for interferons, most interleukins, and various cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL.

[0005] TYK2 plays a crucial role in the signaling of type I interferons (IFN-α, INF-β), IL-6, IL-10, IL-12, and IL-23. Therefore, TYK2 signals in combination with other members of the JAK kinase family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2. TYK2 has demonstrated importance in the differentiation and function of various cell types, including natural killer cells, B and T helper cells, which are essential for inflammatory and autoimmune diseases.

[0006] Some autoimmune diseases are thought to be mediated by TYK2 signaling of certain pro-inflammatory cytokines (see, for example, JS Tokarski et al., Journal of Biochemistry). J. Biol. Chem. ), Vol. 290(17):11061-11074 (2015); and L. Marroqui et al., Diabetes ( Diabetes ), Vol. 64: 3808-3817 (2015). Psoriasis and other autoimmune diseases such as diabetes are thought to be mediated by TYK2 signaling of certain pro-inflammatory cytokines. TYK2 is considered to be a psoriatic skin inflammation (Ishizaki et al., International Journal of Immunology, Vol. 64: 3808-3817 (2015)). Int Immunol. )》 2014 26(5):257-67), Psoriatic Arthritis (Mease et al., Rheumatology Yearbook ( Ann Rheum Dis. )》 2022 81(6): 815-822) and inflammatory bowel disease (IBD) (Nielsen et al., Trends in Pharmacological Sciences ( Trends Pharmacol Sci. The therapeutic target of ( )》 2022 43(5): 424-436).

[0007] TYK2 mediates signal transduction via IL-12 family receptors (IL-12R and IL-23R). Interleukin-23 (IL-23) cytokines are considered to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and conditions such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the major roles of IL-23R and downstream effector cytokines in disease pathogenesis.

[0008] IL-12 and IL-23, which respectively encompass the subunits p40 / p35 and p40 / p19, signal through receptor complexes of IL-12Rβ1 / IL-12Rβ2 and IL-12Rβ1 / IL-23R, respectively. IL-12 is essential for the differentiation of IFN-γ-producing T helper (Th)1 cells and the development of the TH1 immune response, while IL-23 maintains the survival, proliferation, and effector function of Th17 cells. Activated Th17 cells produce various effector cytokines, including IL-17A and IL-17F.

[0009] Inhibition of the IL-23 pathway has been shown to be effective in treating IL-23-related diseases and conditions. Several antibodies binding to IL-23 or IL-23R have been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn's disease, and moderate to severe active ulcerative colitis. Clinical trials using briakinumab (which also targets the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which targets the unique p19 subunit of IL-23) in Crohn's disease or psoriasis highlight the potential of IL-23 signaling blockade in the treatment of human inflammatory diseases. While these findings are promising, challenges remain in identifying stable and selective agents that preferentially target one or more components of the IL-23 pathway.

[0010] JAK inhibitors have been successfully developed for clinical use, initially for organ transplant rejection, but later for other immune-inflammatory indications such as inflammatory bowel disease (IBD), atopic dermatitis (AD), rheumatoid arthritis (RA), psoriasis, and Crohn's disease (http: / / clinicaltrials.gov / ). TYK2 is a target for the treatment of autoimmune and inflammatory diseases, as confirmed by human genetics and mouse knockout studies.

[0011] There is a search for potent and selective compounds for the treatment of autoimmune and inflammatory diseases. Clearly, there remains a need in the art for novel therapeutic agents for these diseases, and agents targeting JAK family protein kinases, particularly TYK2, are promising candidates. Compounds that inhibit TYK2 should be readily synthesized in acceptable yields, stable, bioavailable, and administerable, exhibiting high efficiency, selectivity, and superior pharmacokinetic properties against TYK2. This disclosure describes such compounds and methods for treating and preventing autoimmune and inflammatory diseases using such compounds. Summary of the Invention

[0012] This invention provides a novel class of effective and selective small-molecule TYK2 activity modulators. The exemplary compounds described in this disclosure are effective and selective inhibitors of TYK2, and upon binding to TYK2, the compounds reduce the activity of this kinase, and in some embodiments, this reduction in TYK2 activity leads to a concomitant reduction in certain cytokine signaling (e.g., IL-23 signaling). In some embodiments, the compounds are selective for TYK2 compared to other JAKs.

[0013] In an exemplary embodiment, the present invention provides a compound according to Formula I:

[0014] ,

[0015] Or its solvates, hydrates, pharmaceutically acceptable salts, tautomers, or prodrugs.

[0016] In equation I, X 1 Selected from N and CR 1 R 1 It is a member selected from the following: H, halogens, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 alkoxy groups. X and X 2 Independently selected from N and CH. R 2 Members selected from the following:

[0017]

[0018] Where R 5 It is a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C6 alkyl group (C1, C2, C3, C4, C5, or C6). R 5' R 6 and R 6' It is a member independently selected from H and substituted or unsubstituted alkyl groups (e.g., substituted or unsubstituted C1-C6 alkyl groups). X 3 Selected from N and CR 7 X 4 Selected from N and CR 8 X 5 Selected from N and CR 9 Part of R 7 R 8 R 9 and R 10 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl groups (C1, C2, C3, C4, C5, or C6), and substituted or unsubstituted C1-C6 aminoalkyl groups (C1, C2, C3, C4, C5, or C6), wherein R 7 and R8 Or R 8 and R 9 It is optionally linked together with the carbon atom to which it is attached to form a ring selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl.

[0019] In an exemplary embodiment, when R 7 and R 8 and R 8 and R 9 None of them are bonded together with the carbon they are attached to to form a ring, and no more than one is selected from R. 7 R 8 and R 9 When the member is not H, R 9 The following are not included:

[0020]

[0021] Where z is 0 or 1.

[0022] In an exemplary embodiment, when at least one is selected from R 7 R 8 and R 9 When the member is Me, R 2 yes:

[0023] .

[0024] This document also provides pharmaceutical formulations that combine the compounds of the present invention with / or their solvates, hydrates, pharmaceutically acceptable salts, tautomers, or prodrugs in combination with pharmaceutically acceptable carriers.

[0025] In some embodiments, a method is provided for inhibiting TYK2 using a compound of the present invention or a solvate, hydrate, pharmaceutically acceptable salt, tautomer, or prodrug thereof. The method may be performed in vitro or in vivo and generally involves contacting TYK2 with a compound of the present invention, said compound being a TYK2 inhibitor in an amount sufficient to inhibit TYK2. Exemplary methods further include detecting and / or quantifying the degree of TYK2 inhibition. In some embodiments, the inhibition occurs in a subject and forms the basis of a method for treating a subject requiring such treatment who suffers from a disease sensitive to treatment with a TYK2 inhibitor.

[0026] Further objects and embodiments of the invention will become apparent from the following detailed description. Attached Figure Description

[0027] Figure 1A-Figure 1BThe exemplary compound (EC) of the present invention exhibits dose-dependent inhibition of ear swelling and skin IL-17A levels in an IL-23-induced PD inflammation model. (A) Ear swelling. (B) Ear skin IL-17A. For the untreated group (two-tailed t-test); Countermeasures (one-dimensional ANOVA and Dunnett multiple comparison test).

[0028] Figures 2A-2H Exemplary compounds of the present invention show dose-dependent inhibition of the psoriasis score (PASI), dorsal skin histopathological score, and relative spleen weight in a 7-day imiquimod-induced psoriasis mouse model. (A) PASI score. ; ; (B) Histopathological score. (A) Two-way ANOVA and Dunnett multiple comparison test. For the untreated group (two-tailed t-test); (C) Relative spleen weight. (Using mediators: one-dimensional ANOVA and Dunnet multiple comparison test) For the untreated group (two-tailed t-test); ; Mediators (one-way ANOVA and Dernett multiple comparison test). (D) Representative sections of H&E-stained skin tissue show IMQ-induced mild epidermal inflammation (small arrows) and significant dermal inflammation ( And significant epidermal hyperplasia (large arrow) and improvement in animals treated with exemplary compounds. Improvement of the disease was also observed by the levels of pro-inflammatory cytokines / chemokines in the dorsal skin tissue of the following: (E) IL-17A (pg / mL); (F) GM-CSF (pg / mL); (G) TNF-α (pg / mL); and (H) MIP1a (pg / mL). ; ; For the untreated group (two-tailed t-test); ; ; Countermeasures (one-dimensional ANOVA and Dunnett multiple comparison test).

[0029] Figure 3 Exemplary compounds of the present invention exhibit selective kinase maps. (A) Screening against the scanEDGE kinase map: TYK2-JH2 against IC50 for pABL1 (E255K), pABL1 (T315I), pABL1, and ABL1. 50(app) The selectivity values ​​were 580x, 1300x, 370x, and 200x, respectively. Kinase fractionation index. The selectivity relative to safety was also measured across 47 groups: IC50 across a group of GPCRs, ion channels, enzymes, and receptors. 50 > 1 µM [LCK IC] 50 =20 nM, incorporated into the kinase group P TYK2-JH2 middle]. Cheng et al., *Journal of Medicinal Chemistry (JMC)*, 2010. IC 50(app) = 2-point IC50 approximation.

[0030] Figures 4A-4B Exemplary compounds of the present invention exhibit selectivity for TYK2-JH2. (A) Selectivity for TYK2-JH2 measured against individual members of the JAK family (JH1 kinase domain and JH2 pseudokinase domain) in a biochemical binding assay. Cellular selectivity against (B) TYK2-JH2 (IL-12 / pSTAT4) relative to the JAK1 / JAK2 (IL-6 / pSTAT3) pathway was demonstrated in a cytokine-induced phosphorylation assay.

[0031] Figures 5A-5B Exemplary compounds of the present invention have been shown to be effective against TYK2-JH2 in whole blood in the (A) IFNα / pSTAT5 and (B) IL-23 / pSTAT3 signaling pathways.

[0032] Figure 6A-6I Exemplary compounds of the present invention demonstrate dose-dependent inhibition of (A) colon weight-to-length ratio and (B) colon histopathological score in a 7-day anti-CD40-induced inflammatory bowel disease (IBD) mouse model. (C) Representative sections of H&E-stained colon tissue show glandular absence. Improvements were observed in animals treated with the exemplary Atomwise compound. Improvements were also observed in colon tissue levels of the following pro-inflammatory cytokines / chemokines: (D) IFNγ (pg / mL); (E) IL-1β (pg / mL); (F) TNF-α (pg / mL); (G) IL-6 (pg / mL); (H) IL-22 (pg / mL); and (I) IP-10 (pg / mL). ; For the untreated group (two-tailed t-test); ; ; ; Countermeasures (one-dimensional ANOVA and Dunnett multiple comparison test).

[0033] Figures 7A-7BExemplary compounds of the present invention exhibit dose-dependent inhibition of clinical scores in a 28-day MOG(35-55)-induced chronic experimental autoimmune encephalomyelitis (EAE) model in C57BL / 6 mice. Inhibition was observed by prophylactic administration of the exemplary compounds and by therapeutic administration of the exemplary compounds in (A) and (B) respectively. Detailed Implementation

[0034] A. Introduction

[0035] The compounds, their solvates, hydrates, pharmaceutically acceptable salts, tautomers, and prodrugs of the present invention are potent and selective TYK2 inhibitors. The TYK2 kinase inhibitory activity and selectivity for this target of the compounds provided herein can be readily determined using assays recognized in the art (such as those illustrated in the examples below).

[0036] The TYK2 kinase-modulating activity of a compound can be advantageously utilized in various methods of treating diseases in which TYK2 plays a role in the development or progression of diseases (e.g., autoimmune diseases and inflammatory diseases). Various uses of the compound generally involve contacting a therapeutically effective amount of the compound with a TYK2 kinase, thereby modulating the activity of TYK2. Modulation of the TYK2 kinase can be performed in vitro to study the disease or its treatment, or in vivo to treat the disease. In an exemplary embodiment, the modulation is the inhibition of the TYK2 kinase.

[0037] The potency and selectivity of the compounds of the present invention are advantageous in the chronic and acute treatment of inflammatory diseases and autoimmune diseases. In the context of the present invention, autoimmune diseases are diseases at least in part caused by an immune response of the body to its own components (e.g., proteins, lipids, or DNA). In various embodiments, the treated diseases are mediated by IL-12 and / or IL-23, and TYK2 plays a role in the signaling pathways of these cytokines.

[0038] Examples of diseases that can be treated by the compounds, formulations, and methods of the present invention include, but are not limited to, psoriasis, plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and lupus.

[0039] Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population. It is characterized by red, scaly plaques of skin, typically found on the scalp, elbows, and knees, and can be associated with severe arthritis. The lesions are caused by abnormal proliferation of keratinocytes and infiltration of inflammatory cells into the dermis and epidermis (Schon et al., 2005, *The New England Journal of Medicine*). New Engl. J. Med. )》 352: 1899-1912).

[0040] The suitability of a compound for the treatment of psoriasis can be determined by testing its effect on imiquimod-induced psoriasis-like skin inflammation in mice: see, for example, Mori et al., Kobe J. Med. Sci., Vol. 62, No. 4, pp. E79-E88, 2016; van der Fits et al., Journal of Immunology ( The Journal of Immunology ( ), 2009; 182: 5836-5845; and Lin et al., PLOS ONE, IDOI:10.1371 / joumal.pone.0137890 September 10, 2015. Therefore, imiquimod can be applied topically to mice (e.g., to the skin on the back of mice) to induce psoriasis-like inflammation and desquamation, and the levels of inflammation and desquamation can be compared with those in mice (or areas of the mouse body) treated with the same compound of the present invention or a control without imiquimod.

[0041] Inflammatory bowel disease (IBD) is characterized by chronic, relapsing bowel inflammation. IBD is subdivided into Crohn's disease and ulcerative colitis phenotypes. Crohn's disease most frequently involves the terminal ileum and colon and is transmural and discontinuous. In contrast, in ulcerative colitis, the inflammation is continuous and confined to the rectal and colonic mucosa. In approximately 10% of cases confined to the rectum and colon, a clear classification between Crohn's disease and ulcerative colitis is not possible, and it is designated as 'indeterminate colitis'. Both diseases involve extraintestinal inflammation of the skin, eyes, or joints. Neutrophil-induced damage can be prevented by using neutrophil migration inhibitors (Asakura et al., 2007, World Journal of Gastroenterology). World J. Gastroenterol. )》 13(15): 2145-9).

[0042] Systemic lupus erythematosus (SLE) is a chronic inflammatory disease caused by T-cell-mediated B-cell activation, which leads to glomerulonephritis and renal failure. Early human SLE is characterized by the expansion of long-term autoreactive CD4+ memory cells (D'Cruz et al., 2007, Lancet 369(9561):587-596).

[0043] Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings. Numerous specific details are set forth in the following detailed description to provide a thorough understanding of this disclosure. However, it will be apparent to those skilled in the art that this disclosure can be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to unnecessarily obscure various aspects of the embodiments.

[0044] It should also be understood that although the terms first, second, etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first property may be referred to as a second property without departing from the scope of this disclosure, and similarly, a second property may be referred to as a first property. Both the first property and the second property are properties, but they are not the same property.

[0045] B. Definition

[0046] The terminology used in this disclosure is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used in the description of the invention and the appended claims, the singular forms “a / an” and “the” are intended to equally include the plural forms unless the context clearly indicates otherwise. It should also be understood that, as used herein, the term “and / or” refers to and covers any and all possible combinations of one or more of the related enumerated items. It will be further understood that, when used in this specification, the terms “comprises” and / or “comprising” specify the presence of the stated features, integers, steps, but do not exclude the presence or addition of one or more other features, integers, steps, and / or groups thereof.

[0047] As used herein, depending on the context, the term “if” can be interpreted as meaning “when”, “upon”, “in response to determination”, or “in response to detection”. Similarly, depending on the context, the phrase “if determination” or “if [the stated condition or event] is detected” can be interpreted as meaning “when determination”, “in response to determination”, “when [the stated condition or event] is detected”, or “in response to the detection of [the stated condition or event]”.

[0048] As used herein, the terms "about" or "approximately" can mean within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which can depend in part on how the value was measured or determined, for example, limitations of the measurement system. For example, according to practice in the art, "about" can mean within one or more standard deviations. "About" can mean a range of ±20%, ±10%, ±5%, or ±1% for a given value. When a particular value is described in this application and claims, unless otherwise stated, the term "about" means within an acceptable margin of error for that particular value. The term "about" can have the meaning commonly understood by one of ordinary skill in the art. The term "about" can mean ±10%. The term "about" can mean ±5%.

[0049] As used herein, “substantially” means at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 94%, at least about 96%, at least about 98%, or at least about 90% of the total weight of gangliosides in the composition.

[0050] The term "in vivo" refers to events that occur within the body of a subject.

[0051] The term "in vitro" refers to an event that occurs outside the subject's body. In vitro assays encompass cell-based assays using live or dead cells, and may also encompass cell-free assays that do not use intact cells.

[0052] In exemplary embodiments, the pharmaceutical formulations of the present invention comprise a therapeutically effective amount of the compounds of the present invention. As used herein, "therapeutically effective amount" or "effective amount" means an amount of the pharmaceutical formulation of the present invention that is effective in treating cells or in curing, alleviating, relieving, or improving symptoms of a disease when administered to a subject in a single or multiple doses. The effective amount of a composition can vary depending on factors such as an individual's disease state, age, sex, and weight, and the ability of the compound to elicit a desired response in an individual. The term also applies to the dose that will induce a specific response in target cells. The specific dose will vary depending on the particular compound selected, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue in which the compound is administered, and the physical delivery system in which the compound is carried. An effective amount is also an amount in which the beneficial therapeutic effect outweighs any toxic or adverse effects of the composition.

[0053] In various embodiments, the term "therapeuticly effective amount" refers to the amount of compound that provides the desired therapeutic effect when administered according to the desired dosing regimen. Dosing may occur at intervals of minutes, hours, days, weeks, months, or years, or may occur continuously within any of these time periods. Exemplary suitable doses may range from about 0.1 ng / kg body weight / dose to 1 g / kg body weight / dose, such as from 1 mg / kg body weight / dose to 1 g / kg body weight / dose. In one embodiment, the dose may range from 1 mg / kg body weight / dose to 500 mg / kg body weight / dose. In another embodiment, the dose may range from 1 mg / kg body weight / dose to 250 mg / kg body weight / dose. In yet another embodiment, the dose may range from 1 mg / kg body weight / dose to 100 mg / kg body weight / dose.

[0054] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of a disease or symptom, slowing, stopping or reversing the progression of a disease or symptom, or any combination thereof.

[0055] In exemplary embodiments, the compositions of the present invention are useful when administered to a subject in an effective amount to prevent disease or symptoms of disease. As used herein, the term “preventing” as used in the context of administering a medicament to a subject means subjecting the subject to a regimen, such as administration of the pharmaceutical formulation of the present invention, such that the onset of at least one symptom of the disease is delayed compared to what would be observed in the absence of said regimen.

[0056] In various embodiments, the compositions of the present invention are administered to a subject to treat or prevent a disease or symptoms of a disease. As used herein, the term "subject" is intended to include both humans and non-human animals. Exemplary human subjects include human patients suffering from a condition, such as those described herein, or normal subjects. The term "non-human animal" includes all vertebrates, such as non-mammals (e.g., chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, such as sheep, dogs, cats, cattle, pigs, etc.

[0057] As used herein, the term "treat / treating" refers to subjecting a patient with a condition to a treatment, such as administration of the pharmaceutical formulation of the present invention, that results in the cure, eradication, relief, mitigation, alteration, remedy, reduction, or improvement of at least one symptom of the condition. Treatment includes the administration of an amount that effectively relieves, alleviates, alters, remedies, reduces, improves, or influences the condition or its symptoms. Treatment can inhibit the worsening or exacerbation of the symptoms of the condition.

[0058] In various embodiments, the compounds of the present invention are administered to subjects in therapeutically effective amounts to achieve therapeutic effects, thereby treating or preventing disease, improving or preventing disease symptoms. As used herein, the terms “administer / administration / administering” mean (1) being provided, given, administered, and / or prescribed by a healthcare professional or authorized agent or under the guidance of a healthcare professional or authorized agent, in accordance with this disclosure; and / or (2) being placed in the body, taken or ingested by a mammal, in accordance with this disclosure.

[0059] In various embodiments, the compounds of the present invention are co-administered with the present invention or other second compounds to a subject to achieve, enhance, or modulate the therapeutic effect of the compounds of the present invention. As used herein, the terms “co-administration,” “co-administering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent” cover the administration of two or more active pharmaceutical ingredients to a subject such that the two active pharmaceutical ingredients and / or their metabolites are simultaneously present in the subject’s body. Co-administration includes simultaneous administration in the form of individual compositions, administration in the form of individual compositions at different times, or administration in the form of a composition containing two or more active pharmaceutical ingredients.

[0060] The term "pharmaceutically acceptable salt" includes salts of active compounds prepared with a relatively non-toxic acid or base using specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired base, either purely or in a suitable inert solvent. Examples of pharmaceutically acceptable salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, either purely or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids (such as arginine) and salts of organic acids (such as glucuronic acid or galacturonic acid) (see, for example, Berge et al., *Journal of Pharmaceutical Sciences*). Journal of Pharmaceutical Science (Reference: 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt.

[0061] Basic nitrogen-containing groups can be quaternized with the following reagents: such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfate esters, such as dimethyl sulfate and diethyl sulfate; and others.

[0062] The neutral form of the compound may optionally be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salt is equivalent to the parent form of the compound.

[0063] It should be understood that any compound that serves as a prodrug of the compounds of this invention is also within the scope and spirit of this invention. Therefore, the compounds of this invention can be administered to a subject in a pharmaceutically acceptable prodrug form. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of this invention. Such derivatives are readily apparent to those skilled in the art. Other literature commonly describing prodrugs (and their preparation) includes: [The text abruptly ends here, likely due to an incomplete translation or a missing section.] Design of Prodrugs ) , 1985, H. Bundgaard (Elsevier); Medicinal Chemistry Practice ( The Practice of Medicinal Chemistry ) , 1996, Camille G. Wermuth et al., Chapter 31 (Academic Press); and "Textbook of Drug Design and Development" ( A Textbook of Drug Design and Development (Ref. , 1991, Bundgaard et al., Chapter 5, Harwood Academic Publishers). For example, the N atom on the hydroxyindole ring can react with an acid (e.g., acetic acid). An exemplary pharmaceutically acceptable prodrug is a pharmaceutically acceptable ester.

[0064] Some compounds of the present invention can exist in both non-solventized and solvated forms (including hydrated forms). Generally, the solvated form is equivalent to the non-solventized form and is covered within the scope of the present invention. Some compounds of the present invention can exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0065] The term "solvent" refers to the physical association of one of the compounds of the present invention with one or more solvent molecules. This physical association includes hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" encompasses both the solution phase and the insoluble solvate. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, semi-ethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and solvates of other physiologically acceptable solvents, such as those of Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). The compounds described herein also include each of their solvates and mixtures thereof.

[0066] As used herein, "pharmaceuticalally acceptable excipient" refers to a recognized additive in the pharmaceutical formulation of an active pharmaceutical preparation. Exemplary excipients include buffers, salts (e.g., NaCl), sugars, sugar alcohols, and amino acids (e.g., arginine, glycine). These excipients are generally safe for human administration according to established government standards, including those issued by the United States Food and Drug Administration. Representative non-limiting examples include agar, alginate, calcium carbonate, carboxymethyl cellulose, cellulose, gum, low-substituted hydroxypropyl cellulose, sodium glycolate starch, carbonates, calcium phosphate, dicalcium phosphate, tricalcium sulfate, calcium carboxymethyl cellulose, cellulose, dextrin derivatives, dextrin, dextran, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, sorbitol, starch, sucrose, sugar, xylitol, calcium stearate, ethyl oleate, ethyl laurate, glycerol, palmitoyl stearate, mannitol, porrosham, diol, sodium benzoate, and sodium lauryl sulfate.

[0067] Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and monomeric isomers are covered within the scope of the present invention.

[0068] The compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may contain radioactive isotopes (e.g., tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14C) Radioactive labeling. 2 H may be present at one or more sites in the compounds of the present invention. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be covered within the scope of the present invention.

[0069] The terms "pharmaceutically acceptable carrier, adjuvant, or mediator" and equivalent expressions refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated with them. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0070] "Pharmaceutical acceptable derivative" means any non-toxic salt, ester, ester salt, prodrug, prodrug salt or other derivative of the compound described in this specification that, when administered to a recipient, can directly or indirectly provide the compound described in this specification or its inhibitory active metabolites or residues.

[0071] As used herein, “exemplary compound” or “EC” refers to a compound that is presented as a test article in examples and whose data are provided in the accompanying drawings, and refers to structurally closely related analogs such as compounds 1-80 shown in Table 1.

[0072] "Known TYK2 inhibitor" refers to a small molecule therapeutic agent that is known in the art as a TYK2 inhibitor and has been shown to have favorable biological, pharmacological, and (in some instances) therapeutic properties in indications involving TYK2 inhibition.

[0073] As used herein, “biological media” refers to biological environments both in vitro and in vivo. Exemplary in vitro “biological media” include, but are not limited to, cell cultures, tissue cultures, homogenates, plasma, and blood. In vivo applications are typically performed in mammals, preferably humans.

[0074] The compounds and methods of this invention are particularly useful for treating or preventing inflammatory and autoimmune diseases. As used herein, an "inflammatory disease" is a disease in which the proliferation of lymphoid tissue leads to damage to the tissue or organ that causes the disease. For example, excessive T cell proliferation at a site of tissue or organ will cause damage to said tissue or organ. Inflammatory processes are well known in the art and have been extensively described in medical textbooks (see, for example, Harrison's Principles of Experimental Medicine, 13th edition, McGraw-Hill, Inc., NY). An "autoimmune disease" is a disease caused at least in part by an immune response of the body to its own components, such as proteins, lipids, or DNA.

[0075] In an exemplary embodiment, the present invention provides a method for treating or preventing an inflammatory process, the method involving administering a therapeutically effective amount of the compound of the present invention to a subject suffering from an inflammatory process.

[0076] Many diseases are associated with abnormalities in the inflammatory process.

[0077] "alkyl" refers to an unsaturated group consisting of only carbon and hydrogen atoms, having one to ten carbon atoms (e.g., C1). 1-10 )alkyl or C 1-10 Alkyl groups are straight-chain or branched hydrocarbon chain groups. Whenever they appear herein, numerical ranges such as “1 to 10” refer to each integer within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” without a specifically specified numerical range. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butylisobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl moiety can be linked to the rest of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and 3-methylhexyl. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more substituents, which are independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a)2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0078] "alkylaryl" means -(alkyl)aryl, wherein the alkyl and aryl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein for the substituents applicable to the alkyl and aryl groups.

[0079] "alkylheteroaryl" means -(alkyl)heteroaryl, wherein the alkyl and heteroaryl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the alkyl and heteroaryl groups.

[0080] "alkyl heterocyclic alkyl" means -(alkyl)heterocyclic alkyl, wherein the alkyl and heterocyclic alkyl are as disclosed herein and they are optionally substituted with one or more of the substituents described herein for the substituents applicable to the alkyl and heterocyclic alkyl.

[0081] "Alkenyl" or "olefin" refers to an olefin consisting only of carbon and hydrogen atoms, containing at least one double bond and having two to ten carbon atoms (i.e., C2O4 ... 2-10 alkenyl or C 2-10An alkenyl group is a straight-chain or branched hydrocarbon chain group. Whenever it appears herein, numerical ranges such as “2 to 10” refer to each integer within a given range; for example, “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, including 10 carbon atoms. The alkenyl moiety can be connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, and pentenyl-1,4-dienyl. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with one or more substituents, which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0082] "Alkenyl-cycloalkyl" means -(alkenyl)cycloalkyl, wherein the alkenyl and cycloalkyl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the alkenyl and cycloalkyl groups.

[0083] "Alkyne" or "alkynyl group" refers to a hydrocarbon consisting of two to ten carbon atoms, containing at least one triple bond, and composed only of carbon and hydrogen atoms. 2-10 ) acetylene or C 2-10 A alkynyl group is a straight-chain or branched hydrocarbon chain group. Whenever it appears herein, numerical ranges such as "2 to 10" refer to each integer within a given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, including 10 carbon atoms. The alkynyl group can be linked to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentyynyl, and hexynyl. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a )2, where each R aIt is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0084] "Alynyl-cycloalkyl" means -(alkynyl)cycloalkyl, wherein the alkynyl and cycloalkyl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the alkynyl and cycloalkyl groups.

[0085] The terms "aromatic," "aryl," or "Ar," either on their own or as part of another substituent, refer to an aromatic ring system (e.g., an aromatic group) having at least one ring with a π-electron system of a carbocyclic ring (e.g., phenyl, fluorenyl, and naphthyl). The aryl group can have any suitable number of carbocyclic atoms and any suitable number of rings. The aryl group can include any suitable number of carbocyclic atoms, such as C6, C7, C8, C9, C10, C20, C30, C40, C50, C60, C70, C80, C90, C10, C2 ... 10 C 11 C 12 C 13 C 14 C 15 Or C 16 , and C 6-12 C 6-10 Or C 6-l4 A divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene. Divalent groups derived from monovalent polycyclic hydrocarbon groups whose names end in "-" are named by removing a hydrogen atom from a carbon atom with a free valence; for example, a naphthyl group with two bonding sites is called a naphthylene group. Whenever used herein, numerical ranges are indicated as "6 to 10" (e.g., C6-C). 10 Aromatic or C6-C 10 Aryl () refers to any integer within a given range; for example, "6 to 10 ring atoms" means that an aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. Aryl groups can be monocyclic, fused (i.e., rings sharing adjacent ring atom pairs) to form bicyclic (e.g., benzocyclohexyl) or tricyclic or polycyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Unless otherwise specifically stated in the specification, the aryl portion is optionally substituted by one or more substituents, which are independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyxamic acid salt, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a-S(O) t R a - (where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO(OR) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0086] "Arylalkyl" or "arylalkyl" means (aryl)alkyl, wherein the aryl and alkyl groups are as disclosed herein and they are optionally substituted with one or more of the substituents applicable to the aryl and alkyl groups, respectively.

[0087] The term "aryloxy group" refers to the -O-aryl group.

[0088] The term "substituted aryloxy group" refers to an aryloxy group in which the aryl substituent is substituted (i.e., -O-(substituted aryl)). Unless otherwise specifically stated in the specification, the aryl portion of the aryloxy group is optionally substituted by one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a-OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0089] "Imidazole formaldehyde" refers to the -(C=O)H group.

[0090] "Carboxyl group" refers to the -(C=O)OH group.

[0091] "Cyano" refers to the -CN group.

[0092] "Cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and can be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms (i.e., C1, C2, C3, C4, C5, C6, C7, C83-10 )cycloalkyl or C 3-10(Cycloalkyl). Whenever it appears herein, numerical ranges such as "3 to 10" refer to each integer within a given range; for example, "3 to 10 carbon atoms" means that a cycloalkyl group can consist of 3 carbon atoms, or at most 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, etc. Unless otherwise specifically stated in the specification, a cycloalkyl group may optionally be substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamide, heterocycloalkyl, isohydroxyxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a - (where t is 1 or 2), -S(O) t R a - (where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO(OR) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0093] "Cycloalkyl-alkenyl" refers to -(cycloalkyl)alkenyl, wherein the cycloalkyl and alkenyl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the cycloalkyl and alkenyl groups.

[0094] "Cycloalkyl-heterocycloalkyl" means -(cycloalkyl)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are as disclosed herein and they are optionally substituted with one or more of the substituents described herein for the substituents applicable to the cycloalkyl and heterocycloalkyl.

[0095] "Cycloalkyl-heteroaryl" refers to -(cycloalkyl)heteroaryl, wherein the cycloalkyl and heteroaryl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the cycloalkyl and heteroaryl groups.

[0096] The term "alkoxy" refers to an -O-alkyl group, including straight-chain, branched, cyclic configurations, and combinations thereof connected to a parent structure by oxygen, comprising 1 to 8 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing one to six carbon atoms.

[0097] The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O-(substituted alkyl)). Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxy group is optionally substituted by one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a(where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0098] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy) (C=O)- linked by a carbonyl carbon, wherein the alkoxy group has an indicated number of carbon atoms. Therefore, (C 1-6 An alkoxycarbonyl group is an alkoxy group with 1 to 6 carbon atoms connected by an oxygen group to a carbonyl group. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group in which the alkoxy group is a lower alkoxy group.

[0099] The term "substituted alkoxycarbonyl" refers to a group (substituted alkyl) -OC(O)-, wherein the group is linked to the parent structure via a carbonyl functional group. Unless otherwise specified in the specification, the alkyl portion of the alkoxycarbonyl group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O)t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0100] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclic alkyl)-C(O)-, wherein the groups are connected to the parent structure via a carbonyl functional group. If the R group is a heteroaryl or heterocyclic alkyl, the heterocyclic or chain atoms contribute to the total number of chain or ring atoms. Unless otherwise specified in the specification, the alkyl, aryl, or heteroaryl portion of the acyl group is optionally substituted by one or more substituents, which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a(where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0101] "Acyloxy group" refers to an R(C=O)O- group, where R is an alkyl, aryl, heteroaryl, heteroalkyl, or heterocyclic alkyl group as described herein. If the R group is a heteroaryl or heterocyclic alkyl group, the heterocyclic or chain atom contributes to the total number of chain or ring atoms. Unless otherwise specifically stated in the specification, the R of the acyloxy group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a)2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0102] "Acylsulfonamide" refers to -S(O)2-N(R a )-C(=O)- group, where R a It is hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl. Unless otherwise specified in the specification, the acylsulfonamide group is optionally substituted by one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or 1PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0103] "Amino" or "amine" refers to -N(R) a )2 groups, wherein each R a Independently, it is hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, unless otherwise specified in the specification. In -N(R a The )2 group has two R groups other than hydrogen. a When substituents are present, they can combine with nitrogen atoms to form 4-, 5-, 6-, or 7-membered rings. For example, -N(R a )2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise specifically stated in the specification, the amino group may optionally be substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0104] The term "substituted amino" also refers to the respective groups as described above -NHR a and NR a R a N-oxides. N-oxides can be prepared by treating the corresponding amino group with, for example, hydrogen peroxide or m-chlorobenzoic acid peroxide.

[0105] "Amide" or "amine" refers to a chemical moiety having the formula -C(O)N(R)2 or -NHC(O)R, wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocycloalicyclic (by cyclic carbon bonding), each of which may optionally be substituted. The R2 in the -N(R)2 of the amide may optionally form a 4-, 5-, 6-, or 7-membered ring together with the nitrogen to which it is attached. Unless otherwise specifically stated in the specification, the amine group may optionally be independently substituted by one or more substituents of alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups as described herein. The amide may be an amino acid or peptide molecule linked to a compound disclosed herein to form a prodrug. The procedures and specific groups used to prepare such amides are known to those skilled in the art and can be readily found in pioneering sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999, which are incorporated herein by reference in their entirety.

[0106] "Ester" refers to a chemical group of the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heteroalicyclic (by cyclic carbon bonding). Procedures and specific groups used to prepare esters are known to those skilled in the art and can be readily found in pioneering sources such as Greene and Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, John Wiley & Son Publishing, New York, NY, 1999, which are incorporated herein by reference in their entirety. Unless otherwise specifically stated in the specification, the ester group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogenated, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a-C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0107] The terms “halogenated,” “halide,” or alternatively “halogen” are intended to mean fluorine, chlorine, bromine, or iodine. The terms “halogenated alkyl,” “halogenated alkenyl,” “halogenated alkynyl,” and “halogenated alkoxy” include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halogenated groups or combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” respectively include halogenated alkyl and halogenated alkoxy, wherein the halogen is fluorine.

[0108] "Fluoroalkyl" refers to an alkyl group as defined above, which is substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of a fluoroalkyl group may be optionally substituted as defined above for alkyl groups.

[0109] "Heteroaryl" or "heteroaromatic" or "HetAr" or "Het" refers to a 5- to 18-membered aromatic group (e.g., C5-C6) comprising one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur, and which may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. 13(Heteroaryl). Whenever it appears in this document, numerical ranges such as “5 to 18” refer to each integer within a given range; for example, “5 to 18 ring atoms” means that a heteroaryl can consist of 5 ring atoms, 6 ring atoms, etc., up to 18 ring atoms, including 18 ring atoms. Divalent groups derived from monovalent heteroaryl groups whose names end with “-aryl” are named by removing a hydrogen atom from an atom with a free valence, and are named by adding “subunit” to the name of the corresponding monovalent group; for example, a pyridinyl group with two connection points is a pyridylene group. The N-containing “heteroaromatic” or “heteroaryl” part refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups can be fused or unfused. The heteroatoms in a heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule by any atom of the ring. Examples of heteroaryl groups include, but are not limited to, azirroheptenyl, acridineyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzoxazolyl, and benzo[ d ]Thiazolyl, benzothiadiazolel, benzo[ b [1,4]dioxane-heptanetrienyl, benzo[ b [1,4]oxazinyl, 1,4-benzodioxyl, benzonaphthylfuranyl, benzoxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzoxazolyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzopyranoneyl, benzofuranyl, benzothiazolyl, benzothiophene (benzothiophenyl), benzothiophene [3,2- d ]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2- a ]pyridyl, carbazole, cyclopentenyl[ d ]Pyrimidinyl, 6,7-dihydro-5 H -cyclopenteno[4,5]thieno[2,3- d ]pyrimidinyl, 5,6-dihydrobenzo[ h Quinazolinyl, 5,6-dihydrobenzo[ h ] borylene, 6,7-dihydro-5 H -Benz[6,7]cyclohepta[1,2- c ]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanoneyl, furano[3,2- c ]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctane[ d ]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctane[ d ]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctane[ d]pyridyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indole, isoindole, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphthidone, oxadiazolyl, 2-oxoazacycloheptenyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[ h Quinazolinyl, 1-phenyl-1 H -pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purineyl, pyranyl, pyrroleyl, pyrazolyl, pyrazolo[3,4- d ]pyrimidinyl, pyridinyl, pyrido[3,2- d ]pyrimidinyl, pyrido[3,4- d Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thiophene[2,3- d ]Pyrimidinyl, 6,7,8,9-tetrahydro-5 H -Cyclohepta[4,5]thiopheno[2,3- d ]pyrimidinyl, 5,6,7,8-tetrahydropyridyl[4,5- c ]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3- d ]pyrimidinyl, thiophene[3,2- d ]Pyrimidine group, thiophene[2,3- c Pyridyl and phenylthio (i.e., thiophene). Unless otherwise specified in the specification, the heteroaryl moiety is optionally substituted by one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, nitro, oxo, thio, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a)C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0110] Substituted heteroaryl groups also include ring systems substituted with one or more oxide (-O-) substituents (e.g., pyridyl N-oxide).

[0111] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic cyclic group comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, numerical ranges such as "3 to 18" refer to each integer within the given range; for example, "3 to 18 ring atoms" means that a heterocyclic alkyl group can consist of 3 ring atoms, 4 ring atoms, etc., up to 18 ring atoms, including 18 ring atoms. Unless otherwise specifically stated in the specification, a heterocyclic alkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in a heterocyclic alkyl group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. The heterocyclic alkyl group is partially or fully saturated. A heterocyclic alkyl group can be attached to the remainder of the molecule by any atom of the ring. Examples of such heterocyclic alkyl groups include, but are not limited to, dioxolanecycloyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaranyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the heterocyclic alkyl portion is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, nitro, oxo, thio, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O)t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or -PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0112] "Heterocyclic alkyl" also includes bicyclic ring systems in which, in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and combinations containing at least one of the aforementioned heteroatoms, a non-aromatic ring (typically having 3 to 7 ring atoms) contains at least 2 carbon atoms; and another ring (typically having 3 to 7 ring atoms) optionally contains 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and is not aromatic.

[0113] "Heteroalkyl," "heteroalkenyl," and "heteroynyl" refer to optionally substituted alkyl, alkenyl, and ynyl groups having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given, for example, C1-C4 heteroalkyl, which refers to the total chain length; in this example, the chain length is 4 atoms long. Heteroalkyl groups may be substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, halogen, cyano, nitro, oxo, thio, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a)2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3(R) a )2, where each R a It is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0114] "Heteroalkylaryl" means -(heteroalkyl)aryl, wherein the heteroalkyl and aryl groups are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the heteroalkyl and aryl groups.

[0115] "Heteroalkylheteroaryl" means -(heteroalkyl)heteroaryl, wherein the heteroalkyl and heteroaryl are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the heteroalkyl and heteroaryl substituents.

[0116] "Heteroalkylheterocyclic alkyl" means -(heteroalkyl)heterocyclic alkyl, wherein the heteroalkyl and heterocyclic alkyl are as disclosed herein and they are optionally substituted with one or more of the substituents described herein for the substituents applicable to the heteroalkyl and heterocyclic alkyl.

[0117] "Heteroalkylcycloalkyl" means -(heteroalkyl)cycloalkyl, wherein the heteroalkyl and cycloalkyl are as disclosed herein and they are optionally substituted with one or more of the substituents described herein as applicable to the heteroalkyl and cycloalkyl substituents.

[0118] "Heteroarylalkyl" refers to a portion having an aryl moiety as described herein and an alkylene moiety as described herein, wherein the connection with the rest of the molecule is made via the alkylene moiety.

[0119] "O-" refers to the -O- group.

[0120] "Oxo" refers to the =O group.

[0121] "Nitro" refers to the -NO2 group.

[0122] "Thioalkyl" refers to a group including -S- (optionally substituted alkyl), -S- (optionally substituted aryl), -S- (optionally substituted heteroaryl), and -S- (optionally substituted heterocyclic alkyl).

[0123] "Sulfinyl group" refers to a group including -S(O)-H, -S(O)- (optionally substituted alkyl), -S(O)- (optionally substituted amino), -S(O)- (optionally substituted aryl), -S(O)- (optionally substituted heteroaryl), and -S(O)- (optionally substituted heterocyclic alkyl).

[0124] "Sulfoyl" refers to a group including -S(O2)-H, -S(O2)- (optionally substituted alkyl), -S(O2)- (optionally substituted amino), -S(O2)- (optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), and -S(O2)- (optionally substituted heterocyclic alkyl).

[0125] "Sulfonamidyl" or "sulfonamido" refers to a -S(=O)2-NRR group, where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocyclic (by cyclic carbon bonding). The R group in the -NRR of the -S(=O)2-NRR group can form a 4-, 5-, 6-, or 7-membered ring with the nitrogen to which it is attached. The sulfonamidyl group is optionally substituted with one or more substituents from the substituents described for alkyl, cycloalkyl, aryl, and heteroaryl groups, respectively.

[0126] "Sulfoyloxy" refers to the -S(=O)2OH group.

[0127] "Sulfonate" refers to an S(=O)2-OR group, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding) and heterocyclocyclic compounds (by cyclic carbon bonding). The sulfonate group may optionally be substituted at R by one or more substituents from the substituents described for alkyl, cycloalkyl, aryl, and heteroaryl groups, respectively.

[0128] "Partial" refers to a specific segment or functional group of the molecule of the present invention. A chemical portion is generally a recognized chemical entity embedded in or attached to a molecule.

[0129] "Isomers" are different compounds of the present invention having the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of atoms (i.e., have different stereochemical configurations). "Enantiomers" are stereoisomer pairs that are non-overlapping mirror images of each other. A 1:1 mixture of enantiomer pairs is a "racemic" mixture. The term "(±)" is used where appropriate to denote racemic mixtures. "Diastereomers" are stereoisomers having at least two asymmetric atoms, but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be determined by ( R )or( S The absolute configuration of a resolved compound may be designated as (+) or (-), depending on the direction (right-handed or left-handed) of its plane-polarized light at the sodium D line wavelength. Some of the compounds described herein contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and isomers that can be defined in absolute stereochemistry as (+). R )-or( S Other stereoisomers of ). The chemical entities, pharmaceutical compositions, and methods of this invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active ( R )-and( S The α-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Where the compounds described herein contain an olefinic double bond or other geometrically asymmetric centers, and unless otherwise stated, it is intended that the compounds include both the E-geometric isomer and the Z-geometric isomer.

[0130] As used herein, "enantiomer purity" refers to the relative amount, expressed as a percentage, of the presence of a particular enantiomer of a compound of the present invention relative to another enantiomer. For example, if it is possible to potentially have ( R )-or( S If a compound with an isomer configuration exists in the form of a racemic mixture other than the isomer, then the enantiomer purity is relative to ( R )-or( S The percentage of isomers is approximately 50%. If one isomer of the compound is more predominant than another, for example, 80% ( S )-Isomer and 20% ( R )-isomer, then the compound relative to ( SThe enantiomer purity of the isomer is 80%. The enantiomer purity of the compounds of the present invention can be determined in a variety of ways known in the art, including but not limited to chromatography using chiral supports, polarization measurement by measuring polarization of polarized light rotation, nuclear magnetic resonance spectroscopy using chiral shift reagents (including but not limited to chiral complexes containing lanthanides or Pirkle reagents), or compound derivatization using chiral compounds such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0131] In some embodiments, the enantiomer-rich composition is more potent than a racemic mixture of the composition in terms of therapeutic efficacy per unit mass. Enantiomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds, Wiley Interscience, New York (1994).

[0132] As used herein, the terms "enantiomer-rich" and "non-racemic" refer to compositions of compounds of the invention in which one enantiomer is present in a weight percentage greater than that enantiomer in a control mixture of racemic compositions (e.g., greater than 1:1 by weight). For example, ( S Enantiomeric formulations rich in enantiomeric compounds refer to formulations that are relatively (enantiomeric) R - The enantiomer has greater than 50% by weight (e.g., at least 75% by weight or at least 80% by weight) ( SFormulations of enantiomers. In some embodiments, enrichment may be significantly greater than 80% by weight, providing a "substantially enantiomer-rich" or "substantially non-racemic" formulation, wherein the formulation refers to a composition having at least 85% by weight, such as at least 90% by weight, or such as at least 95% by weight, of one enantiomer relative to another. The terms "enantiomer-pure" or "substantially enantiomer-pure" refer to a composition containing at least 98% of a single enantiomer and less than 2% of opposite enantiomers.

[0133] "Tautomers" are structurally different isomers of the compounds of this invention that interconvert through tautomerization. "Tautomerization" is a form of isomerization and includes proton-transfer tautomerization or proton-transfer tautomerization, considered a subset of acid-base chemistry. Proton-transfer tautomerization or proton-transfer tautomerization involves proton migration accompanied by a change in bond order, typically the exchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is pyridine-4-ol and pyridine-4(1... H Interconversion of )-keto tautomers.

[0134] The compounds of the present invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof. The terms "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0135] A "solvent" is a compound that is physically associated with one or more molecules of a pharmaceutically acceptable solvent.

[0136] "Leaving group or atom" is any group or atom that, under reaction conditions, will cleave the starting material, thereby promoting a reaction at a specific site. Unless otherwise stated, examples of such groups include halogen atoms and methanesulfonyloxy, p-nitrobenzenesulfonyloxy, and toluenesulfonyloxy.

[0137] The term "protecting group" is intended to refer to a group that selectively blocks one or more reactive sites in a multifunctional compound, allowing a chemical reaction to selectively occur at another unprotected reactive site, and which can then be readily removed or deprotected after the selective reaction is complete. Various protecting groups are disclosed in the following literature: for example, TH Greene and PGM Wuts, *Protecting Groups in Organic Synthesis*, 3rd ed., John Willie & Son Publishing, New York (1999).

[0138] "Substituted" means that the referenced group may be attached to one or more additional groups, radicals, or portions selected individually and independently from: acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate ester, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, sulfonate, urea, and amino (including monosubstituted and disubstituted amino groups) and their protected derivatives. The substituent itself may be substituted; for example, a cycloalkyl substituent itself may have a halide substituent on one or more of its ring carbons. The term "optionally substituted" means optional substitution with a specific group, radical, or portion.

[0139] For the avoidance of doubt, it is intended that specific features (e.g., integers, properties, values, uses, diseases, molecular formulas, compounds, or groups) described in connection with a particular aspect, embodiment, or example of the invention be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible with it. Therefore, such features may be used in conjunction with any definition, claim, or embodiment defined herein, where appropriate. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except where at least some features and / or steps are mutually exclusive combinations. The invention is not limited to any details of any disclosed embodiment. The invention extends to any novel feature or novel combination of said features disclosed in this specification (including any appended claims, abstract, and drawings) or to any novel step or any novel combination of said steps in any method or process so disclosed.

[0140] When ranges are used herein to describe, for example, physical or chemical properties (such as molecular weight or chemical formula), it is intended to include all combinations and sub-combinations of ranges, as well as specific embodiments thereof.

[0141] Furthermore, the transitional terms “comprising,” “consisting essentially of,” and “consisting of,” when used in the original and modified forms of the appended claims, define the scope of the claims relative to which additional unlisted claim elements or steps (if present) are excluded from the scope of the claims. The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unstated elements, methods, steps, or materials. The term “consisting of” excludes any elements, steps, or materials other than those specified in the claims, and in the latter case, excludes impurities typically associated with the specified materials. The term “consisting essentially of” limits the scope of the claims to the specified elements, steps, or materials and those elements, steps, or materials that do not substantially affect the essential and novel characteristics of the claimed invention. Alternatively, all embodiments of the invention may be more specifically defined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of.” The term “comprising” (and related terms such as “including” or “containing” or “having” or “including)”) includes embodiments of any composition of a substance, method, or process that is, for example, “consisting of the described features” or “consisting substantially of the described features”.

[0142] C. Example

[0143] 1. Compound

[0144] In an exemplary embodiment, the present invention provides a compound according to Formula I:

[0145] ,

[0146] Or its solvates, hydrates, pharmaceutically acceptable salts, tautomers, or prodrugs.

[0147] In equation I, X 1 Selected from N and CR 1 R 1 It is a member selected from the following: H, halogens, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 alkoxy groups. X and X 2 Independently selected from N and CH. R 2 Members selected from the following:

[0148]

[0149] Where R 5It is a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C6 alkyl group (C1, C2, C3, C4, C5, or C6). R 5' R 6 and R 6' It is a member independently selected from H and substituted or unsubstituted alkyl groups (e.g., substituted or unsubstituted C1-C6 alkyl groups). X 3 Selected from N and CR 7 X 4 Selected from N and CR 8 X 5 Selected from N and CR 9 Part of R 7 R 8 R 9 and R 10 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl groups (C1, C2, C3, C4, C5, or C6), and substituted or unsubstituted C1-C6 aminoalkyl groups (C1, C2, C3, C4, C5, or C6), wherein R 7 and R 8 Or R 8 and R 9 It is optionally linked together with the carbon atom to which it is attached to form a ring selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl.

[0150] In an exemplary embodiment, when R 7 and R 8 and R 8 and R 9 None of them are bonded together with the carbon they are attached to to form a ring, and no more than one is selected from R. 7 R 8 and R 9 When the member is not H, R 9 The following are not included:

[0151]

[0152] Where z is 0 or 1.

[0153] In an exemplary embodiment, when at least one is selected from R 7 R 8 and R 9 When the member is Me, R 2 yes:

[0154] .

[0155] This document also provides pharmaceutical formulations that combine the compounds of the present invention with / or their solvates, hydrates, pharmaceutically acceptable salts, tautomers, or prodrugs in combination with pharmaceutically acceptable carriers.

[0156] In some embodiments, R 2 It is S(O)2Me.

[0157] In the exemplary embodiment, X is N; X 1 and X 2 It is CH; and X 3 and X 4 CR 7 and CR 8 .

[0158] In some embodiments, R 1 It's fluorine.

[0159] In an exemplary embodiment, when R 7 and R 8 and R 8 and R 9 None of them are bonded together with the carbon they are attached to to form a ring, and no more than one is selected from R. 7 R 8 and R 9 When the member is not H, R 9 The following are not included:

[0160]

[0161] Where z is 0 or 1.

[0162] In an exemplary embodiment, when at least one is selected from R 7 R 8 and R 9 When the member is Me, R 2 yes:

[0163] .

[0164] In various embodiments, X 3 X 4 and X 5 CR 7 CR 8 and CR 9 .

[0165] In some embodiments, CR 7 CR 8 and CR 9At least one of them comprises a ring system selected from monocyclic or bicyclic ring systems having one or two heteroatoms and four, five, six, or seven carbon atoms. The ring system optionally includes oxygen, nitrogen, or both oxygen and nitrogen.

[0166] In some embodiments, where R 7 R 8 and R 9 Independently selected from H, .

[0167] In Formula II or III, one or more carbon atoms of the ring are optionally substituted by members independently selected from halogens and substituted or unsubstituted alkyl groups. The index a is selected from integers 0 and 1. R 10 and R 11 Independently selected from H, halogens, and substituted or unsubstituted C1-C6 alkyl groups. The indices c and d are independently selected from integers 0, 1, 2, 3, and 4, provided that the sum c+d is selected from integers 3, 4, 5, and 6. A is a cyclic system selected from substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocyclic alkyl groups. X 6 Selected from O, NR 12 and CR 12 R 13 , where R 12 and R 13 Independently selected from H and substituted or unsubstituted alkyl groups.

[0168] In various embodiments, R 7 R 8 and R 9 At least one of them is selected from formulas II and III. In an exemplary embodiment, R 7 R 8 and R 9 No more than one or both of the terms are selected from Formula II or Formula III. In some embodiments, R 7 R 8 and R 9 H is one or more than one or two of the following.

[0169] In an exemplary embodiment, a compound according to Formula IV is provided:

[0170]

[0171] The ring system B is a partially substituted cycloalkyl group selected from formulas II and III. The ring system B is a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocycloalkyl group, and is optionally selected from substituted or unsubstituted cyclopentylamine and substituted or unsubstituted cyclohexylamine.

[0172] In an exemplary embodiment, a compound of the present invention is provided, wherein R 7 R 8 and R 9 Selected independently from:

[0173] .

[0174] In various embodiments, a compound according to formula V is provided:

[0175] .

[0176] In an exemplary embodiment, a compound according to Formula VI is provided:

[0177] .

[0178] X is selected from N and CH. R 2 Selected from:

[0179] .

[0180] R 5 It is a C1-C6 alkyl group. R 5' R 6 and R 6' It is a member independently selected from H and C1-C6 alkyl groups. X 3 and X 4 CR 7 and CR 8 R 7 and R 8 Independently selected from H, and

[0181] .

[0182] In Formula II or III, one or more carbon atoms of the ring are optionally substituted by members independently selected from halogens and substituted or unsubstituted alkyl groups. The index a is selected from integers 0 and 1. R 10 and R 11 Independently selected from H, halogens, and substituted or unsubstituted C1-C6 alkyl groups. The indices c and d are independently selected from integers 0, 1, 2, 3, and 4, provided that the sum c+d is selected from integers 3, 4, 5, and 6. A is a cyclic system selected from substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocyclic alkyl groups. X 6 Selected from O, NR 12 and CR 12 R 13 , where R 12 and R 13 Independently selected from H and substituted or unsubstituted alkyl groups.

[0183] In various embodiments, the present invention provides a compound according to formula VI, wherein R 9 The following are not included:

[0184]

[0185] Where z is selected from 0 and 1.

[0186] In an exemplary embodiment, R 10 and R 11 One of them is CF3.

[0187] In various embodiments, a compound of formula Ib is provided:

[0188]

[0189] Where R 1 It is a member selected from the following: H, halogen, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 alkoxy groups; R 5 It is a C1-C6 alkyl group; X 3 Selected from N and CR 7 ;X 4 Selected from N and CR 8 ;R 7 and R 8 Independently selected from H, substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 aminoalkyl groups, wherein R 7 and R 8 Optionally linked together with the carbon atom to which it is attached to form a ring selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl, wherein when R 7 and R 8 When not bonded together with the carbon atoms to form a ring, no more than one carbon atom selected from R 7 and R 8 and R 9 The member is not H.

[0190] In an exemplary embodiment, a compound according to formula Ib is provided, wherein CR 8 Ring systems including monocyclic or bicyclic ring systems having one or two heteroatoms and four, five, six or seven carbon atoms.

[0191] In some embodiments, a compound according to formula Ib is provided, wherein the ring system comprises oxygen and nitrogen.

[0192] In some embodiments, a compound according to formula Ib is provided, wherein R 8Selected from H,

[0193]

[0194] Wherein A is a cyclic system selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic alkyl, wherein one or more carbon atoms are substituted with a halogen; R 10 and R 11 Independently selected from H, halogens, and substituted or unsubstituted C1-C6 alkyl groups; a is selected from integers 0 and 1; c and d are independently selected from integers 0, 1, 2, 3, and 4, provided that the sum c+d is selected from integers 3, 4, 5, and 6; and X 6 Selected from O, NR 12 and CR 12 R 13 , where R 12 and R 13 It is independently selected from H, halogens and substituted or unsubstituted alkyl groups.

[0195] In some embodiments, a compound according to formula Ib is provided, wherein R 13 Selected from H and halogens.

[0196] In various embodiments, a compound according to Formula IV is provided:

[0197]

[0198] Wherein ring system B is a partially substituted cycloalkyl group selected from formulas II and III.

[0199] In some embodiments, a compound according to formula Ib is provided, wherein the ring system B is selected from substituted or unsubstituted cyclopentylamine and substituted or unsubstituted cyclohexylamine.

[0200] Exemplary compounds of the present invention include compounds of the following formula:

[0201]

[0202] Where R w Selected from H and halogens; R x It is an H or C1-C3 alkyl group, which optionally reacts with R y Bonded to form a 5- or 6-membered cycloalkyl ring fused with a pyridyl ring; R y Is it H, Me, or R? x The key; the exponent n is selected from 0, 1, 2, and 3; R z It is H or, where R z' It is a C1-C3 alkyl group, and R z and R z'The nitrogen atoms bonded to both form a first 3-, 4-, or 5-membered substituted or unsubstituted heterocycle. In the exemplary compound, the heterocycle is substituted by a second 3-, 4-, or 5-membered substituted or unsubstituted heterocycle. In the exemplary compound, the first and second heterocycles are in a spiro configuration. In the exemplary compound, the second heterocycle includes an oxygen atom.

[0203] The exemplary compound of the present invention has a ligand efficiency of at least about 0.39 in the TYK-JH2 binding assay. ).

[0204] The exemplary compounds of the present invention have an efficacy against TYK2 of less than about 1000 nm, preferably less than about 500 nm, more preferably less than about 250 nm, and still more preferably less than about 100 nm, less than about 50 nm, less than about 25 nm or less than about 10 nm.

[0205] The exemplary compounds of the present invention exhibit potency against TYK2 less than about 100 nm (IL-12 / pSTAT4) and cellular selectivity against TYK2 on JAK1 / 2 greater than about 10,000 nM (IL-6 / pSTAT3). The exemplary compounds of the present invention demonstrate ligand efficiencies greater than about 0.39 (TYK-JH2 binding assay) and potency against TYK2 less than about 100 nm (IL-12 / pSTAT4) or cellular selectivity against TYK2 greater than about 10,000 nM (IL-6 / pSTAT3 or GM-CSF / pSTAT5).

[0206] The exemplary compound of the present invention is characterized by C max The concentration is at least about 1500 (ng / mL). The exemplary compounds of the present invention are characterized by AUCinf ( The value is at least about 2000. In some embodiments, the T1 / 2 of the compound is greater than about one hour, for example, greater than about 1.5 hours. Exemplary compounds of the present invention can be demonstrated to possess these properties in mouse PO PK experiments administered at about 10-15 mg / kg. Exemplary compounds of the present invention are characterized in that two or more of these parameters have the listed amounts.

[0207] The exemplary compounds of the present invention have similar or improved properties in one or more of the assays set forth herein, relative to equivalent doses of one or more known TYK2 inhibitors. Exemplary known TYK2 inhibitors that can be used as comparisons with the exemplary compounds of the present invention include ritlecitinib, deucravacitinib, upadacitinib, and abrocitinib.

[0208] Exemplary compounds having the properties described above are examples of exemplary compound test articles incorporated herein and in the accompanying drawings.

[0209] As will be apparent to those skilled in the art, the exemplary compounds of the present invention may have any combination of the properties and parameters listed above. The examples provided above are illustrative only and not limiting.

[0210] In various embodiments, the present invention provides a compound selected from the compounds described in Table 1.

[0211] Table 1: TYK2 Inhibitors

[0212]

[0213] a. ligand efficiency

[0214] In an exemplary embodiment, the present invention provides a TYK2 inhibitor exhibiting excellent ligand efficiency. Optimization of ligand efficiency is typically achieved by optimizing both molecular size and lipophilicity. For example, ligand efficiency is the combination free energy / heavy atom count (LE = ΔG / HA) and lipophilic ligand efficiency (LLE = pIC50 or Ki - cLogP / D). Ligand efficiency is measured using techniques recognized in the art. In one embodiment, ligand efficiency is measured using the TYK-JH2 binding assay described in Example 2.

[0215] The exemplary compound of the present invention has a ligand efficiency of at least about 0.39 in the TYK-JH2 binding assay. In various embodiments, the compounds of the present invention exhibit ligand efficiencies of about 0.37 to about 0.39. In exemplary embodiments, the compounds of the present invention exhibit ligand efficiencies of less than about 0.37. ).

[0216] b. Compound efficacy

[0217] This invention provides compounds as highly effective inhibitors of TYK2. The potency of the TYK2 inhibitors can be readily assessed using the assay described in Example 3a. In an exemplary embodiment, the compounds of this invention have a potency against TYK2 of less than about 100 nm ( In various embodiments, the potency of the compound is from about 100 nm to about 1000 nm. In some embodiments, the compounds of the present invention have a potency greater than about 1,000 nm. In various embodiments, compounds with TYK2 potency of less than about 1000 nm, preferably less than about 500 nm, more preferably less than about 250 nm, and still more preferably less than about 100 nm, less than about 50 nm, less than about 25 nm, or less than about 10 nm are deemed sufficiently effective to be clinically relevant TYK2 inhibitors.

[0218] c. Compound selectivity

[0219] For compounds intended as pharmaceutically useful TYK2 inhibitors, candidate compounds ideally exhibit excellent cellular selectivity for the target TYK2. Compound selectivity can be conveniently assessed using the IL-6 / pSTAT3 assay provided in Example 3b.

[0220] In various embodiments, these compounds of the present invention exhibit selectivity for TYK2 of at least about 10,000 nM. In some embodiments, the compounds of the present invention exhibit selectivity of about 4000 nM to about 10,000 nM. In some embodiments, the selectivity is less than about 4000 nM. Compounds with a selectivity of about 4,000 (e.g., about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000 nM or greater than about 10,000 nM) can be used as clinically relevant TYK2 inhibitors.

[0221] In various embodiments, the compounds of the present invention exhibited excellent cell selectivity as measured by the GM-CSF / pSTAT5 assay. Using this assay, in various embodiments, the compounds of the present invention exhibited selectivity against TYK2 of at least about 10,000 nM. In some embodiments, the compounds of the present invention exhibit selectivity of about 4000 nM to about 10,000 nM. In some embodiments, the selectivity is less than about 4000 nM. Compounds with a selectivity of about 4,000 (e.g., about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000 nM or greater than about 10,000 nM) can be used as clinically relevant TYK2 inhibitors. See Example 5.

[0222] d. Compound toxicity

[0223] The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, which can be expressed as the ratio between LD50 (the amount of compound that is lethal in 50% of the population) and ED50 (the amount of compound that is effective in 50% of the population). Compounds exhibiting a high therapeutic index are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used to formulate a range of doses for human use. The doses of such compounds are preferably within a plasma concentration range that includes the ED50 and has very low or no toxicity. The dose can vary within this range depending on the dosage form and route of administration used. See, for example, […]. Pharmacological basis of therapeutics ( The Pharmacological Basis of Therapeutics ( ), Chapter 1, Page 1, 1975. Precise preparation, route of administration, and dosage can be chosen by individual physicians based on the patient's condition and the specific method of using the compound.

[0224] The exemplary compounds according to the present invention are characterized by an acceptable therapeutic index.

[0225] e. CNS penetration

[0226] The exemplary compounds of the present invention are characterized by sufficient CNS penetration to enable them to have therapeutic efficacy in treating diseases of the CNS, such as autoimmune and inflammatory diseases of the CNS. When administered to a subject at a therapeutically effective dose and via a route suitable for targeting the subject's CNS, such compounds are further characterized by an acceptable therapeutic index. The exemplary subject is a human subject suffering from a disease that can be improved by administration of the exemplary compounds of the present invention to the subject.

[0227] f. Pharmacokinetics

[0228] The exemplary compounds of the present invention are characterized by their favorable pharmacokinetic properties in mice. Exemplary pharmacokinetic studies characterizing the compounds involved administration of about 5 mg / kg to mice. In some embodiments, the C1 of the compounds of the present invention... max The concentration is at least approximately 1500 (ng / mL). The selected compound is characterized by AUCinf ( The value is at least about 2000. In some embodiments, the T1 / 2 of the compound is greater than about one hour, for example, greater than about 1.5 hours. See Example 6.

[0229] g. Selected compounds

[0230] In various embodiments, compounds characterized by specific combinations of pharmacological parameter ranges are provided. These compounds possess an excellent combination of properties, making them excellent clinical candidates.

[0231] Therefore, in one embodiment, the present invention provides a compound having a potency against TYK2 of less than about 100 nm (IL-12 / pSTAT4) and a cell selectivity against TYK2 of greater than about 10,000 nM (IL-6 / pSTAT3). In various embodiments, the present invention provides a compound having a ligand efficiency greater than about 0.39 (TYK-JH2 binding assay) and a potency against TYK2 of less than about 100 nm (IL-12 / pSTAT4) or a cell selectivity against TYK2 of greater than about 10,000 nM (IL-6 / pSTAT3 or GM-CSF / pSTAT5). In some embodiments, the present invention provides a compound wherein the ligand efficiency is greater than about 0.39 (TYK-JH2 binding assay), the potency against TYK2 is less than about 100 nm (IL-12 / pSTAT4), and the cell selectivity against TYK2 is greater than about 10,000 nM (IL-6 / pSTAT3 or GM-CSF / pSTAT5).

[0232] In an exemplary embodiment, the selected compound of the present invention is characterized by C max The concentration is at least approximately 1500 (ng / mL). The selected compound is characterized by AUCinf ( The value is at least about 2000. In some embodiments, the T1 / 2 of the compound is greater than about one hour, for example, greater than about 1.5 hours. Exemplary compounds of the present invention can be demonstrated to possess these properties in mouse PO PK experiments administered at about 5 mg / kg. Certain selected compounds are characterized in that two or more of these parameters have the listed amounts.

[0233] As will be apparent to those skilled in the art, the selected compound may have any combination of the properties and parameters listed above. The examples provided above are illustrative only and not limiting.

[0234] 2. Drug formulations

[0235] The present invention further provides a pharmaceutical formulation comprising a compound of the present invention according to formula (I), a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a tautomer, or a prodrug, mixed with a pharmaceutically acceptable excipient. In an exemplary embodiment, the compound is a compound according to formula (II), and more preferably according to formula (III).

[0236] In exemplary embodiments, the compounds of the present invention, their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or prodrugs are used to prepare medicaments for treating or preventing TYK2-mediated diseases or symptoms in subjects of need.

[0237] The compounds described herein, or their pharmaceutically acceptable addition salts or hydrates, can be formulated for delivery to patients using a wide variety of routes or modalities of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, ocular, rectal, transmucosal, enteral, and parenteral administration, including intramuscular, subcutaneous, and intravenous injection. In one embodiment, the formulation is prepared for parenteral or oral administration. In exemplary embodiments, the formulation is prepared for intravenous, subcutaneous, intrathecal, intraventricular, or intraperitoneal injection.

[0238] The compounds described herein, or their pharmaceutically acceptable salts and / or hydrates, may be administered alone, in combination with other compounds of the present invention, and / or in mixtures with other therapeutic agents. The choice of therapeutic agents that may be co-administered with the compounds of the present invention will depend in part on the condition being treated.

[0239] For example, when administered to patients with autoimmune or inflammatory processes, the compounds of the present invention can be given in the form of a mixture containing agents for treating pain, infection, and other symptoms and side effects commonly associated with inflammatory processes. Such agents include, for example, analgesics, antibiotics, etc. The compounds can also be given in the form of a mixture containing other agents commonly used to treat inflammatory processes, including butyrate and butyrate derivatives (Perrine et al., New England Journal of Medicine 328(2): 81-86 (1993)); hydroxyurea (Charache et al., New England Journal of Medicine 323(20):1317-1322 (1995)); erythropoietin (Goldberg et al., New England Journal of Medicine 323(6):366-372 (1990)); and dietary salts, such as magnesium (De Franceschi et al., Blood 88(648a):2580 (1996)).

[0240] The pharmaceutical compositions used according to the invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the processing of the active compound into a pharmaceutically usable formulation. A suitable formulation depends on the chosen route of administration.

[0241] For injection, the pharmaceutical preparations of the present invention can be prepared in an aqueous solution, preferably in a physiologically compatible buffer (such as Hanks's solution, Ringer's solution, or physiological saline buffer). In exemplary embodiments, the formulation includes water and alcohol and / or ethylene glycol. Other useful components of the formulation include, for example, surfactants, emulsifiers, and materials such as ethoxylated oils. An exemplary formulation includes the compound of the present invention, poly(ethylene glycol) 400, ethanol, and water in a ratio of 1:1:1. Another exemplary formulation includes the compound of the present invention, water, poly(ethylene glycol) 400, and Cremophor-EL.

[0242] For transmucosal administration (e.g., via the buccal, rectal, nasal, ocular, etc.), a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art.

[0243] For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient to be treated. Pharmaceutical formulations for oral use can be combined with solid excipients, optionally milling the resulting mixture, and, if desired, processing the mixture of granules after the addition of suitable adjuvants to obtain tablets or sugar-coated pill cores. Suitable excipients are specifically fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added if desired.

[0244] A suitable coating is provided for the sugar-coated pill core. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or sugar-coated pill coating to facilitate the identification or characterization of different combinations of active compound agents.

[0245] Orally administered pharmaceutical formulations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations intended for oral administration should be at a dosage suitable for such administration.

[0246] For buccal administration, the composition can be prepared in tablet or lozenge form using conventional methods.

[0247] The compound can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Injectable formulations can be present in unit dosage forms, such as in ampoules or multi-dose containers, and may contain preservatives. The composition can be in the form of a suspension, solution, or emulsion in an oily or aqueous medium, and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate.

[0248] Pharmaceutical formulations intended for parenteral administration include aqueous solutions of the active compound in a water-soluble form, as described above for intravenous administration. Alternatively, suspensions of the active compound can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of high-concentration solutions.

[0249] Alternatively, the active ingredient can be in powder form so that it can be formulated with a suitable medium (e.g., sterile, pyrogen-free water) before use.

[0250] The compound can also be formulated into rectal compositions (such as suppositories or retention enemas) containing, for example, a conventional suppository base (such as cocoa butter or other glycerides).

[0251] For inhalation administration, the compounds used according to the invention can be conveniently delivered from pressurized packages or nebulizers in the form of an aerosol spray using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering the amount of the dose. Capsules and cartridges (e.g., gelatin) for inhalers or blowpipes can be formulated into powder mixtures containing the compound and a suitable powder matrix (such as lactose or starch).

[0252] In addition to the formulations previously described, the compounds can also be formulated into reservoir formulations. Such long-acting formulations can be administered via implantation or transdermal delivery (e.g., subcutaneous or intramuscular), intramuscular injection, or transdermal patches. Thus, for example, the compounds can be formulated using suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0253] Pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers (such as polyethylene glycol).

[0254] a. Effective dose

[0255] Pharmaceutical compositions applicable to the present invention include compositions containing a therapeutically effective amount (i.e., an amount that effectively achieves its intended purpose). The actual amount effective for a particular application will depend particularly on the condition being treated. For example, when administered to reduce the incidence of psoriasis or IBD (Crohn's disease, ulcerative colitis), such compositions will contain a certain amount of active ingredient that effectively achieves that result. The determination of the effective amount is entirely within the competence of those skilled in the art, especially based on the detailed disclosure herein.

[0256] For any of the compounds described herein, the therapeutically effective amount can be initially determined by cell culture assays. The target plasma concentration will be those of the active compounds capable of inducing inhibition of TYK2. In an exemplary embodiment, TYK2 activity is inhibited by at least 25%. Target plasma concentrations of active compounds capable of inducing at least about 50%, 75%, or even 90% or higher TYK2 inhibition are within the scope of this disclosure. The percentage of TYK2 inhibition in the subject can be monitored to assess the appropriateness of the achieved plasma drug concentration, and the dose can be adjusted up or down to achieve the desired percentage of inhibition and associated therapeutic effect.

[0257] In an exemplary embodiment, a single dose of the compound of the present invention maintains IC 50 IC 60 IC 70 IC 80 or IC 90 This lasts for at least about 15 hours, at least about 20 hours, or at least about 24 hours. In an exemplary embodiment, the compound of the invention is applied in a manner sufficient to maintain IC. 90 The effective therapeutic dose was administered to the subject over a period of at least approximately 24 hours.

[0258] As is well known in the art, therapeutically effective doses for humans can also be determined from animal models. For example, human doses can be formulated to achieve effective circulating concentrations already found in animals. As described above, human doses can be adjusted by monitoring IK1 channel inhibition and by adjusting the dose upwards or downwards.

[0259] Adjusting the dosage to achieve maximum efficacy in humans using the methods described above and other methods well known in the art is entirely within the capabilities of a person skilled in the art. In the case of local application, the systemic circulating concentration of the applied compound is not particularly important. In such cases, the compound is applied to achieve a concentration at the local area that effectively yields the desired results.

[0260] The range of patient doses for oral administration of the compounds described herein (which is the preferred mode of administration for the prevention and treatment of inflammatory processes) is generally from about 1 mg / day to about 10,000 mg / day, more generally from about 10 mg / day to about 1,000 mg / day, and most generally from about 50 mg / day to about 500 mg / day. In terms of patient weight, the typical dose range is from about 0.01 mg / kg / day to about 150 mg / kg / day, more generally from about 0.1 mg / kg / day to about 15 mg / kg / day, and most generally from about 1 mg / kg / day to about 10 mg / kg / day.

[0261] For any administration regimen, the dosage and interval can be individually adjusted to provide plasma levels of the administered compound that are effective for the specific clinical indication being treated. For example, if an acute inflammatory process is the most prominent clinical manifestation, in one embodiment, the compound according to the invention may optionally be administered once or more daily at a relatively high concentration. Alternatively, if the subject exhibits periodic inflammatory crises only on an infrequent, periodic, or irregular basis, in one embodiment, it may be more desirable to administer the compound of the invention at the minimum effective concentration and use a less frequent administration regimen. This will provide a treatment regimen commensurate with the severity of the individual's inflammatory condition.

[0262] Using the teachings provided herein, effective preventative or therapeutic treatment regimens can be planned that do not cause significant toxicity and remain effective in treating clinical symptoms exhibited by a particular subject. This planning should involve the careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, preferred administration method, and the toxicity spectrum of the chosen agent.

[0263] 3. Methods

[0264] The present invention also provides methods for using the compounds of the present invention to study autoimmune diseases and inflammatory diseases and to treat these diseases in subjects who require such treatment.

[0265] In an exemplary embodiment, a method is provided for treating a subject with a TYK2-mediated disease by administering to a subject in need a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, a solvate, or a hydrate thereof, wherein the autoimmune disease is sensitive to treatment with a TYK2 inhibitor. In an exemplary embodiment, the inhibitor is administered in the form of a pharmaceutical formulation.

[0266] In some embodiments, the present invention provides a method for treating a subject with a disease, said disease being an autoimmune disease or an inflammatory disease. The method comprises inhibiting the subject's TYK2 kinase by administering a therapeutically effective amount of a compound of the present invention to the subject, wherein said autoimmune disease or inflammatory disease is sensitive to treatment with a TYK2 inhibitor.

[0267] Examples of diseases that can be treated by the methods of the present invention include psoriasis, plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease (Crohn's disease, ulcerative colitis).

[0268] The embodiments covered herein are now described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure covered herein should in no way be construed as limiting to these examples, but rather as covering any and all variations that become apparent as a result of the teachings provided herein. Example

[0269] Example 1: Synthesis of TYK2 inhibitor compounds.

[0270] The following examples describe the preparation of compounds 1-80.

[0271] Example 1a: Preparation of compound 1 and compound 17.

[0272]

[0273] 2-Bromo-3-(methylthio)pyridine (1,2A). Add to a solution of 2-bromopyridine-3-amine (30.0 g, 173.40 mmol) and 1,2-dimethyldithionane (32.60 g, 346.82 mmol) in MeCN (500 mL). t -BuONO (35.72 g, 346.82 mmol). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (hexane: EtOAc = 10:1) to give 1.2A (23.50 g, 66.4% yield) as a yellow solid. LC-MS m / z: 204.0 [M+H] + LCMS purity (254 nm): 99.2%; t R = 1.445 minutes.

[0274] N 4-(3-(methylthio)pyridin-2-yl)pyrimidine-4,6-diamine (1.1A). A mixture of 1.2A (23.50 g, 115.20 mmol), pyrimidine-4,6-diamine (15.20 g, 138.24 mmol), Brettphos-Pd-G3 (5.21 g, 5.76 mmol), Xantphos (3.33 g, 5.76 mmol), and Cs2CO3 (75.11 g, 230.39 mmol) in 1,4-dioxane (400 mL) was stirred at 110 °C for 8 hours under an argon atmosphere. After the reaction was complete, the mixture was filtered, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 20: 1) to give 1.1A (19.50 g, 72.6% yield) as a yellow solid. LC-MS m / z: 234.2 [M+H] + LCMS purity (214 nm): 96.96%; t R = 1.200 minutes.

[0275] N 4 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1A). 30% H2O2 (195 mL) was added to a solution of 1.1A (19.50 g, 83.59 mmol) in AcOH (200 mL) and H2O (200 mL), and the mixture was stirred at 40 °C for 8 hours. After the reaction was complete, the mixture was poured into water (500 mL) and the pH was adjusted to 7–8 with an aqueous Na2CO3 solution. The mixture was then filtered, and the filter cake was dried to give 1A as a yellow solid (15.50 g, 69.9% yield). LC-MS m / z: 266.2 [M+H] + LCMS purity (214 nm): 89.47%; t R = 1.083 minutes.

[0276] 1-(6-chloropyridin-3-yl)ethanol (1.2B). NaBH4 (1.46 g, 38.46 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)acetone (3.0 g, 19.28 mmol) in EtOH (40 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated, diluted with H2O (40 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 2:3) to give 1.2B as a colorless liquid (2.80 g, 92.2% yield). LC-MS m / z: 158.2 [M+1] + LCMS purity (214 nm): 99.4%, t R = 1.106 minutes.

[0277] 5-(1-Bromoethyl)-2-chloropyridine (1.1B). PBr3 (4.80 g, 17.72 mmol) was added to a mixture of 1.2B (2.80 g, 17.77 mmol) and THF (40 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated, diluted with H2O (40 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 1:11) to give 1.1B (2.60 g, 66.4% yield) as a pale yellow liquid. LC-MS m / z: 221.9 [M+1] + Purity (214 nm): 87.2%, t R = 1.624 minutes.

[0278] 6-(1-(6-chloropyridin-3-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (1B). DIEA (6 mL) was added to a mixture of 1.1B (2.60 g, 11.79 mmol) and 2-oxa-6-azaspiro[3.3]heptane (1.29 g, 13.00 mmol) in MeCN (50 mL), and the reaction mixture was stirred overnight at 80 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated, diluted with H2O (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc) to give 1B (2.0 g, 71% yield) as a pale yellow liquid. LC-MS m / z: 239.2 [M+1] + Purity (214 nm) 80%, t R = 1.232 minutes.

[0279] N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1.1). A mixture of 1B (268 mg, 1.12 mmol), 1A (200 mg, 0.75 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), Xantphos (87 mg, 0.15 mmol), and Cs2CO3 (734 mg, 2.25 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 115 °C under an argon atmosphere. The reaction was repeated three times in parallel on the same scale. After the reaction was complete, the three reaction mixtures were combined and concentrated, diluted with H2O (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 11:1) to give crude product 1.1 (550 mg). The crude product (150 mg) was further purified by reversed-phase preparative HPLC to give pure 1.1 (90 mg, 31.0% yield) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.43 (s, 1H), 8.76 (s, 1H), 8.67 (dd, J= 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 7.6, 1.6 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 4.59 (t, J = 6.4 Hz, 4H), 3.39 (s, 3H), 3.25(d, J = 7.2 Hz, 2H), 3.20 (q, J = 6.4 Hz, 1H), 3.13 (d, J = 6.8 Hz, 2H), 1.11(d, J = 6.4 Hz, 3H). LC-MS m / z: 468.3 [M+ H] + HPLC purity (214 nm): > 99.9%; t R =7.172 minutes.

[0280] ( S )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1) and ( R )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (17). The crude product 1.1 (400 mg) was further purified by SFC to give 1 (154 mg, 19.9% ​​yield) and 17 (148 mg, 19.2% yield) as white solids. Compound 1: 1 H NMR (400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.43 (s, 1H), 8.76 (s,1H), 8.67 (dd,J = 4.8, 2.0 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 7.6, 1.6 Hz,1H), 8.19 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.4,2.0 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 4.59 (t, J = 6.8 Hz, 4H), 3.39(s, 3H), 3.25 (d, J = 6.8 Hz, 2H), 3.21 (q, J = 6.4 Hz, 1H), 3.13 (d, J = 7.2Hz, 2H), 1.11 (d, J = 6.4 Hz, 3H). LC-MS m / z: 468.3 [M + H] + . HPLC purity (214 nm): >99.9%; t R = 7.178 minutes. Chiralpak AS-3: >99.9%ee, t R = 1.154 minutes. Compound 17: 1 H NMR(400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.44 (s, 1H), 8.76 (s, 1H), 8.67 (dd, J =4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 7.6, 1.6 Hz, 1H), 8.19 (d, J =2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.27(dd, J = 8.0, 4.8 Hz, 1H), 4.59 (s, 4H), 3.39 (s, 3H), 3.25 (d, J= 7.2 Hz, 2H), 3.21 (q, J = 6.4 Hz, 1H), 3.13 (d, J = 7.2 Hz, 2H), 1.11 (d, J = 6.4 Hz, 3H). LC-MS m / z: 468.2 [M+ H] + HPLC purity (214 nm): > 99.9%; t R = 7.182 minutes. Chiralpak AS-3: 99.8%ee, t R = 1.524 minutes.

[0281] Example 1b: Preparation of compound 2.

[0282]

[0283] 6-(1-(6-chloropyridin-3-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (1B). 30% AcOH (3.85 g, 64.10 mmol) and NaBH(OAc)3 (27.18 g, 128.20 mmol) were added to a mixture of 1-(6-chloropyridin-3-yl) ethyl ketone (10.0 g, 64.10 mmol) and 2-oxa-6-azaspiro[3.3]heptane (7.61 g, 76.92 mmol) in 1,2-dichloroethane (200 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was repeated in parallel on the same scale. After the reaction was complete, the mixture was concentrated, diluted with H2O (200 mL), the pH was adjusted to 8–9 with aqueous K2CO3 solution, and extracted with CH2Cl2 (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (EtOAc) followed by reversed-phase column chromatography (MeOH: H₂O = 1: 3) to give 1B as a pale yellow liquid (52.2% yield for 24.0 g in 3 batches). LC-MS m / z: 239.4 [M+1] + Purity (at 214nm): 94.1%; t R = 1.424 minutes.

[0284] ( S)-6-(1-(6-chloropyridin-3-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (2.2-S). Product 1B was further purified by SFC to give pure 2.2-R (11.4 g) and 2.2-S (11.6 g) as pale yellow liquids. 2.2-R: Chiralpak AS-3, MeOH (0.2% 7M NH3): > 99.9%ee, t R = 1.103 minutes. 2.2-S: ChiralpakAS-3, MeOH (0.2% 7M NH3): 99.8%ee, t R = 1.650 minutes.

[0285] 2-Bromo-5-fluoro-3-(methylthio)pyridine (2.3). Carefully add 2-bromo-5-fluoropyridine-3-amine (15.0 g, 78.53 mmol) and 1,2-dimethyldithionane (20 mL, 235.59 mmol) to a solution in MeCN (150 mL). t -BuONO (25 mL, 235.59 mmol), the mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc:hexane = 1:19) to give 2.3 (11.7 g, 67.1% yield) as a yellow solid. LC-MS m / z: 222.2 [M+ 1] + LCMS purity (254 nm): 94.2%; t R = 1.827 minutes.

[0286] N 4 -(5-fluoro-3-(methylthio)pyridin-2-yl)pyrimidine-4,6-diamine (2.2). A mixture of 2.3 (6.70 g, 30.17 mmol), pyrimidine-4,6-diamine (6.64 g, 60.36 mmol), Pd2(dba)3 (1.93 g, 2.11 mmol), Xantphos (2.44 g, 4.22 mmol), and Cs2CO3 (29.52 g, 90.54 mmol) in 1,4-dioxane (100 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 19:1) to give 2.2 (3.95 g, 52.1% yield) as a yellow solid. LC-MS m / z: 252.3 [M+ 1] + LCMS purity (214 nm): 93.0%; tR = 1.444 minutes.

[0287] N 4 -(5-fluoro-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (2.1). 30% H2O2 (40 mL) was added to a solution of 2.2 (5.90 g, 23.48 mmol) in AcOH (40 mL) and H2O (40 mL), and the mixture was stirred overnight at room temperature. LCMS showed an MS value of 268.2 (M-15). Then, an additional 30% H2O2 (40 mL) and Na2WO4·2H2O (7.75 g, 23.50 mmol) were added to the mixture, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into water (200 mL) and the pH was carefully adjusted to 7–8 with an aqueous K2CO3 solution to obtain a precipitate. The mixture was filtered and the filter cake was dried to give 2.1 (5.60 g, 84.2% yield) as a yellow solid. LC-MS m / z: 284.2 [M+ H] + LCMS purity (214 nm): 82.2%; t R = 1.345 minutes.

[0288] ( S )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6 -(5-fluoro-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (2). A mixture of 2,1 (3.0 g, 10.59 mmol), 2,2-S (2.53 g, 10.59 mmol), Pd2(dba)3 (0.97 g, 1.06 mmol), Xantphos (1.23 g, 2.12 mmol), and Cs2CO3 (10.37 g, 31.80 mmol) in 1,4-dioxane (100 mL) was stirred overnight at 110 °C under an argon atmosphere. LCMS showed that 2,1 and 2,2-S were not completely consumed. The reaction was repeated in parallel on the same scale. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 15:1) and then by reverse-phase preparative HPLC to give 2 as a white solid (2.6 g for 2 batches, 25.3% yield).1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.30 (brs, 1H), 8.76 (d, J = 2.8 Hz, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.25 (dd, J = 7.6, 2.8 Hz, 1H), 8.23 ​​(s, 1H), 7.64-7.58 (m,2H), 4.60-4.57 (m, 4H), 3.45 (s, 3H), 3.25 (d, J = 6.8 Hz, 2H), 3.20 (q, J =6.4 Hz, 1H), 3.13 (d, J = 6.8 Hz, 2H), 1.11 (d, J = 6.8 Hz, 3H). LC-MS m / z:486.2 [M+1] + HPLC purity (214 nm): > 99.9%; t R = 7.106 minutes. Chiralpak OJ-3, MeOH (0.2% 7M NH3): 99.72%ee, t R = 2.461 minutes.

[0289] Example 1c: Preparation of compound 3.

[0290]

[0291] Methyl 2-bromo-5-methoxy-3-(methylthio)pyridine (3.3). 1,2-Dimethyldithion (1856 mg, 19.7 mmol) was added to a solution of 2-bromo-5-methoxypyridine-3-amine (2 g, 9.85 mmol) in CH3CN (60 mL). t -BuONO (2031 mg, 19.7 mmol). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. Further purification by chromatography (EtOAc: hexane = 3:7) gave the title product 3.3 (800 mg, 34.7% yield) as a yellow solid. LC-MS m / z: 235.2 [M+ H] + LCMS purity (254 nm): 95.06%; t R = 0.684 minutes.

[0292] N 4 -(5-methoxy-3-(methylthio)pyridin-2-yl)pyrimidine-4,6-diamine (3.2). Pyrimidine-4,6-diamine (377 mg, 3.42 mmol), Cs₂CO₃ (2229 mg, 6.84 mmol), and Brettphos-Pd-G₃ (154 mg, 0.17 mmol) and Xantphos (98 mg, 0.17 mmol) were added to a solution of 3.3 (800 mg, 3.42 mmol) in dioxane (40 mL). The reaction mixture was heated to 110 °C and stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. Further purification by chromatography (CH₂Cl₂: MeOH = 10 / 1) gave the title product 3.2 (550 mg, 61.1% yield) as a green solid. LC-MS m / z: 264.2 [M+ H] + LCMS purity (254 nm): 95.14%; t R = 0.411 minutes.

[0293] N 4 -(5-methoxy-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (3.1). H₂O₂ (30% wt, 0.5 mL) was added to a solution of 3.2 (150 mg, 0.57 mmol) in AcOH (2 mL). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (70 mL). The pH of the mixture was adjusted to 7–8 with NaHCO₃ solution. The mixture was extracted with CH₂Cl₂:MeOH (10:1, 80 mL). The organic phase was evaporated under vacuum to give the crude product. Further purification by chromatography (CH₂Cl₂:MeOH = 20:1) gave 3.1 as a yellow solid (200 mg, 59.5% yield). LC-MS m / z: 296.2 [M+ H] + LCMS purity (254 nm): 78.04%; t R = 0.397 minutes.

[0294] ( S )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6-(5-methoxy-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (3). A solution of 2,2-S (80 mg, 0.27 mmol), 3.1 (65 mg, 0.27 mmol), Brettphos-Pd-G3 (25 mg, 0.027 mmol), Xantphos (31 mg, 0.054 mmol), and Cs2CO3 (177 mg, 0.54 mmol) in dry 1,4-dioxane (10 mL) was stirred overnight at 110 °C under nitrogen. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2 = 1 / 20) and reversed-phase HPLC to give 3 (50.63 mg, 37.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.03 (br, 1H), 9.20 (br, 1H), 8.54 (br, 1H), 8.44 (d, J = 3.2 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.83 (d, J =2.8 Hz, 1H), 7.61 (s, 2H), 4.59 (s, 4H), 3.93 (s, 3H), 3.40 (s, 3H), 3.26 (d, J = 7.2 Hz, 2H), 3.22-3.19 (m, 1H), 3.13 (d, J = 7.2 Hz, 2H), 1.11 (d, J =6.4 Hz, 3H). LC-MS m / z: 498.0 [M+ H] + HPLC purity (214 nm): > 99.9%; t R = 2.708 minutes.

[0295] Example 1d: Preparation of compound 4.

[0296]

[0297] ( R,E )- N -(1-(6-chloropyridin-3-yl)ethylene)-2-methylpropane-2-sulfinamide (4.4). 1-(6-chloropyridin-3-yl)ethyl-1-one (1.00 g, 6.43 mmol), ( RA stirred solution of 2-methylpropane-2-sulfinamide (1.56 g, 12.85 mmol) and Ti(i-PrO)₄ (5.44 g, 19.29 mmol) in MeCN (60 mL) was stirred overnight at 80 °C under nitrogen. After the initial material was consumed (monitored by LC-MS), H₂O (100 mL) was added to the mixture, the solid was filtered, and the filtrate was extracted with EtOAc (100 mL) and washed with water (50 mL × 2) followed by brine (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The target product was purified by silica gel column chromatography (EtOAc / hexane = 5 / 1) to give 4.4 g (1.4 g, 84.2% yield) as a yellow oil. LC-MS m / z: 259.1 [M+1] + LCMS purity (214 nm): 94.01%; t R = 1.812 minutes.

[0298] ( R )- N -((S)-1-(6-chloropyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (4.3). At -78 °C, tri-sec-butylborohydride (6 mL, 5.95 mmol) was added to a stirred solution of 4.4 (1.4 g, 5.41 mmol) in THF (30 mL). The mixture was stirred at -78 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), H2O (100 mL) was added to the mixture, and it was extracted with EtOAc (100 mL) and washed with water (50 mL × 2) followed by brine (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The target product was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 4.3 (800 mg, 56.7% yield) as a grayish-white solid. LC-MS m / z: 261.2 [M+1] + LCMS purity (254 nm): 88.98%; t R = 0.320 minutes.

[0299] ( S1-(6-chloropyridin-3-yl)ethylamine (4.2). A solution of 4.3 (20 g, 76.69 mmol) was stirred overnight at room temperature in 4 N HCl / EtOAc (400 mL). After the initial material was consumed (monitored by LC-MS), the mixture was filtered and the filter cake was washed with EtOAc (50 mL). The filter cake was dried to give 4.2 (11.0 g, 91.6% yield) as a yellow solid. LC-MS m / z: 157.4 [M+1] + LCMS purity (214 nm): 85.50%; t R = 0.709 minutes.

[0300] 3-Bromoquinoline-8-carboxylic acid (4.1). CH₂O (949 mg, 10.53 mmol), AcOH (3 drops), and NaBH₃CN (662 mg, 10.53 mmol) were added to a solution of 4.2 (550 mg, 3.51 mmol) in MeOH (30 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was evaporated under vacuum and purified by reversed-phase preparative HPLC to give 4.1 (150 mg, 23.1% yield) as a yellow oil. LC-MS m / z: 185.4 [M+1] + LCMS purity (214 nm): 94.33%; t R = 0.381 minutes.

[0301] ( S )- N 4 -(5-(1-(dimethylamino)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (4). N was added to a solution of 4.1 (150 mg, 0.81 mmol) in dioxane (5 mL). 4 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1A, 215 mg, 0.81 mmol), Cs₂CO₃ (528 mg, 1.62 mmol), and Brettphos-Pd-G₃ (73 mg, 0.081 mmol) and Xantphos (47 mg, 0.081 mmol). The reaction mixture was heated to 110 °C and stirred at 110 °C and MW for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by reversed-phase preparative HPLC to give 4 (31.32 mg, 9.4% yield) as a yellow solid. 1H NMR (400 MHz, DMSO- d 6) δ10.14 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.27 (dd, J = 7.6, 1.6 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 (dd, J = 8.0, 5.2 Hz, 1H), 3.39 (s, 3H), 3.37-3.35(m, 1H), 2.10 (s, 6H), 1.30 (d, J = 6.8 Hz, 3H). LC-MS m / z: 414.2 [M+ H] + HPLC purity (254 nm): 99.29%, t R = 6.961 minutes.

[0302] Example 1e: Preparation of compound 5.

[0303]

[0304] 2-Chloro-5,6,7,8-Tetrahydroquinoline-5-ol (5.4). EtOH (5 mL) containing NaBH4 (42 mg, 1.10 mmol) was added to a stirred solution of 2-chloro-7,8-dihydroquinoline-5(6H)-one (200 mg, 1.10 mmol). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over sodium, and concentrated under vacuum to give 5.4 (200 mg, 99% yield) as a yellow oil. LC-MS m / z: 184.2 [M+1]+. LCMS purity (254 nm): > 99.9%; t R = 1.391 minutes.

[0305] 2,5-Dichloro-5,6,7,8-Tetrahydroquinoline (5.3). CH₂Cl₂ (5 mL) containing MsCl (250 mg, 2.18 mmol) and Et₃N (331 mg, 3.27 mmol) was added to a stirred solution of 5.4 (200 mg, 1.09 mmol). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LC-MS), the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1) to give 5.3 (150 mg, 68% yield) as a yellow oil. LC-MS m / z: 202.2 [M+1] + LCMS purity (254 nm): 78.40%; t R = 2.085 minutes.

[0306] 6-(2-chloro-5,6,7,8-tetrahydroquinolin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (5.2). CH3CN (6 mL) containing 2-oxa-6-azaspiro[3.3]heptane (64 mg, 0.64 mmol) and DIEA (250 mg, 1.94 mmol) was added to a stirred solution of 5.3 (130 mg, 0.64 mmol). The mixture was stirred overnight at 80 °C. After the initial material was consumed (monitored by LCMS), the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 20 / 1) to give 5.2 (100 mg, 59% yield) as a yellow oil. LC-MS m / z: 265.2 [M+1] + LCMS purity (254 nm): > 99.9%; t R = 1.554 minutes.

[0307] ( R )- N 4 -(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5,6,7,8-tetrahydroquinoline-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (5). Dioxane (5 mL) containing 1A (100 mg, 0.38 mmol), Brettphos-Pd-G3 (36 mg, 0.04 mmol), X-phos (19 mg, 0.04 mmol), and Cs2CO3 (248 mg, 0.76 mmol) was added to a stirred solution at 5.2 mL (100 mg, 0.38 mmol). The mixture was stirred overnight at 130 °C. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with water (20 mL × 2) followed by washing with brine (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 10 / 1) and reversed-phase preparative HPLC to give 5.1 (59 mg, 32% yield) as a white solid. 5.1 (59 mg, 0.12 mmol) was then further purified by SFC to give 5 (21 mg, 36% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.06 (s, 1H), 9.46 (s, 1H), 9.04 (br, 1H), 8.63 (dd, J = 4.8, 2.0 Hz, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.26 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.32-7.25 (m, 2H), 4.58 (s, 4H), 3.41 (s, 1H), 3.39 (s, 4H), 3.17-3.12 (m, 3H), 2.82-2.66 (m, 2H), 2.09-2.04 (m, 1H), 1.80-1.75 (m, 1H), 1.71-1.66 (m, 1H), 1.59-1.50 (m, 1H). LC-MS m / z: 494.0 [M+ 1] + HPLC purity (214 nm): >99.9%; t R = 7.835 minutes.

[0308] Example 1f: Preparation of compound 6.

[0309]

[0310] 6-Chloro-2-methyl-N-(3-methyloxetane-3-yl)pyridine-3-amine (6.1). A suspension of 3-bromo-6-chloro-2-methylpyridine (500 mg, 2.42 mmol), 3-methyloxetane-3-amine (253 mg, 2.91 mmol), Pd2(dba)3 (222 mg, 0.24 mmol), Xantphos (280 mg, 0.48 mmol), and Cs2CO3 (1578 mg, 4.84 mmol) in dried 1,4-dioxane (30 mL) was stirred overnight at 110 °C under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 60%) to give 6.1 (220 mg, 42.7% yield) as a yellow oil. LC-MS m / z: 213.1 [M+ H] + LCMS purity (214 nm): 98.77%; t R = 1.438 minutes.

[0311] N 4 -(6-Methyl-5-((3-methyloxetane-3-yl)amino)pyridin-2-yl) -N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (6). 6.1 (220 mg, 1.03 mmol), 1A (329 mg, 1.24 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (120 mg, 0.21 mmol) and t A suspension of BuONa (199 mg, 2.07 mmol) in dry toluene (30 mL) was stirred overnight at 130 °C under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (MeOH / CH2Cl2 15%). The mixture was then further purified by reversed-phase preparative HPLC to give 6 (80 mg, 17.5% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.69(s, 1H), 9.37 (s, 1H), 8.75 (br, 1H), 8.60 (dd, J = 5.2, 2.0 Hz, 1H), 8.29(d, J= 1.2 Hz, 1H), 8.25 (dd, J = 8.0, 1.6 Hz, 1H), 7.27-7.24 (m, 2H), 6.45(d, J = 8.8 Hz, 1H), 5.28 (s, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.48 (d, J = 5.6Hz, 2H), 3.38 (s, 3H), 2.36 (s, 3H), 1.55 (s, 3H). LC-MS m / z: 442.4 [M+ H] + HPLC purity (214 nm): > 99.9%; t R = 6.984 minutes.

[0312] Example 1g: Preparation of compound 7.

[0313] 1-(6-chloropyridin-3-yl)-4-cyclopropylpiperazine (7.1). 5-bromo-2-chloropyridine (2.00 g, 10.38 mmol), Cs₂CO₃ (6.76 g, 20.76 mmol), Xantphos (301 mg, 0.52 mmol), and Pd₂(dba)₃ (238 mg, 0.26 mmol) were added to a solution of 1-cyclopropylpiperazine (1.31 g, 10.38 mmol) in dioxane (30 mL). The mixture was then stirred overnight at 110 °C under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 2 / 5) to give 7.1 (130 mg, 5% yield) as a yellow solid. LC-MS m / z: 238.4 [M+1] + LCMS purity (214 nm): > 99.9%; t R = 0.395 minutes.

[0314] N 4 -(5-(4-Cyclopropylpiperazin-1-yl)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (7). Add 1A (56 mg, 0.21 mmol) to a solution of 7.1 (50 mg, 0.21 mmol) in dioxane (3 mL). t -BuONa (40 mg, 0.42 mmol), Xantphos (12 mg, 0.021 mmol), and Pd2(dba)3 (10 mg, 0.011 mmol). The mixture was then microwave-irradiated at 110 °C for 1 hour under a nitrogen atmosphere. After the starting material was consumed (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 7 (18 mg, 18% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.90 (s, 1H), 9.38 (s, 1H), 8.66 (dd, J = 4.8, 2.0 Hz, 1H), 8.62 (br, 1H), 8.34 (d, J = 0.8 Hz, 1H), 8.25 (dd, J = 8.0, 1.6 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.60 (d, J =8.8 Hz, 1H), 7.42 (dd, J = 9.2, 3.2 Hz, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H),3.38 (s, 3H), 3.08 (t, J = 5.2 Hz, 4H), 2.69 (t, J = 5.2 Hz, 4H), 1.70-1.62(m, 1H), 0.49-0.42 (m, 2H), 0.36-0.31(m, 2H). LC-MS m / z: 467.2 [M + 1] + HPLC purity (214 nm): > 99.9%; t R = 7.974 minutes.

[0315] Example 1h: Preparation of compound 8.

[0316]

[0317] ( S 8.3. 5-Bromo-2-chloropyridine (19.22 g, 99.86 mmol) was added to a solution of (S)-3-methylpiperazine-1-carboxylate (20.0 g, 99.86 mmol) in dioxane (400 mL). t -BuONa (19.19 g, 199.72 mmol), Pd2(dba)3 (2.29 g, 2.50 mmol), and Xantphos (1.44 g, 2.50 mmol). The mixture was stirred at 100 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (90 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1) to give 8.3 (23.00 g, 74% yield) as a pale yellow oil. LC-MS m / z: 312.2 [M + 1] + LCMS purity (214 nm): 94.60%; t R = 2.165 minutes.

[0318] ( S 1-(6-chloropyridin-3-yl)-2-methylpiperazine (8.2). A solution of 8.3 (10.00 g, 32.07 mmol) in EtOAc (3 N, 120 mL) containing HCl was stirred overnight at room temperature. After the starting material was consumed (monitored by LCMS), the solvent was removed under vacuum. The residue was diluted with saturated aqueous NaHCO3 solution (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over sodium sulfate, and concentrated to dryness to give 8.2 (6.70 g, crude product) as a light brown solid, which could be used directly in the next step. LC-MS m / z: 212.3 [M +1] + LCMS purity (254 nm): 97.60%; t R = 1.338 minutes.

[0319] ( S1-(6-chloropyridin-3-yl)-4-cyclopropyl-2-methylpiperazine (8.1). To a solution of 8.2 (6.7 g, 31.65 mmol) in THF (70 mL) and MeOH (70 mL), add (1-ethoxycyclopropoxy)trimethylsilane (16.55 g, 94.95 mmol), NaBH3CN (5.97 g, 94.95 mmol), and HOAc (1.90 g, 31.65 mmol). The mixture was stirred overnight at 50 °C. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (90 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give 8.1 (6.00 g, 75% yield, two steps) as a light brown oil. LC-MS m / z: 252.4 [M + 1] + LCMS purity (254nm): 91.41%; t R = 2.008 minutes.

[0320] ( S )- N 4 -(5-(4-Cyclopropyl-2-methylpiperazin-1-yl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (8). Add 1A (3.69 g, 13.90 mmol) to a solution of 8.1 (3.50 g, 13.90 mmol) in dioxane (110 mL). t -BuOK (3.12 g, 27.80 mmol), Pd2(dba)3 (637 mg, 0.70 mmol), and Xantphos (804 mg, 1.39 mmol). The mixture was stirred overnight at 130 °C under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (60 mL), and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 8 (1.80 g, 27% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 9.90 (s, 1H), 9.39 (s, 1H), 8.66(dd, J = 4.8, 2.0 Hz, 1H), 8.62 (br, 1H), 8.35 (d, J = 0.8 Hz, 1H), 8.25 (dd, J = 8.0, 2.0 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 9.2, 3.2 Hz, 1H), 7.25 (dd, J = 7.6, 4.8 Hz, 1H), 3.82-3.71 (m,1H), 3.38 (s, 3H), 3.20-3.10 (m, 1H), 2.95-2.78 (m, 2H), 2.70-2.58 (m, 2H),2.49-2.42 (m, 1H), 1.70-1.58 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.51-0.41 (m,2H), 0.41-0.32 (m, 1H), 0.32-0.19 (m, 1H). LC-MS m / z: 481.4 [M + 1] + HPLC purity (254 nm): > 99.9%; t R = 9.001 minutes.

[0321] Example 1i: Preparation of compound 9.

[0322]

[0323] 6-(2-chloro-6,7-dihydro-5H-cyclopenten[ b]pyridin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (9.2). 2-oxa-6-azaspiro[3.3]heptane (2.75 g, 27.75 mmol), NaBH(AcO)3 (11.76 g, 55.49 mmol) and HOAc (1.11 g, 18.50 mmol) were added to a solution of 2-chloro-6,7-dihydro-5H-cyclopenteno[b]pyridin-5-one (3.10 g, 18.50 mmol) in THF (5 mL) and DCE (50 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (90 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / THF = 1 / 1) to give 9.2 g (2.00 g, 43% yield) as a light brown oil. LC-MS m / z: 251.2 [M + 1] + LCMS purity (214 nm): 97.04%; t R = 1.462 minutes.

[0324] N 4 -((5 S )-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-6,7-dihydro-5 H -cyclopenten[ b ]pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (9). 1A (118 mg, 0.45 mmol), Cs₂CO₃ (293 mg, 0.90 mmol), X-phos (21 mg, 0.045 mmol), and Brettphos Pd G₃ (41 mg, 0.045 mmol) were added to a stirred solution of 9.2 (112 mg, 0.45 mmol) in dioxane (5 mL). The mixture was stirred overnight at 110 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 8 / 1), reversed-phase preparative HPLC to give 9.1, which was then further purified by SFC to give 9 (13 mg, 6% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d6) δ 10.13 (s, 1H), 9.46 (br, 1H), 9.06 (s, 1H), 8.63(dd, J J = 4.8, 2.0Hz, 1H), 8.39 (d, J J = 0.8 Hz, 1H), 8.26 (dd, J J = 7.6, 1.6Hz, 1H), 7.59 (d, J J = 8.0 Hz, 1H), 7.32 (d, J J = 8.4 Hz, 1H), 7.27 (dd, J J =7.6, 4.8 Hz, 1H), 4.59(s, 4H), 3.72 (dd, J J =6.8, 2.8 Hz, 1H), 3.39(d, J J = 6.4 Hz, 5H), 3.28 (d, J J =6.8 Hz, 2H), 3.02-2.91(m, 1H), 2.82-2.70 (m, 1H), 2.12-2.01(m, 1H), 1.85-1.76(m, 1H). LC-MS m / z: 480.2 [M + 1] + . HPLC purity (214 nm): > 99.9%; t R Rt = 6.877 min.

[0325] Example 1j: Preparation of compound 10.

[0326]

[0327] 2-(1-(6-chloropyridin-3-yl)ethyl)-6-fluoro-2-azaspiro[3.3]heptane (10.2). 5-(1-bromoethyl)-2-chloropyridine (150 mg, 0.68 mmol) and DIEA (220 mg, 1.70 mmol) were added to a solution of 6-fluoro-2-azaspiro[3.3]hept-2-onium 2,2,2-trifluoroacetate (130 mg, 0.57 mmol) in MeCN (10 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give 10.2 mg (140 mg, 97% yield) of a colorless oil. LC-MS m / z: 255.0 [M+1]. LC-MS purity (254 nm): > 99.9%; t R = 1.523 minutes.

[0328] N 4 -(5-((1 R )-1-(6-fluoro-2-azaspiro[3.3]hept-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (10). 1A (146 mg, 0.55 mmol), Cs₂CO₃ (358 mg, 1.10 mmol), Xantphos (32 mg, 0.055 mmol), and Pd₂(dba)₃ (25 mg, 0.027 mmol) were added to a solution of 10.2 (140 mg, 0.55 mmol) in dioxane (10 mL). The mixture was then stirred overnight at 110 °C under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to obtain 10.1, which was then further purified by preparative SFC to obtain 10 (14 mg, 5% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d6) δ10.12 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.67 (dd, J = 8.8, 1.6 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.27 (dd, J = 8.0,5.2 Hz, 1H), 5.06-4.78 (m, 1H), 3.39 (s, 3H), 3.27-3.16 (m, 1H), 3.15-3.03(m, 2H), 3.02-2.90 (m, 2H), 2.50-2.37 (m, 2H), 2.28-2.11 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H). LC-MS m / z: 484.0 [M + 1] + HPLC purity (214 nm): > 99.9%; t R = 8.083 minutes.

[0329] Example 1k: Preparation of compound 11.

[0330]

[0331] 3-(ethoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide (11.8). At 0 °C, CO(NH2)2·H2O2 (37.5 g, 398.8 mmol) was added to a solution of ethyl 2-(trifluoromethyl)nicotinate (38 g, 173.4 mmol) in CH2Cl2 (1000 mL). The mixture was stirred at 0 °C for 1 hour. Then, at 0 °C, a solution of TFAA (72.8 g, 346.8 mmol) in CH2Cl2 (200 mL) was added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the reaction mixture was washed with Na2CO3 solution (250 mL) and NaHSO3 (250 mL × 2). The organic phase was concentrated to give 11.8 μg of 3-(ethoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide (crude product), which was a colorless oil. LC-MS m / z: 236.1 [M+ H] +LCMS purity (254 nm): 95.74%; t R = 1.443 minutes.

[0332] Ethyl-6-chloro-2-(trifluoromethyl)nicotinate (11.7). A solution of 3-(ethoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide 11.8 (crude product, 388.03 mmol) in POCl3 (150 mL) was heated to 80 °C and stirred overnight at 80 °C. After the initial material was consumed (monitored by LCMS), the mixture was cooled to 0 °C and quenched with Na2CO3 solution (500 mL) below 10 °C. The mixture was extracted with MTBE (250 mL). The organic phase was concentrated and purified by silica gel column chromatography (0-25% EtOAc / hexane) to give ethyl 6-chloro-2-(trifluoromethyl)nicotinate 11.7 as a colorless oil (58 g, 59.08% yield, two steps). LC-MS m / z: 254.1 [M+ H] + LCMS purity (214 nm): 88.85%; t R =1.902 minutes.

[0333] (6-Chloro-2-(trifluoromethyl)pyridin-3-yl)methanol (11.6). At 0 °C, 11.7 (19 g, 74.9 mmol) of ethyl 6-chloro-2-(trifluoromethyl)nicotinate in 500 mL of CH₂Cl₂ was added dropwise to a THF solution containing 1 M DIBAL-H (150 mL, 149.8 mmol). The mixture was warmed to room temperature and stirred at room temperature for 3 hours. After the initial material was consumed (monitored by LCMS), the reaction mixture was quenched with 30 mL of water below 10 °C. The mixture was filtered through diatomaceous earth and the filter cake was washed with 250 mL of CH₂Cl₂. The filtrate was concentrated to give (6-chloro-2-(trifluoromethyl)pyridin-3-yl)methanol 11.6 (crude product) as a colorless oil. LC-MS m / z: 212.1 [M+ H] + LCMS purity (214 nm): 92.14%; t R = 1.576 minutes.

[0334] 6-Chloro-2-(trifluoromethyl)nicotinaldehyde (11.5). Dess-Martin (38.9 g, 91.7 mmol) was added to a solution of (6-chloro-2-(trifluoromethyl)pyridin-3-yl)methanol 11.6 (crude product, 74.9 mmol) in CH2Cl2 (300 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the reaction mixture was filtered through diatomaceous earth and the filter cake was washed with CH2Cl2 (200 mL). The filtrate was concentrated and purified by silica gel column chromatography (0-25% EtOAc / hexane) to give 6-chloro-2-(trifluoromethyl)nicotinaldehyde 11.5 (9.5 g, 60.7% yield, two steps) as a colorless oil. LC-MS m / z: None. LCMS purity (254 nm): 96.85%; t R = 1.758 minutes.

[0335] 1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)ethanol (11.4). Methyl magnesium bromide (1.0 M in THF, 2.4 mL, 2.36 mmol) was added to a solution of 11.5 (330 mg, 1.57 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was poured into an aqueous solution of NH4Cl (saturated, 50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL). The organic phases were dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc / hexane 30%) to give 11.4 (320 mg, 90.1% yield) as a yellow oil. LC-MS m / z: 226.1 [M+ H] + LCMS purity (254 nm): >99%; t R = 1.669 minutes.

[0336] 1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)acetone (11.3). PCC (191 mg, 0.89 mmol) was added to a solution of 11.4 (100 mg, 0.44 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 12%) to provide 11.3 as a yellow oil (70 mg, 70.6% yield). LC-MS m / z: 224.1 [M+ H] + LCMS purity (214 nm): 95.79%; t R= 1.729 minutes.

[0337] 1-(6-((6-((3-(methanesulfonyl)pyridin-2-yl)amino)pyrimidin-4-yl)amino)-2-(trifluoromethyl)pyridin-3-yl)acetone (11.2). A suspension of 11.3 (70 mg, 0.31 mmol), 1A (100 mg, 0.38 mmol), Brettphos-Pd-G3 (28 mg, 0.031 mmol), Xantphos (36 mg, 0.063 mmol) and K3PO4 (133 mg, 0.63 mmol) in dry 1,4-dioxane (30 mL) was stirred overnight at 110 °C under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 100%) to give 11.2 (100 mg, 70.6% yield) as a yellow solid. LC-MS m / z: 453.1 [M+ H] + LCMS purity (254 nm): 89.51%; t R = 1.624 minutes.

[0338] N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)-6-(trifluoromethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (11.1). 2-oxa-6-azaspiro[3.3]heptane (44 mg, 0.44 mmol) and tetraisopropoxide titanium (126 mg, 0.44 mmol) were added to a stirred solution of 11.2 (100 mg, 0.22 mmol) in THF (20 mL). The mixture was stirred overnight at 60 °C. Then, NaBH4 (17 mg, 0.44 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with 20 mL of water. The mixture was filtered through diatomaceous earth and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reversed-phase preparative HPLC to give 11.1 (33 mg, 27.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-) d6) δ 10.50 (s, 1H), 9.53 (s, 1H), 8.86 (s, 1H), 8.55 (dd, J =4.8, 1.6 Hz, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.0, 5.2Hz, 1H), 4.59 (s, 4H), 3.56-3.54 (m, 1H), 3.40 (s, 3H), 3.23 (d, J = 7.2 Hz, 2H), 3.18 (d, J = 7.2 Hz, 2H), 1.10 (d, J = 6.0 Hz, 3H). LC-MS m / z: 536.0 [M+H] + HPLC purity (214 nm): > 99.9%; t R = 8.382 minutes.

[0339] ( R )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)-6-(trifluoromethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (11). 11.1 (80 mg) was purified by preparative SFC to give 11 (33.84 mg, 84.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.50 (s, 1H), 9.53 (s, 1H), 8.86 (s, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.09 (d, J= 8.4Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 7.6, 4.8 Hz, 1H), 4.59 (s,4H), 3.56-3.54 (m, 1H), 3.40 (s, 3H), 3.23 (d, J = 7.2 Hz, 2H), 3.18 (d, J =7.2 Hz, 2H), 1.10 (d, J = 6.0 Hz, 3H). LC-MS m / z: 536.1 [M+ H] + HPLC purity (214nm): 97.67%; t R = 8.213 minutes.

[0340] Example 11: Preparation of compound 12.

[0341]

[0342] 1-(6-chloro-2-methylpyridin-3-yl)ethanol (12.4). MeMgBr (1 M in THF, 6.4 mL, 6.43 mmol) was added to a solution of 6-chloro-2-methylnicotinaldehyde (500 mg, 3.21 mmol) in THF (10 mL) at 0 °C. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with NH4Cl solution (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was then dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 12.4 (496 mg, 90% yield) as a colorless oil. LC-MS m / z: 172.0 [M+ H] + LCMS purity (214 nm): > 99.9%, t R = 1.177 minutes.

[0343] 6-Chloro-3-(1-Chloroethyl)-2-methylpyridine (12.3). TEA (531 mg, 5.24 mmol) and MsCl (400 mg, 3.5 mmol) were added to a solution of 12.4 (300 mg, 1.75 mmol) in CH2Cl2 (10 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL). The organic phase was then dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 12.3 (300 mg, 90% yield) as a colorless oil. LC-MS m / z: 190.2 [M+H] + LCMS purity (254 nm): 97.75%, t R = 1.628 minutes.

[0344] 6-(1-(6-chloro-2-methylpyridin-3-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (12.2). 2-oxa-6-azaspiro[3.3]heptane (209 mg, 2.10 mmol) and DIEA (408 mg, 3.16 mmol) were added to a solution of 12.3 (200 mg, 1.05 mmol) in MeCN (10 mL). The mixture was stirred at 50 °C for 8 hours. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 12.2 (200 mg, 75% yield) as a white solid. LC-MS m / z: 253.2 [M+ H] + LCMS purity (214 nm): > 99.9%, t R = 1.284 minutes.

[0345] N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)-6-methylpyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (12). Brettphos Pd G3 (36 mg, 0.04 mmol), Xantphos (23 mg, 0.04 mmol), and Cs2CO3 (258 mg, 0.79 mmol) were added to a solution of 12.2 (100 mg, 0.40 mmol) and 1A (105 mg, 0.40 mmol) in dioxane (4 mL). The mixture was stirred in a microwave at 110 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give crude product 12.1, which was purified by reversed-phase preparative HPLC and preparative SFC to give 12 (40.81 mg, 43% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.04 (s, 1H), 9.47 (s, 1H), 9.09 (s, 1H), 8.63 (d, J = 3.6 Hz,1H), 8.38 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.34-7.26 (m, 2H), 4.60 (s, 4H), 3.45-3.41 (m, 1H), 3.34 (s, 3H), 3.27-3.18 (m,4H), 2.50 (s, 3H), 1.05 (d, J = 6.4 Hz, 3H). LC-MS m / z: 482.3 [M+ H] + HPLC purity (214 nm): > 99.9%, t R = 7.123 minutes.

[0346] Example 1m: Preparation of compound 13.

[0347]

[0348] 1-(6-chloropyridin-3-yl)-2-methylprop-1-ol (13.4). Added to a solution of 5-bromo-2-chloropyridine (1.0 g, 5.20 mmol) in dry THF (30 mL) at 0 °C. i-PrMgCl (2 M in THF, 10 mL, 20.79 mmol). The mixture was stirred at 0 °C until the reaction became turbid. Isobutyraldehyde (1.87 g, 25.98 mmol) was then added dropwise to the mixture below 5 °C. The reaction mixture was slowly warmed to room temperature and stirred overnight at room temperature. After the starting material was consumed (monitored by LCMS), the reaction mixture was quenched with saturated NH4Cl solution (50 mL). The mixture was washed with EtOAc (50 mL). The organic layer was concentrated under vacuum and purified by silica gel column chromatography (hexane to hexane / EtOAc = 3 / 1) to give 13.4 (850 mg, 88% yield) as a yellow solid. LC-MS m / z: 186.4 [M+ H] + LCMS purity (254 nm): > 99.9%; t R = 0.566 minutes.

[0349] 1-(6-chloropyridin-3-yl)-2-methylprop-1-one (13.3). PCC (929 mg, 4.31 mmol) was added to a solution of 13.4 (400 mg, 2.15 mmol) in CH2Cl2 (20 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (hexane to hexane / EtOAc = 3 / 1) to give 13.3 (210 mg, 53% yield) as a colorless oil. LC-MS m / z: 184.1 [M+ H] + LCMS purity (254 nm): > 99.9%; t R = 0.823 minutes.

[0350] 6-(1-(6-chloropyridin-3-yl)-2-methylpropyl)-2-oxa-6-azaspiro[3.3]heptane (13.2). 2-oxa-6-azaspiro[3.3]heptane (54 mg, 0.55 mmol), AcOH (33 mg, 0.55 mmol), and NaBH(AcO)3 (351 mg, 1.65 mmol) were added to a stirred solution of 13.3 (100 mg, 0.55 mmol) in a DCE (5 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (30 mL) and extracted with CH2Cl2 (40 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 10 / 1) to give 13.2 mg (82 mg, 56% yield) of a light brown oil. LC-MS m / z: 267.2 [M+1] + LCMS purity (254 nm): 93.50%; tR = 1.823 min.

[0351] ( S )- N 4 -(5-(2-methyl-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)propyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (13). 1A (80 mg, 0.30 mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol), X-phos (14 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), and Cs2CO3 (196 mg, 0.60 mmol) were added to a stirred solution of 13.2 (80 mg, 0.30 mmol) in dioxane (6 mL). The mixture was stirred at 130 °C for 2 h. After the initial material was consumed (monitored by LCMS), the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 10 / 1) and reversed-phase preparative HPLC to give 13.1 (48 mg, 32% yield). 13.1 (48 mg, 0.097 mmol) was then further purified by preparative SFC to give 13 (10 mg, 21% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 10.14 (s, 1H), 9.44 (s, 1H), 8.73 (s, 1H), 8.64 (dd, J = 4.8, 2.0 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.69 (d, J =8.8 Hz, 1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H),4.62-4.57 (m, 4H), 3.39 (s, 3H), 3.23-3.15 (m, 4H), 3.03 (d, J = 4.4 Hz, 1H),1.89-1.81 (m, 1H), 0.72 (d, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H). LC-MSm / z: 496.0 [M+ 1] + HPLC purity (214 nm): >99.9%; t R = 8.378 minutes.

[0352] Example 1n: Preparation of compound 14 and compound 14a.

[0353]

[0354] 2-Bromo-5-chloro-3-(methylthio)pyridine (14.4). At room temperature, 1,2-dimethyldithionane (2.74 g, 29.10 mmol) and t-BuONO (3.0 g, 29.10 mmol) was added, and the reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated, diluted with water (50 mL), extracted with CH2Cl2 (50 mL × 2), washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 1:10) to give 14.4 g (2.15 g, 93.5% yield) as a brown solid. LC-MS m / z: 237.6 [M+1] + LCMS purity (214 nm): 30.92%; t R = 1.671 minutes.

[0355] N 4 -(5-chloro-3-(methylthio)pyridin-2-yl)pyrimidine-4,6-diamine (14.3). A mixture of 14.4 (500 mg, 2.10 mmol), pyrimidine-4,6-diamine (279 mg, 2.53 mmol), Pd2(dba)3 (193 mg, 0.21 mmol), Xantphos (244 mg, 0.42 mmol), and Cs2CO3 (2.06 g, 6.33 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with CH2Cl2 (30 mL × 3). The organic extract was washed with brine (50 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (CH₂Cl₂: MeOH = 10:1) to give 14.3 mg (325 mg, 57.9% yield) as a brown solid. LC-MS m / z: 267.8 [M+1] + LCMS purity (214 nm): > 99.9%; t R = 1.363 minutes.

[0356] N 4-(5-chloro-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (14.2). At room temperature, 30% H2O2 (5.26 g, 46.44 mmol) was added to a solution of 14.3 (620 mg, 2.32 mmol) in AcOH (5 mL) and H2O (5 mL), and the reaction mixture was stirred at 40 °C for 24 h. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (20 mL × 3). The organic extract was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 10: 1) to give 14.2 (300 mg, 43.2% yield) as a yellow solid. LC-MS m / z: 300.0 [M+ 1] + LCMS purity (214 nm): 61.18%; t R = 1.231 minutes.

[0357] ( S )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6 -(5-chloro-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (14) and ( R )- N 4 -(5-(1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)- N 6-(5-chloro-3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (14a). A mixture of 14.2 (120 mg, 0.40 mmol), 1B (105 mg, 0.44 mmol), Brettphos-Pd-G3 (73 mg, 0.08 mmol), X-phos (76 mg, 0.16 mmol), and Cs2CO3 (392 mg, 1.20 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with CH2Cl2 (20 mL × 3). The organic extract was washed with brine (50 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (CH₂Cl₂: MeOH = 10:1) followed by reversed-phase preparative HPLC to give compound 14.1 (35 mg, 20.9% yield) as a white solid. This was further purified by SFC to give compounds 14 (6.73 mg, 4.1% yield) and 14a (7.78 mg, 4.6% yield) as white solids. Compound 14: 1 H NMR (400 MHz, DMSO- d 6) δ 10.15(s, 1H), 9.47 (s, 1H), 8.78 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.40 (d, J =0.8 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.64-7.59(m, 2H), 4.59 (t, J = 7.2 Hz, 4H), 3.47 (s, 3H), 3.26 (d, J = 7.2 Hz, 2H),3.22-3.20 (m, 1H), 3.13 (d, J = 6.8 Hz, 2H), 1.12 (d, J = 6.4 Hz, 3H). LC-MSm / z: 502.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R = 7.665 minutes. Compound 14a: 1 H NMR (400 MHz, DMSO-) d6) δ 10.15 (s, 1H), 9.47 (s, 1H), 8.78 (s, 1H), 8.74 (d, J =2.4 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.25 (d, J =1.6 Hz, 1H), 7.64-7.59 (m, 2H), 4.59 (t, J = 6.8 Hz, 4H), 3.47 (s, 3H), 3.27-3.21 (d, J = 7.2 Hz, 2H), 3.22-3.20 (m, 1H), 3.13 (d, J = 7.2 Hz, 2H), 1.12(d, J = 6.4 Hz, 3H). LC-MS m / z: 502.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R =7.664 minutes.

[0358] Example 1o: Preparation of compound 15.

[0359]

[0360] 2-Chloro-5-(1-(pyrrolidine-1-yl)ethyl)pyridine (15.2). DIEA (469 mg, 3.63 mmol) and pyrrolidine (64 mg, 0.91 mmol) were added to a stirred solution of 5-(1-bromoethyl)-2-chloropyridine (200 mg, 0.91 mmol) in MeCN (10 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was poured into ice water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 3) to give 15.2 (140 mg, 73.2% yield) as a pale yellow oil. LC-MS m / z: 211.4 [M +1] + LCMS purity (254 nm): 85.66%; t R = 1.706 minutes.

[0361] N 4 -(3-(methylsulfonyl)pyridin-2-yl)- N 6 -(5-(1-(pyrrolidone-1-yl)ethyl)pyridin-2-yl)pyrimidine-4,6-diamine (15.1). 1A (101 mg, 0.38 mmol), Cs₂CO₃ (247 mg, 0.76 mmol), Xantphos (21 mg, 0.038 mmol), and Brettphos Pd G₃ (34 mg, 0.038 mmol) were added to a stirred solution of 15.2 (80 mg, 0.38 mmol) in dioxane (5 mL). The mixture was stirred overnight at 100 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) and reversed-phase preparative HPLC to give 15.1 (68 mg, 40.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.43 (s, 1H), 8.77 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.27(dd, J = 8.0, 2.0 Hz, 1H), 8.22 (dd, J = 1.6, 1.6 Hz, 1H), 7.72-7.62 (m, 2H),7.27 (dd, J = 8.0, 4.8 Hz, 1H), 3.38 (s, 3H), 3.27-3.19 (m, 1H), 2.49-2.42(m, 2H), 2.35-2.23 (m, 2H), 1.74-1.60 (m, 4H), 1.36-1.27 (m, 3H). LC-MS m / z:440.3 [M + 1] + HPLC purity (214 nm): 99.14%; t R = 8.257 minutes.

[0362] ( R)- N 4 -(3-(methylsulfonyl)pyridin-2-yl)- N 6 -(5-(1-(pyrrolidone-1-yl)ethyl)pyridin-2-yl)pyrimidine-4,6-diamine (15). 15.1 (55, 0.12 mmol) was purified by preparative SFC to give 15 (20 mg, 36% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.15 (br, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 8.0, 2.0Hz, 1H), 8.24 (s, 1H), 7.69 (s, 2H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 3.39 (s,3H), 3.28-3.12 (m, 1H), 2.49-2.41 (m, 2H), 2.40-2.18 (m, 2H), 1.77-1.58 (m,4H), 1.44-1.30 (m, 3H). LC-MS m / z: 440.0 [M + 1] + HPLC purity (214 nm): > 99.9%; t R = 7.575 minutes.

[0363] Example 1p: Preparation of compound 16.

[0364]

[0365] 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl ketone (16.5). Added to a solution of 5-bromo-2-chloropyridine (2 g, 10.39 mmol) in THF (20 mL) at -78 °C. n-BuLi (2.5 M in hexane, 5 mL, 12.47 mmol). The mixture was stirred at -78 °C for 1 hour, and then 2,2,2-trifluoro-1-morpholinoacetone (1.9 g, 10.39 mmol) was added. After the reaction was complete, the mixture was quenched with NH4Cl solution (40 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 16.5 g (700 mg, 32% yield) as a yellow solid. LC-MS m / z: 228.2 [M+H2O+H] + LCMS purity (214 nm): 82.79%, t R = 1.258 minutes.

[0366] 2,2,2-Trifluoro-1-(6-((6-(((3-(methanesulfonyl)pyridin-2-yl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)acetone (16.4). Brettphos-Pd-G3 (86 mg, 0.095 mmol), Xantphos (55 mg, 0.095 mmol), and K3PO4 (405 mg, 1.91 mmol) were added to a solution of 16.5 (200 mg, 0.95 mmol) and 1A (253 mg, 0.95 mmol) in dioxane (10 mL). The mixture was stirred at 105 °C for 5 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 16.4 (120 mg, 29% yield) as a yellow solid. LC-MS m / z: 456.9 [M+H2O+H] + LCMS purity (254 nm): 94.55%, t R = 1.376 minutes.

[0367] 2,2,2-Trifluoro-1-(6-((6-(((3-(methanesulfonyl)pyridin-2-yl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)ethanol (16.3). NaBH4 (15 mg, 0.41 mmol) was added to a solution of 16.4 (120 mg, 0.27 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 16.3 (100 mg, 83% yield) as a yellow solid. LC-MS m / z: 440.9 [M+ H] + LCMS purity (214 nm): > 99.9%, t R = 1.451 minutes.

[0368] N 4 -(5-(1-chloro-2,2,2-trifluoroethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (16.2). TEA (69 mg, 0.68 mmol) and MsCl (31 mg, 0.27 mmol) were added to a solution of 16.3 (100 mg, 0.23 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 16.2 (100 mg, 96% yield) as a white solid. LC-MS m / z: 458.8 [M+ H] + LCMS purity (254 nm): 54.57%, t R = 1.706 minutes.

[0369] ( R )- N 4 -(3-(methylsulfonyl)pyridin-2-yl)- N 6-(5-(2,2,2-trifluoro-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)pyridin-2-yl)pyrimidin-4,6-diamine (16). DIEA (84 mg, 0.65 mmol) was added to a solution of 16.2 (100 mg, 0.22 mmol) and 2-oxa-6-azaspiro[3.3]heptane (43 mg, 0.44 mmol) in MeCN (8 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was evaporated under vacuum to give crude product 16.1, which was further purified by reversed-phase preparative HPLC and preparative SFC to give 16 (21.06 mg, 37% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.48 (br, 1H), 8.78 (s,1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.44 (d, J = 1.2 Hz, 1H), 8.30-8.26 (m,2H), 7.80 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.8, 2.0 Hz, 1H), 7.29 (dd, J =8.0, 4.8 Hz, 1H), 4.61 (s, 4H), 4.18-4.15 (m, 1H), 3.42-3.34 (m, 7H). LC-MSm / z: 522.2 [M+ H] + HPLC purity (214 nm): > 99.9%, t R = 7.799 minutes.

[0370] Example 1q: Preparation of compound 18.

[0371]

[0372] N 4 -(6-Methylpyridin-2-yl)- N 6 -(3-(methylthio)pyridin-2-yl)pyrimidine-4,6-diamine (18.1). 2-Bromo-3-(methylthio)pyridine (1.2A) was prepared as described in Example 1a. 1.2A (290 mg, 1.42 mmol) was... N 4A mixture of (6-methylpyridin-2-yl)pyrimidine-4,6-diamine (285 mg, 1.42 mmol), Brettphos-Pd-G3 (127 mg, 0.14 mmol), Xphos (133 mg, 0.28 mmol), and Cs₂CO₃ (1.39 g, 4.26 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc:hexane = 7:3) to give 18.1 (380 mg, 82.5% yield) as a yellow liquid. LC-MS m / z: 325.3 [M+1] + Purity (214 nm) 93.6%, t R = 1.618 minutes.

[0373] N 4 -(6-Methylpyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (18). A mixture of 18.1 (330 mg, 1.02 mmol) and 30% H2O2 (3.5 mL) in AcOH (5 mL) and H2O (5 mL) was stirred at 60 °C for 2 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 18 (101 mg, 27.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.08 (s, 1H), 9.47 (s, 1H), 9.12 (s, 1H), 8.64 (dd, J = 4.8, 2.0 Hz, 1H),8.39 (s, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.34(d, J = 8.0 Hz, 1H), 7.28 (dd, J = 7.6, 4.8 Hz, 1H), 6.85 (d, J= 7.2 Hz,1H), 3.39 (s, 3H), 2.48 (s, 3H). LC-MS m / z: 357.1 [M+ H] + HPLC purity (214 nm): 99.3%; t R = 8.083 minutes.

[0374] Example 1r: Preparation of compound 19.

[0375]

[0376] N 4 -(3-(methylsulfonyl)pyridin-2-yl)- N 6 Synthesis of -(6-(trifluoromethyl)pyridin-2-yl)pyrimidine-4,6-diamine (19). Preparation as described in Example 1a. N 4 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1A). Brettphos-Pd-G3 (34 mg, 0.038 mmol), Xantphos (22 mg, 0.038 mmol), and Cs₂CO₃ (246 mg, 0.75 mmol) were added to a solution of 1A (100 mg, 0.38 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (68 mg, 0.38 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 8 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product, which was further purified by reversed-phase preparative HPLC to give 19 (9.94 mg, 6.4% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.59 (s, 1H), 9.56 (s,1H), 8.96 (s, 1H), 8.57 (dd, J = 4.8, 2.0 Hz, 1H), 8.47 (d, J = 1.2, 1H), 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.99 (dd, J = 8.0, 8.0 Hz, 1H), 7.86 (d, J =8.4, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.30 (dd, J= 8.0, 5.2 Hz, 1H), 3.40 (s, 3H). LC-MS m / z: 411.0 [M+ H] + HPLC purity (214 nm): 99.39%, t R = 8.964 minutes.

[0377] Example 1s: Preparation of compound 20.

[0378]

[0379] ( S )-1-(6-chloropyridin-3-yl)-2,4-dimethylpiperazine (20.1). To ( S A solution of 1,3-dimethylpiperazine (100 mg, 0.87 mmol) and 2-chloro-5-iodopyridine (209 mg, 0.87 mmol) in dioxane (5 mL) was supplemented with Pd2(dba)3 (80 mg, 0.087 mmol), Xantphos (50 mg, 0.087 mmol), and... t -BuONa (336 mg, 3.51 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product, which was purified by silica gel column chromatography (MeOH / CH2Cl2 = 1 / 20) to give 20.1 mg (97 mg, 49.2% yield) as a yellow oil. LC-MS m / z: 226.3 [M+ H] + LCMS purity (254 nm): 88.47%; t R = 1.383 minutes.

[0380] ( S )- N 4 -(5-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (20). Brettphos-Pd-G3 (40 mg, 0.043 mmol), Xantphos (25 mg, 0.043 mmol), and Cs2CO3 (281 mg, 0.86 mmol) were added to a solution of 20.1 (97 mg, 0.43 mmol) and 1A (114 mg, 0.43 mmol) in dioxane (3 mL). The mixture was stirred in a microwave at 110 °C for 1.5 h. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product, which was further purified by reversed-phase preparative HPLC to give the title product 20 (37.16 mg, 18.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.89 (s, 1H), 9.38 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J = 1.2,1H), 8.25 (dd, J = 8, 2 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 9.2Hz, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 7.25 (dd, J = 8.0, 5.2 Hz, 1H),3.83-3.81 (m, 1H), 3.38 (s, 3H), 3.19-3.16 (m, 1H), 3.00-2.95 (m, 1H), 2.71-2.66 (m, 1H), 2.37-2.32 (m, 1H), 2.20 (s, 3H), 2.18-2.15(m, 1H), 0.98 (d, J =6.4 Hz, 3H). LC-MS m / z: 455.2 [M+ H] + HPLC purity (214 nm): 97.04%, t R = 4.659 minutes.

[0381] Example 1t: Preparation of compound 21.

[0382]

[0383] 6-Chloro- N -(3-Methyloxetane-3-yl)pyridine-3-amine (21.1). Brettphos-Pd-G3 (156 mg, 0.17 mmol), Xantphos (100 mg, 0.17 mmol), and Cs₂CO₃ (1.12 g, 3.44 mmol) were added to a solution of 21.2 (150 mg, 1.72 mmol) and 5-bromo-2-chloropyridine (331 mg, 1.72 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 8 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product, which was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 20 / 1) to give 21.1 (300 mg, 87.7% yield) as a brown oil. LC-MS m / z: 199.3 [M+ H] + LCMS purity (214 nm): 96.19%; t R = 1.263 minutes.

[0384] N 4 -(5-((3-methyloxetane-3-yl)amino)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (21). Brettphos-Pd-G3 (46 mg, 0.050 mmol), Xantphos (29 mg, 0.050 mmol), and Cs2CO3 (328 mg, 1.01 mmol) were added to a solution of 21.1 (100 mg, 0.50 mmol) and 1A (134 mg, 0.50 mmol) in dioxane (4 mL). The mixture was stirred in a microwave at 110 °C for 4 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give a crude product; further purification was performed by reversed-phase preparative HPLC to give 21 (14.00 mg, 6.5% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.72(s, 1H), 9.35 (s, 1H), 8.59 (dd, J =4.8, 1.6 Hz, 1H), 8.42 (br, 1H), 8.30 (d, J = 1.2 Hz, 1H), 8.25 (dd, J= 8.0, 2.0 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 6.85 (dd, J = 8.8, 2.8 Hz, 1H), 6.02 (s, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 3.37 (s, 3H), 1.56 (s, 3H). LC-MS m / z: 428.2 [M+ H] + HPLC purity (214 nm): 95.62%, t R = 5.705 minutes.

[0385] Example 1u: Preparation of compound 22.

[0386]

[0387] 2-Chloro-5-(1-(3-fluorozacricyclobutan-1-yl)ethyl)pyridine (22.1). A mixture of 5-(1-bromoethyl)-2-chloropyridine (3.30 g, 14.97 mmol), 3-fluorozacricyclobutane hydrochloride (2.08 g, 18.0 mmol), and DIEA (10.0 mL) in CH3CN (50 mL) was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc:hexane = 1:3) to give 22.1 (1.76 g, 54.8% yield) as a colorless oil. LC-MS m / z: 215.4 [M+1] + LCMS purity (214 nm): 91.48%; t R = 1.674 minutes.

[0388] N 4 -(5-(1-(3-fluorozacricyclobutan-1-yl)ethyl)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (22). A mixture of 1A (150 mg, 0.57 mmol), 22,1 (120 mg, 0.57 mmol), Pd2(dba)3 (52 mg, 0.057 mmol), Xantphos (65 mg, 0.113 mmol), and Cs2CO3 (553 mg, 1.70 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 10:1) and then by reversed-phase preparative HPLC to give 22 (68 mg, 26.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 9.43 (s, 1H), 8.78 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.23 ​​(d, J = 1.6 Hz, 1H), 7.70-7.64 (m, 2H), 7.27(dd, J =8.0, 4.8 Hz, 1H), 5.23-5.03 (m, 1H), 3.64-3.57 (m, 1H), 3.39-3.28(m, 5H), 3.12-2.98 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H). LC-MS m / z: 444.2 [M+1] + HPLC purity (214 nm): > 99.9%; t R = 7.834 minutes.

[0389] Example 1v: Preparation of compound 23.

[0390]

[0391] 6-Chloro-4-methyl- N-(3-methyloxetane-3-yl)pyridine-3-amine (23.1). A mixture of 23.2 (500 mg, 2.42 mmol), 3-methyloxetane-3-amine (253 mg, 2.91 mmol), Pd2(dba)3 (222 mg, 0.24 mmol), Xantphos (280 mg, 0.48 mmol), and Cs2CO3 (1.6 g, 4.84 mmol) in 1,4-dioxane (10 mL) was stirred at 110 °C for 16 h under an argon atmosphere. After the reaction was complete, the mixture was quenched with water (50 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (hexane: EtOAc = 4:1) to give 23.1 (300 mg, 58% yield) as a yellow solid. LC-MS m / z: 213.1 [M+1] + LCMS purity (214 nm): 78.10%; t R = 1.476 minutes.

[0392] N 4 -(4-Methyl-5-((3-methyloxetane-3-yl)amino)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (23). 23.1 (270 mg, 1.27 mmol), 1A (337 mg, 1.27 mmol), Pd2(dba)3 (116 mg, 0.13 mmol), Xantphos (147 mg, 0.25 mmol) and t A mixture of BuONa (244 mg, 2.54 mmol) and 1,4-dioxane (5 mL) was stirred at 110 °C for 16 h under an argon atmosphere. After the reaction was complete, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 23 (30.04 mg, 5.4% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.65 (br, 1H), 9.34 (br, 1H), 8.59 (dd, J =4.8, 1.6 Hz, 1H), 8.47 (s, 1H), 8.31 (d,J = 0.8 Hz, 1H), 8.24 (dd, J = 8.0,1.6 Hz, 1H), 7.42 (s, 1H), 7.25 (dd, J = 7.6, 4.8 Hz, 1H), 7.06 (s, 1H), 5.26(s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.37 (s, 3H), 2.14 (s, 3H), 1.61 (s, 3H). LC-MS m / z: 442.2 [M+ 1] + HPLC purity (254 nm): > 99.9%; t R = 7.205 minutes.

[0393] Example 1w: Preparation of compound 24.

[0394]

[0395] 3-(Methylsulfonyl)pyridine-4-amine (24.1). A mixture of 5-bromo-2-chloropyridine (558 mg, 2.90 mmol), 1-oxa-7-azaspiro[3.5]nonane hemioxarate (250 mg, 1.45 mmol), Pd2(dba)3 (266 mg, 0.29 mmol), Xantphos (335 mg, 0.58 mmol), and Cs2CO3 (2.83 g, 8.7 mmol) in 1,4-dioxane (50 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 1:1) to give 24.1 mg (250 mg, 72.3% yield) as a red solid. LC-MS: m / z = 239.2 [M+1] + LCMS purity: 99.34% (254 nm), t R = 1.398 minutes.

[0396] N 4 -(5-(1-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (24). A mixture of 24.1 (230 mg, 0.96 mmol), 1A (257 mg, 0.96 mmol), Brettphos Pd G3 (136 mg, 0.15 mmol), X-phos (143 mg, 0.30 mmol) and Cs2CO3 (975 mg, 3.0 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 1:1) and then by reverse-phase preparative HPLC to give 24 (94.2 mg, 20.9% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.88 (s, 1H), 9.38 (s, 1H), 8.66 (dd, J = 4.8, 2.0 Hz, 1H), 8.61(s, 1H), 8.34 (d, J = 0.8 Hz 1H), 8.25 (dd , J = 8.0, 2.0 Hz, 1H), 8.02 (d , J= 3.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 9.2, 3.2 Hz, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 4.42 (t, J = 8.0 Hz, 2H), 3.38 (s, 3H), 3.25-3.19(m, 2H), 3.06-3.00 (m, 2H), 2.39 (t, J = 8.0 Hz, 2H), 1.95-1.84 (m, 4H). LC-MSm / z=468.3 [M+1] + HPLC purity: > 99.9% (214 nm), t R =7.512 minutes.

[0397] Example 1x: Preparation of compound 25.

[0398]

[0399] (3a R ,6a S )-5-(1-(4-chlorophenyl)ethyl)hexahydro-1 H -furano[3,4-c]pyrrole (25.1). Add (3a) to a solution of 5-(1-bromoethyl)-2-chloropyridine (200 mg, 0.91 mmol) in MeCN (20 mL). R ,6a S Hexahydro-1H-furano[3,4-c]pyrrole (123 mg, 1.09 mmol) and DIEA (235 mg, 1.82 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. Further purification by silica gel column chromatography (CH2Cl2: MeOH = 20:1) gave the title product 25.1 (170 mg, 74.2% yield) as a yellow oil. LC-MS m / z: 253.4 [M+1] + LCMS purity (254 nm): 79.05%; t R = 0.354 minutes.

[0400] N 4 -(3-(methylsulfonyl)pyridin-2-yl)- N 6 -(5-(1-((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)ethyl)pyridin-2-yl)pyrimidine-4,6-diamine (25). Add 1A (180 mg, 0.68 mmol) to a solution of 25.1 (170 mg, 0.68 mmol) in dioxane (25 mL). t BuONa (131 mg, 1.36 mmol), Pd2(dba)3 (62 mg, 0.068 mmol), and Xantphos (39 mg, 0.068 mmol) were added. The reaction mixture was heated to 110 °C and stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was evaporated under vacuum to give the crude product. The crude product was further purified by silica gel column chromatography (CH2Cl2: MeOH = 10:1) to give the crude product. The crude product was purified by reversed-phase preparative HPLC and preparative SFC to give 25 (19.01 mg, 27.2% yield) as a white solid. 11H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.43 (s, 1H), 8.77 (s,1H), 8.66 (dd, J J = 4.8, 0.8 Hz, 1H), 8.40 (d, J J = 0.8, 1H), 8.27 (dd, J J=8.0, 2.0 Hz, 1H), 8.22 (s, 1H), 7.70-7.65 (m, 2H), 7.27 (dd, J J = 8.0, 4.8 Hz,1H), 3.73-3.66 (m, 2H), 3.42-3.35 (m, 5H), 3.25-3.21 (m, 1H), 2.68-2.65 (m,2H), 2.60-2.57 (m, 1H), 2.46-2.42 (m, 1H), 2.37-2.33(m, 1H), 2.12-2.09 (m,1H), 1.31 (d, J J = 6.4 Hz, 3H). LC-MS m / z: 482.0 [M+ H] + . HPLC purity (214 nm): 95.00%, t R R = 7.655 minutes.

[0401] Example 1y: Preparation of compound 26.

[0402]

[0403] 1-(6-((6-((2-(methanesulfonyl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)acetone (26.2). 6-Chloro-N-(2-(methanesulfonyl)phenyl)pyrimidin-4-amine (1C) was prepared as described in Example 1aa. 1-(6-aminopyridin-3-yl)acetone (191 mg, 1.41 mmol), Cs₂CO₃ (919 mg, 2.82 mmol), X-phos (67 mg, 0.14 mmol), and Brettphos Pd G₃ (127 mg, 0.14 mmol) were added to a stirred solution of 1C (400 mg, 1.41 mmol) in dioxane (10 mL). The mixture was stirred at 100 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 9 / 1) to give 26.2 mg (350 mg, 65% yield) as a gray solid. LC-MS m / z: 384.1 [M+1] + LCMS purity (254 nm): 85.90%; t R = 1.604 minutes.

[0404] N 4 -(2-(methylsulfonyl)phenyl)- N 6 -(5-(1-(tetrahydrofuran-3-ylimino)ethyl)pyridin-2-yl)pyrimidin-4,6-diamine (26.1). Tetrahydrofuran-3-amine hydrochloride (193 mg, 1.56 mmol) and Ti(Oi-Pr)4 (667 mg, 2.35 mmol) were added to a solution of 26.2 (300 mg, 0.78 mmol) in THF (10 mL). The mixture was stirred overnight at 80 °C under nitrogen. After the starting material was consumed (monitored by LC-MS), the mixture was used directly for the next step. LC-MS m / z: 453.3 [M + H] + LCMS purity (254 nm): 72.01%; t R = 1.720 minutes and 1.753 minutes.

[0405] N 4 -(2-(methylsulfonyl)phenyl)- N 6-(5-(1-(tetrahydrofuran-3-ylamino)ethyl)pyridin-2-yl)pyrimidin-4,6-diamine (26). NaBH4 (52 mg, 1.32 mmol) was added to a solution of 26.1 (353 mg, 0.78 mmol) in THF (10 mL). The reaction mixture was then stirred overnight at room temperature. After the starting material was consumed (monitored by LCMS), the mixture was diluted with water (10 mL) and filtered. The filtrate was extracted with CH2Cl2 / MeOH = 10 / 1 (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 8 / 1) and reversed-phase preparative HPLC to give 26 (73.52 mg, 21% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.92 (s, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.2, 1.4 Hz, 1H), 7.78-7.63 (m, 2H), 7.52-7.42 (m, 2H), 7.40-7.32 (m, 1H), 3.78-3.65 (m, 2H), 3.65-3.50 (m, 2H), 3.47-3.41 (m, 0.5H), 3.22 (s, 3H), 3.21-3.18 (m, 0.5H), 3.08-2.97 (m, 1H), 2.35-2.20 (m, 1H), 1.94-1.75 (m, 1H), 1.73-1.64 (m, 0.5H), 1.55-1.44 (m, 0.5H), 1.30-1.20 (m, 3H). LC-MS m / z: 455.2[M + H] + HPLC purity (214 nm): > 99.9%; t R = 6.936 minutes.

[0406] Example 1z: Preparation of compound 27.

[0407]

[0408] 2-Chloro-5,6,7,8-Tetrahydroquinoline-5-ol (27.5). Under ice bath conditions, to 2-chloro-7,8-dihydroquinoline-5 (6... H )-ketone (500 mg, 2.76 mmol) was added to a solution of EtOH (30 mL) with NaBH4 (157 mg, 4.14 mmol). The reaction mixture was warmed to room temperature and stirred overnight. After the starting material was consumed, the reaction mixture was concentrated, the solvent was removed, and the solution was dissolved in EtOAc (100 mL), washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated to give a crude product of 27.5 (480 mg, 95% yield) as a yellow solid. LC-MS m / z: 184.3 [M+1] + LCMS purity (214 nm): >99.9%; t R = 1.349 minutes.

[0409] 2,5-Dichloro-5,6,7,8-Tetrahydroquinoline (27.4). Et3N (167 mg, 1.65 mmol) and MsCl (94 mg, 0.88 mmol) were added to a solution of 27.5 (100 mg, 0.54 mmol) in CH2Cl2 (20 mL), and the reaction mixture was stirred overnight at room temperature. After the starting material was consumed, the reaction mixture was concentrated, dissolved in EtOAc (50 mL), washed with brine (50 mL × 3), dried over Na2SO4, and concentrated to give crude product 27.4 (110 mg) as a white solid, which was used in the next step without purification. LC-MS m / z: 202.4 [M+1] + LCMS purity (254 nm): 76.05%; t R = 2.044 minutes.

[0410] 2-(2-Chloro-5,6,7,8-Tetrahydroquinolin-5-yl)-7-oxa-2-azaspiro[3.5]nonane (27.3). 7-oxa-2-azaspiro[3.5]nonane hydrochloride (820 mg, 5.0 mmol) and DIEA (5 mL) were added to a solution of 27.4 (1.0 g, 5.0 mmol) in CH3CN (50 mL), and the mixture was stirred at 80 °C for 2 days. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (eluting with 0.5% Et3N / EtOAc) to give 27.3 (1.33 g, 91% yield) as a yellow gel. LC-MS m / z: 293.2 [M+H] + LCMS purity (214 nm): 98.09%; t R= 0.705 minutes.

[0411] N 4 -(2-(methylthio)phenyl)pyrimidine-4,6-diamine (27.2). A mixture of (2-bromophenyl)(methyl)thione (4.06 g, 20.0 mmol), pyrimidine-4,6-diamine (2.20 g, 20.0 mmol), Pd2(dba)3 (916 mg, 1.0 mmol), Xantphos (1.16 mg, 2.0 mmol), and Cs2CO3 (14.95 g, 46 mmol) in 1,4-dioxane (150 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the reaction mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc) to give 27.2 (1.74 g, 37.5% yield) as a yellow solid. LC-MS m / z: 233.3 [M+H] + LCMS purity (214 nm): 98.14%, t R = 1.489 minutes.

[0412] N 4 -(2-(methylsulfonyl)phenyl)pyrimidine-4,6-diamine (27.1). 27.2 (1.60 mg, 6.90 mmol) and m A mixture of CPBA (1.79 g, 10.35 mmol) and CH2Cl2 (100 mL) was stirred overnight at room temperature. Another portion was added to the mixture under water bath conditions. m -CPBA (1.79 g, 10.35 mmol), the mixture was stirred for 4 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), alkalized with aqueous K₂CO₃ solution, and extracted with CH₂Cl₂ (50 mL × 2). The organic extract was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product 27.1 g (850 mg, 46.7% yield) as a brown solid. LC-MS m / z: 265.4 [M + H] + LCMS purity (214 nm): 45.23%, t R = 1.294 minutes.

[0413] N 4 -(5-(7-oxa-2-azaspiro[3.5]non-2-yl)-5,6,7,8-tetrahydroquinoline-2-yl) -N 6-(2-(methylsulfonyl)phenyl)pyrimidine-4,6-diamine (27). A mixture of 27.1 (132 mg, 0.50 mmol), 27.3 (146 mg, 0.50 mmol), Brettphos-Pd-G3 (68 mg, 0.075 mmol), Xphos (72 mg, 0.15 mmol), and Cs2CO3 (490 mg, 1.50 mmol) in 1,4-dioxane (25 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 27 (15 mg, 5.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.90 (s, 1H), 8.74 (s, 1H), 8.31 (s,1H), 7.97-7.91 (m, 2H), 7.77-7.73 (m, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.47 (t, J = 4.8 Hz, 4H), 3.25 (t, J = 3.2 Hz, 1H), 3.22 (s, 3H), 3.06 (d, J = 6.4 Hz, 2H), 2.81(d, J = 6.4 Hz, 2H), 2.74-2.63 (m, 2H), 2.08-2.04 (m, 1H), 1.82-1.79 (m, 1H), 1.62-1.52 (m, 6H). LC-MS m / z: 521.3 [M+ H] + HPLC purity (214 nm): > 99.9%; t R =8.481 minutes.

[0414] Example 1aa: Preparation of compound 28.

[0415]

[0416] 6-Chloro- N-(2-(methylthio)phenyl)pyrimidin-4-amine (28.3). To 2-(methylthio)aniline (1.00 g, 7.18 mmol) at... i 4,6-Dichloropyrimidine (1.61 g, 10.77 mmol) and TsOH (247 mg, 1.44 mmol) were added to a stirred solution of PrOH (30 mL). The mixture was stirred overnight at 80 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was poured into a saturated aqueous solution of NaHCO3 (60 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give 28.3 g (1.45 g, 80% yield) as a yellow solid. LC-MS m / z: 252.2 [M + 1] + LCMS purity (254 nm): 97.30%; t R = 1.907 minutes.

[0417] 6-Chloro- N -(2-(methylsulfonyl)phenyl)pyrimidine-4-amine (1C). Add to a stirred solution of 28.3 g (1.45 g, 5.76 mmol) in CH2Cl2 (20 mL) m -CPBA (2.98 g, 17.28 mmol). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was poured into water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give 1C as a yellow solid (800 mg, 49% yield). LC-MS m / z: 284.1 [M + 1] + LCMS purity (254 nm): 83.78%; t R = 1.561 minutes.

[0418] 6-((6-((2-(methanesulfonyl)phenyl)amino)pyrimidin-4-yl)amino)nicotinaldehyde (28.2). 6-aminonicotinaldehyde (129 mg, 1.06 mmol), Cs₂CO₃ (689 mg, 2.11 mmol), X-phos (52 mg, 0.11 mmol), and Brettphos Pd G₃ (100 mg, 0.11 mmol) were added to a stirred solution of 1C (300 mg, 1.06 mmol) in dioxane (10 mL). The mixture was stirred at 100 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 9 / 1) to give 28.2 (350 mg, 90% yield) as a pale green solid. LC-MS m / z: 370.3 [M + 1] + LCMS purity (254 nm): 85.99%; t R = 1.581 minutes.

[0419] N 4 -(2-(methylsulfonyl)phenyl)- N 6 -(5-((tetrahydrofuran-3-ylimino)methyl)pyridin-2-yl)pyrimidin-4,6-diamine (28.1). Tetrahydrofuran-3-amine hydrochloride (201 mg, 1.6 mmol) and Ti(Oi-Pr)4 (692 mg, 2.44 mmol) were added to a solution of 28.2 (300 mg, 0.81 mmol) in THF (8 mL). The mixture was stirred overnight at 80 °C under nitrogen. After the starting material was consumed (monitored by LC-MS), the mixture was used directly for the next step. LC-MS m / z: 439.3 [M + H] + LCMS purity (254 nm): 76.91%; t R = 1.577 minutes.

[0420] N 4 -(2-(methylsulfonyl)phenyl)- N 6-(5-((tetrahydrofuran-3-ylamino)methyl)pyridin-2-yl)pyrimidin-4,6-diamine (28). NaBH4 (52 mg, 1.37 mmol) was added to a solution of 28.1 (355 mg, 0.81 mmol) in THF (8 mL). The reaction mixture was then stirred overnight at room temperature. After the starting material was consumed (monitored by LCMS), the mixture was diluted with water (20 mL) and filtered. The filtrate was extracted with CH2Cl2 / MeOH = 10 / 1 (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 9 / 1) and reversed-phase preparative HPLC to give 28 (44.48 mg, 13% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.92 (s, 1H), 8.78 (br, 1H), 8.31 (d, J = 0.8 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.91(dd, J = 7.8, 1.4 Hz, 1H), 7.77-7.69 (m, 1H), 7.67 (dd, J = 8.6, 2.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.39-7.33 (m, 1H), 3.79-3.56 (m, 5H), 3.44-3.39 (m, 1H), 3.28-3.24 (m, 1H), 3.22 (s, 3H), 2.37-2.18 (m, 1H), 1.99-1.86 (m, 1H), 1.73-1.61 (m, 1H). LC-MS m / z: 441.1 [M+ H] + HPLC purity (214 nm): 95.00%; t R = 6.592 minutes.

[0421] Example 1ab: Preparation of compound 29.

[0422]

[0423] 1-(1-(6-chloropyridin-3-yl)ethyl)-8-oxa-1-azaspiro[4.5]decane (29.2). DIEA (264 mg, 2.04 mmol) and 6-oxa-2-azaspiro[3.5]nonane (115 mg, 0.82 mmol) were added to a solution of 5-(1-bromoethyl)-2-chloropyridine (150 mg, 0.68 mmol) in MeCN (8 mL). The mixture was stirred at 80 °C for 8 hours. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) to give 29.2 (100 mg, 52% yield) as a white solid. LC-MS m / z: 281.2 [M+ H] + LCMS purity (214 nm): 92.51%, t R = 1.738 minutes.

[0424] ( S )- N 4 -(5-(1-(8-oxa-1-azaspiro[4.5]dec-1-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (29). Brettphos-Pd-G3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (139 mg, 0.43 mmol) were added to a solution of 29.2 (60 mg, 0.21 mmol) and 1A (57 mg, 0.21 mmol) in dioxane (4 mL). The mixture was stirred in a microwave at 115 °C for 5 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was evaporated under vacuum to give crude product 29.1, which was further purified by reversed-phase preparative HPLC and preparative SFC to give 29 (8.68 mg, 16% yield) as a white solid. 1 H NMR (400MHz, DMSO- d 6) δ 10.08 (s, 1H), 9.43 (s, 1H), 8.72 (s, 1H), 8.65 (dd, J = 4.4, 1.6 Hz, 1H), 8.39 (d, J = 0.8 Hz, 1H), 8.27-8.25 (m, 2H), 7.72-7.64 (m, 2H),7.27 (dd, J= 8.0, 4.8 Hz, 1H), 4.18-4.13 (m, 1H), 3.88-3.83 (m, 1H), 3.80-3.76 (m, 1H ), 3.39 (s, 3H), 3.37-3.36 (m, 1H), 3.31-3.30 (m, 1H), 2.88-2.82(m, 1H), 2.71-2.66 (m, 1H), 1.82-1.64 (m, 6H), 1.38-1.35 (m, 4H), 1.10-1.06(m, 1H). LC-MS m / z: 510.0 [M+ H] + HPLC purity (254 nm): 97.18%, t R = 9.605 minutes.

[0425] Example 1ac: Preparation of compound 30.

[0426]

[0427] 2-(1-(6-chloropyridin-3-yl)ethyl)-8-oxa-2-azaspiro[4.5]decane (30.1). 8-oxa-2-azaspiro[4.5]decane (189 mg, 1.34 mmol) and DIEA (292 mg, 2.26 mmol) were added to a solution of 5-(1-bromoethyl)-2-chloropyridine (250 mg, 1.13 mmol) in MeCN (20 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was evaporated under vacuum to give the crude product. Further purification by silica gel column chromatography (CH2Cl2: MeOH = 20:1) gave the title product 30.1 (260 mg, 81.9% yield) as a yellow oil. LC-MS m / z: 281.4 [M+1] + LCMS purity (254 nm): 84%; t R = 0.370 minutes.

[0428] ( R )- N 4 -(5-(1-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (30). Add 30.1 (260 mg, 0.93 mmol) to a solution of dioxane (25 mL). N 4-(3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (247 mg, 0.71 mmol), Cs₂CO₃ (606 mg, 1.86 mmol), and Brettphos-Pd-G₃ (83 mg, 0.093 mmol) and Xantphos (48 mg, 0.083 mmol). The reaction mixture was heated to 120 °C and stirred overnight at 120 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was evaporated under vacuum to give the crude product. The crude product was further purified by silica gel column chromatography (CH₂Cl₂:MeOH = 10:1) to give the crude product. The crude product was purified by reversed-phase preparative HPLC and preparative SFC to give 30 (19.75 mg, 38.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s,1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s,1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.22 (s, 1H), 7.70-7.65 (m, 2H), 7.27(dd, J = 8.0, 4.8 Hz, 1H), 3.53-3.47 (m, 4H), 3.39 (s, 3H), 3.24-3.22 (m,1H), 2.67-2.62 (m, 1H), 2.37-2.25 (m, 3H), 1.62-1.58 (m, 2H), 1.50-1.39 (m,4H), 1.28 (d, J = 11.6 Hz, 3H). LC-MS m / z: 510.0 [M+ H] + HPLC purity (214 nm): >99.9%, t R = 8.629 minutes.

[0429] Example 1ad: Preparation of compound 31.

[0430]

[0431] 2-(1-(6-chloropyridin-3-yl)ethyl)-7-oxa-2-azaspiro[3.5]nonane (31.2). DIEA (469 mg, 3.63 mmol) and 7-oxa-2-azaspiro[3.5]nonane (115 mg, 0.91 mmol) were added to a stirred solution of 5-(1-bromoethyl)-2-chloropyridine (200 mg, 0.91 mmol) in MeCN (10 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was poured into ice water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 3) to give 31.2 (200 mg, 82.6% yield) as a pale yellow oil. LC-MS m / z: 267.4 [M + 1] + LCMS purity (254 nm): 76.92%; t R = 1.629 minutes.

[0432] N 4 -(5-(1-(7-oxa-2-azaspiro[3.5]non-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (31.1). 1A (169 mg, 0.64 mmol), Cs₂CO₃ (415 mg, 1.27 mmol), Xantphos (37 mg, 0.064 mmol), and Brettphos Pd G₃ (58 mg, 0.064 mmol) were added to a stirred solution of 31.2 (170 mg, 0.64 mmol) in dioxane (10 mL). The mixture was stirred at 120 °C for 2 days under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20 / 1) and reversed-phase preparative HPLC to give 31.1 (37 mg, 11.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 10.11 (s, 1H), 9.44 (br, 1H), 8.76 (s, 1H), 8.66 (dd, J = 4.8, 2.0 Hz, 1H), 8.40 (d, J = 1.2Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.24-8.20 (m, 1H), 7.71-7.61 (m,2H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 3.46 (t, J = 5.2 Hz, 4H), 3.39 (s, 3H), 3.32-3.26 (m, 1H), 2.93 (d, J = 6.4 Hz, 2H), 2.83 (d, J = 6.4 Hz, 2H), 1.63(t, J = 5.6 Hz, 4H), 1.18-1.09 (m, 3H). LC-MS m / z: 496.2 [M + 1] + HPLC purity (214nm): > 99.9%; t R = 7.486 minutes.

[0433] ( R )- N 4 -(5-(1-(7-oxa-2-azaspiro[3.5]non-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (31). 31.1 (25, 0.05 mmol) was purified by preparative SFC to give 31 (8 mg, 32% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.43 (s, 1H), 8.76 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.27 (dd, J= 8.0, 2.0 Hz, 1H), 8.23-8.19 (m, 1H), 7.72-7.60 (m, 2H),7.27 (dd, J = 8.0, 4.8 Hz, 1H), 3.46 (t, J = 5.2 Hz, 4H), 3.39 (s, 3H), 3.32-3.28 (m, 1H), 2.93 (d, J = 6.4 Hz, 2H), 2.83 (d, J = 6.8 Hz, 2H), 1.63 (t, J = 5.2 Hz, 4H), 1.19-1.07 (m, 3H). LC-MS m / z: 496.3 [M + 1] + HPLC purity (214 nm): 97.09%; t R = 7.597 minutes.

[0434] Example 1ae: Preparation of compound 32 and compound 32a.

[0435]

[0436] 2-(1-(6-chloropyridin-3-yl)ethyl)-6-oxa-2-azaspiro[3.4]octane (32.1). A mixture of 5-(1-bromoethyl)-2-chloropyridine (400 mg, 1.81 mmol), 6-oxo-2-azaspiro[3.4]octane oxalate (2:1) (286 mg, 0.90 mmol), and DIEA (467 mg, 3.62 mmol) in CH3CN (215 mL) was stirred overnight at 60 °C under an argon atmosphere. After the starting material was consumed, the reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (0.5% Et3N / EtOAc) to give 32.1 (150 mg, 32.8% yield) as a pale yellow oil. LC-MS m / z: 253.0 [M+1] + LCMS purity (214 nm): 80.63%; t R = 1.315 minutes.

[0437] ( S )- N 4 -(5-(1-(6-oxa-2-azaspiro[3.4]oct-2-yl)ethyl)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (32) and ( R )- N 4 -(5-(1-(6-oxa-2-azaspiro[3.4]oct-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (32a). A mixture of 32.1 (150 mg, 0.59 mmol), 1A (157 mg, 0.59 mmol), Brettphos-Pd-G3 (54 mg, 0.060 mmol), X-phos (28 mg, 0.059 mmol), and Cs2CO3 (385 mg, 1.18 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 120 °C under an argon atmosphere. After the starting material was consumed, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 32.1 (28.89 mg, 10.1% yield) as a white solid. It was further purified by SFC to give 32 (5.49 mg, 1.9% yield) and 32a (5.34 mg, 1.9% yield) as white solids.

[0438] Compound 32: 1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J = 8.0, 2.0Hz, 1H), 8.22 (s, 1H), 7.67-7.66 (m, 2H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H),3.68 (s, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.39 (s, 3H), 3.29-3.26 (m, 1H), 3.11(t, J = 7.2 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.98 (t,J = 7.2 Hz, 2H), 1.13(d, J = 6.4 Hz, 3H). LC-MS m / z: 482.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R =7.156 minutes. Compound 32a: 1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.27 (dd, J =8.0, 1.6 Hz, 1H), 8.22 (s, 1H), 7.70-7.64 (m, 2H), 7.27 (dd, J = 8.0, 4.8 Hz,1H), 3.68 (s, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.39 (s, 3H), 3.30-3.26 (m, 1H), 3.13-3.09 (m, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.98 (t, J = 7.2 Hz, 2H), 1.13(d, J = 6.4 Hz, 3H). LC-MS m / z: 482.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R =7.159 minutes.

[0439] Example 1af: Preparation of compound 33.

[0440]

[0441] Methyl 2-(6-chloropyridin-3-yl)-2-methylpropionate (33.9). Methyl 2-(6-chloropyridin-3-yl)acetate (7.68 g, 41.40 mmol) was slowly added to a solution of 60% NaH (4.14 g, 103.50 mmol) in dry DMF (150 mL) at 0 °C, and the mixture was slowly warmed to room temperature and stirred overnight at room temperature under argon. After the reaction was complete, the mixture was slowly quenched with water (100 mL) at 0 °C, and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (200 mL × 4), dried over anhydrous Na2SO4, and concentrated to give crude product 33.9 (8.0 g, 90.5% yield) as a brown oil. LC-MS m / z: 214.2 [M+ H] + LCMS purity (254nm): 84.16%; t R = 0.813 minutes.

[0442] 2-(6-chloropyridin-3-yl)-2-methylpropionic acid (33.8). A mixture of 33.9 (8.0 g, 37.40 mmol) and NaOH (7.48 g, 187.0 mmol) in H₂O (100 mL) was stirred overnight at room temperature. After the reaction was complete, the mixture was washed with EtOAc (100 mL). The aqueous layer was acidified with 2 N HCl to adjust the pH to 2–3 and extracted with EtOAc (100 mL × x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄ and concentrated to give crude product 33.8 (7.40 g, 99% yield) as a yellow oil. LC-MS m / z: 200.2 [M + H] + LCMS purity (254nm): 98.67%; t R = 0.383 minutes.

[0443] (2-(6-chloropyridin-3-yl)propyl-2-yl)tert-butyl carbamate (33.7). 33.8 (8.32 g, 41.68 mmol) and Et3N (17.4 mL, 125.10 mmol) were... tDPPA (13.5 mL, 62.60 mmol) was added to a solution of BuOH (100 mL), and the resulting mixture was stirred overnight at 80 °C under argon atmosphere. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluting with 10% EtOAc / hexane) to give 33.7 g (6.18 g, 54.8% yield) as a white solid. LC-MS m / z: 271.3 [M+ H] + LCMS purity (254 nm): 93.53%; t R = 0.866 minutes.

[0444] 2-(6-chloropyridin-3-yl)propyl-2-amine (33.6). A mixture of 33.7 (6.18 g, 22.8 mmol) in a solution of 4 M HCl (g) in 1,4-dioxane (50 mL) was stirred overnight at room temperature. After the reaction was complete, water (50 mL) and an aqueous K₂CO₃ solution were added to adjust the pH to 9–10, and the mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated to give crude product 33.6 (3.83 g, 98.3% yield) as a yellow oil. LC-MS m / z: 171.3 [M + H] + LCMS purity (254 nm): 97.27%; t R = 1.300 minutes.

[0445] (tetrahydro-2) H 33.4. LiAlH4 (4.69 g, 123.64 mmol) was added to a solution of 33.5 (5 g, 24.73 mmol) in THF (50 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then quenched with water (5 mL) and 15% NaOH (5 mL), Mg2SO4 was added, and the mixture was filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 33.4 (3.30 g, 91.3% yield) as a colorless oil. LC-MS m / z: 147.2 [M + 1] + LCMS purity (214 nm): No UV absorption.

[0446] (4-(hydroxymethyl)tetrahydro-2 H33.3 (pyran-4-yl)methyl4-methylbenzenesulfonate. Pyridine (1.08 g, 13.68 mmol) and TsCl (1.56 g, 8.21 mmol) were added to a solution of 33.4 (1 g, 6.84 mmol) in DCM (30 mL), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 2) to give 33.3 as a yellow solid (600 mg, 29.2% yield). LC-MS m / z: 301.1 [M + H] + LCMS purity (254 nm): 95.71%; t R = 1.546 minutes.

[0447] (4-Formyltetrahydro-2) H 33.2 (33.3) was prepared by stirring a mixture of 33.3 (600 mg, 2.00 mmol), Dess-Martin periodinane (1.69 g, 4.00 mmol), and DCM (10 mL) for 2 hours at room temperature. The mixture was then poured into water (10 mL) and extracted with DCM (10 mL × 3), washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 5) to give 33.2 as a yellow solid (300 mg, 50.3% yield). LC-MS m / z: 299.1 [M + 1] + LCMS purity (214 nm): 90.01%; t R = 1.691 minutes.

[0448] 2-(2-(6-chloropyridin-3-yl)propyl-2-yl)-7-oxa-2-azaspiro[3.5]nonane (33.1). One drop of AcOH was added to a mixture of 33.2 (260 mg, 0.87 mmol) and 33.6 (149 mg, 0.87 mmol) in MeOH (5 mL). The resulting mixture was stirred at 60 °C for 4 hours. Then, Pic-BH3 (186 mg, 1.74 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (20 mL) and neutralized to pH 7–8 with 2 N NaOH, extracted with EtOAc (20 mL × 3), washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 33.1 mg (110 mg, 45.1% yield) as a yellow solid. LC-MS m / z: 281.2 [M + 1] + LCMS purity (214 nm): 97.18%; t R = 1.167 minutes.

[0449] N 4 -(5-(2-(7-oxa-2-azaspiro[3.5]non-2-yl)prop-2-yl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (33). A mixture of 33.1 (90 mg, 0.32 mmol), 1A (85 mg, 0.32 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), XantPhos (35 mg, 0.06 mmol), Cs2CO3 (209 mg, 0.64 mmol), and dioxane (3 mL) was stirred overnight at 110 °C under nitrogen. The mixture was then poured into water (10 mL) and extracted with EtOAc (10 mL × 3), washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) and reversed-phase preparative HPLC to give 33 as a white solid (25.43 mg, 15.6% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 9.40 (s,1H), 8.69 (s, 1H), 8.63 (dd, J= 4.4, 1.6 Hz, 1H), 8.37 (d, J = 0.8 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 7.6, 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 7.6, 4.8 Hz, 1H), 3.44(t, J = 4.8 Hz, 4H), 3.36 (s, 3H), 2.87 (s, 4H), 1.57 (t, J = 5.2 Hz, 4H), 1.25 (s, 6H). LC-MS m / z: 510.0 [M + H] + HPLC purity (214 nm): > 99.9%; t R = 8.419 minutes.

[0450] Example 1ag: Preparation of compound 34.

[0451]

[0452] 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (34.5). Under nitrogen and at 0 °C, LDA (2.0 N, 2.6 mL, 5.12 mmol) was added dropwise to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.92 g, 8.52 mmol) in THF (30 mL). The reaction solution was then warmed to room temperature and stirred at room temperature for 2 h. 34.6 (900 mg, 4.26 mmol) dissolved in THF (10 mL) was added dropwise. After the addition, the reaction solution was stirred under nitrogen at 60 °C for 3 h. After the starting material was consumed (monitored by LCMS), the mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / THF = 10 / 1) to give 34.5 mg (320 mg, 31% yield) of a pale yellow oil. LC-MS m / z: 184.4 [M - 55] + LCMS purity (214 nm): 97.15%; tR = 1.955 minutes.

[0453] 6-Formyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (34.4). In a 100 mL single-necked round-bottom flask, a mixture of 34.5 (300 mg, 1.25 mmol) and 2,2,2-trichloroacetic acid (614 mg, 3.76 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. After the initial material was consumed (monitored by LC-MS), the mixture was diluted with water (50 mL) and extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, and concentrated to dryness to give 34.4 (280 mg, 99% yield) as a colorless oil. LC-MS m / z: 170.4 [M -55] + No UV spectral absorption.

[0454] 6-(difluoromethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (34.3). In a 100 mL single-necked round-bottom flask, a mixture of 34.4 (280 mg, 1.24 mmol) and DAST (401 mg, 2.49 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. After the initial material was consumed (monitored by LCMS), the mixture was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, and concentrated to dryness to give 34.3 (260 mg, 85% yield) as a light brown solid. LC-MS m / z: 192.3 [M - 55] + No UV spectral absorption.

[0455] 6-(difluoromethyl)-2-azaspiro[3.3]heptane (34.2). In a 100 mL single-necked round-bottom flask, a mixture of 34.3 (150 mg, 0.61 mmol) and dioxane (4 N, 5 mL) containing HCl was stirred overnight at room temperature. After the starting material was consumed (monitored by LCMS), the solvent was removed under vacuum. The residue was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, and concentrated to dryness to give 34.2 (80 mg, 90% yield) as a light brown oil. LC-MS m / z: 148.4 [M + 1] + No UV spectral absorption.

[0456] 2-(1-(6-chloropyridin-3-yl)ethyl)-6-(difluoromethyl)-2-azaspiro[3.3]heptane (34.1). DIEA (263 mg, 2.04 mmol) was added to 34.2 (100 mg, 0.68 mmol) in MeCN (2 mL), followed by dropwise addition of 5-(1-bromoethyl)-2-chloropyridine (150 mg, 0.68 mmol). The mixture was stirred overnight at room temperature under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (30 mL × 2) and then with brine (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The target product was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 10:1) to give 34.1 mg (60 mg, 31% yield) as a yellow solid. LC-MS m / z: 287.4 [M+1] + LCMS purity (214 nm): 93.51%; t R = 1.826 minutes.

[0457] N 4 -(5-(1-(6-(difluoromethyl)-2-azaspiro[3.3]hept-2-yl)ethyl)pyridin-2-yl)- N 6 -(3-(methanesulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (34). A solution of 34.1 (40 mg, 0.14 mmol), 1A (37 mg, 0.14 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in dioxane (1 mL) was stirred overnight at 120 °C under nitrogen. After the starting material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL × 2) and then with brine (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The product was purified by silica gel column chromatography (CH3OH / CH2Cl2 = 1 / 10) and reversed-phase preparative HPLC to give 34 (9 mg, 12% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 10.11 (s,1H), 9.43 (s, 1H), 8.77 (s, 1H), 8.67(dd, J J = 4.8 Hz, 1.6 Hz, 1H), 8.40 (d, J J = 1.2 Hz, 1H), 8.26 (dd, J J = 8.0 Hz, 2.0 Hz, 1H), 8.21-8.17 (m, 1H),7.68-7.60(m, 2H), 7.27 (dd, J J = 8.0 Hz, 5.2 Hz, 1H), 6.15-5.83 (m, 1H), 3.39 (s, 3H),3.23-3.16 (m,1H), 3.12 (d, J J = 7.2 Hz, 1H), 3.06-2.98 (m, 2H), 2.91 (d, J J =7.2 Hz, 1H), 2.60-2.53 (m, 1H), 2.18-2.11 (m, 2H), 2.06-2.00 (m, 2H), 1.11(d, J J = 6.4 Hz, 3H). LC-MS m / z: 516.2 [M+ 1] + . HPLC purity (254 nm): 99.14%; t R Rt =9.156 min.

[0458] Example 1ah: Preparation of compound 35.

[0459]

[0460] N-(1-(6-chloropyridin-3-yl)ethyl)-3,3-difluorocyclobutylamine (35.1). 3,3-difluorocyclobutylamine (206 mg, 1.93 mmol) and AcOH (12 mg, 0.19 mmol) were added to a solution of 1-(6-chloropyridin-3-yl)ethyl-1-one (150 mg, 0.96 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then, NaBH3CN (121 mg, 1.93 mmol) was added. The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the reaction mixture was concentrated under vacuum. The residue was then diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reversed-phase column chromatography (MeOH / H2O = 1 / 1) to give 35.1 (75 mg, 32% yield) as a white solid. LC-MS m / z: 247.2 [M+1]. LC-MS purity (214 nm): 98.57%; t R = 1.481 minutes.

[0461] N 4 -(5-(1-(3,3-difluorocyclobutylamino)ethyl)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (35). 1A (81 mg, 0.30 mmol), Cs₂CO₃ (198 mg, 0.61 mmol), Xantphos (17 mg, 0.030 mmol), and Brettphos Pd G₃ (14 mg, 0.015 mmol) were added to a solution of 35.1 (75 mg, 0.30 mmol) in dioxane (10 mL). The mixture was then stirred overnight at 110 °C under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 35 (34 mg, 24% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 10.11(s, 1H), 9.43 (br, 1H), 8.77 (s, 1H), 8.65 (dd, J = 4.8, 2.0 Hz, 1H), 8.40(d, J = 1.2 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.24-8.20 (m, 1H), 7.72-7.65 (m, 2H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 3.74-3.61 (m, 1H), 3.39 (s,3H), 2.99-2.82 (m, 1H), 2.77-2.61 (m, 2H), 2.57-2.51 (m, 1H), 2.42-2.15 (m,2H),1.27 (d, J = 6.8 Hz, 3H). LC-MS m / z: 476.2 [M+H] + HPLC purity (254 nm): >99.9%; t R =8.049 minutes.

[0462] Example 1ai: Preparation of compound 36.

[0463]

[0464] 6-Chloro- N -((3-methyloxetane-3-yl)methyl)pyridine-3-amine (36.1). To a solution of 5-bromo-2-chloropyridine (250 mg, 1.30 mmol) in dioxane (20 mL), (3-methyloxetane-3-yl)methylamine (158 mg, 1.56 mmol), Cs₂CO₃ (847 mg, 2.60 mmol), Pd₂(dba)₃ (119 mg, 0.13 mmol), and Xantphos (75 mg, 0.13 mmol) were added. The reaction mixture was heated to 110 °C and stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was evaporated under vacuum to give the crude product. Further purification by silica gel column chromatography (EtOAc: hexane = 9:1) gave the title product 36.1 (160 mg, 57.9% yield) as a yellow solid. LC-MS m / z: 213.3 [M+1] + LCMS purity (254 nm): > 99.9%; t R = 0.532 minutes.

[0465] N 4 -(5-(((3-methyloxetane-3-yl)methyl)amino)pyridin-2-yl)- N 6 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (36). 1A (200 mg, 0.75 mmol), Cs₂CO₃ (490 mg, 1.50 mmol), Pd₂(dba)₃ (69 mg, 0.075 mmol), and Xantphos (44 mg, 0.075 mmol) were added to a solution of 36.1 (160 mg, 0.75 mmol) in dioxane (20 mL). The reaction mixture was heated to 120 °C and stirred overnight at 120 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (CH₂Cl₂: MeOH = 10 / 1) and further purified by reversed-phase preparative HPLC to give 36 as a yellow solid (61.41 mg, 18.5% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s,1H), 9.34 (s, 1H), 8.60 (dd, J = 4.8, 2.0 Hz, 1H), 8.45 (br, 1H), 8.30 (d, J = 1.2 Hz, 1H), 8.25 (dd, J = 8.0, 2.0 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.49(d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 5.2 Hz, 1H), 7.10 (dd, J = 9.2, 3.2Hz, 1H), 5.57 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.26 (d, J = 5.6Hz, 2H), 3.38 (s, 3H), 3.24 (d, J = 6.0 Hz, 2H), 1.34 (s, 3H). LC-MS m / z:442.2 [M+ H]+ HPLC purity (214 nm): 98.68%, t R = 7.157 minutes.

[0466] Example 1aj: Preparation of compound 37.

[0467]

[0468] 6-Chloro- N -(3,3-Difluorocyclobutyl)pyridine-3-amine (37.1). A mixture of 5-bromo-2-chloropyridine (1.00 g, 5.20 mmol), 3,3-difluorocyclobutylamine (557 mg, 5.20 mmol), Pd2(dba)3 (476 mg, 0.52 mmol), XantPhos (601 mg, 1.04 mmol), Cs2CO3 (3.39 g, 10.40 mmol), and dioxane (50 mL) was stirred overnight at 110 °C under nitrogen. The reaction mixture was then poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 37.1 mg (400 mg, 35.2% yield) as a yellow solid. LC-MS m / z: 219.1 [M+1] + LCMS purity (214 nm): 34.11%; t R = 1.676 minutes.

[0469] N 4 -(5-(3,3-difluorocyclobutylamino)pyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (37). A mixture of 37.1 (220 mg, 1.01 mmol), 1A (267 mg, 1.01 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), XantPhos (116 mg, 0.20 mmol), Cs2CO3 (656 mg, 2.01 mmol), and dioxane (10 mL) was stirred overnight at 110 °C under nitrogen. The mixture was then poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 37 (53.26 mg, 11.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.71 (s, 1H), 9.33 (s, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 8.23(dd, J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.0, 4.8 Hz, 1H), 7.00 (dd, J = 8.8, 2.8 Hz, 1H), 6.03 (d, J = 6.8 Hz, 1H), 3.81-3.77 (m, 1H), 3.31 (s, 3H), 3.08-3.01 (m, 2H), 2.46-2.39(m, 2H). LC-MS m / z: 448.3 [M + H] + HPLC purity (254 nm): 98.05%; t R = 8.244 minutes.

[0470] Example 1ak: Preparation of compound 38.

[0471]

[0472] 6-Chloro-N -(3,3-Difluorocyclobutyl)nicotinamide (38.1). 3,3-Difluorocyclobutylamine hydrochloride (228 mg, 1.59 mmol), HATU (905 mg, 2.38 mmol), and DIEA (615 mg, 4.76 mmol) were added to a solution of 6-chloronicotinic acid (250 mg, 1.59 mmol) in DMF (6 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was diluted with brine (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane / EtoAc = 4 / 1) to give 38.1 (230 mg, 59% yield) as a brown solid. LC-MS m / z: 247.2 [M + H] + LCMS purity (254 nm): 96.79%; t R = 1.371 minutes.

[0473] N -(3,3-Difluorocyclobutyl)-6-(6-(3-(methanesulfonyl)pyridin-2-ylamino)pyrimidin-4-ylamino)nicotinamide (38). 1A (183 mg, 0.69 mmol), Cs₂CO₃ (449 mg, 1.38 mmol), X-phos (33 mg, 0.069 mmol), and Brettphos-Pd-G₃ (62 mg, 0.069 mmol) were added to a stirred solution of 38.1 (170 mg, 0.69 mmol) in dioxane (6 mL). The mixture was stirred overnight at 130 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 38 (42 mg, 13% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 10.52 (s, 1H), 9.51 (s, 1H), 8.83-8.79 (m, 3H), 8.67(dd, J = 4.8, 1.6 Hz, 1H), 8.48 (d, J = 0.8 Hz, 1H), 8.28 (dd, J =8.0, 2.0Hz, 1H), 8.14 (dd,J =8.8, 2.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.30 (dd, J =8.0, 5.2 Hz, 1H), 4.34-4.20 (m, 1H), 3.40 (s, 3H), 3.04-2.90 (m, 2H), 2.83-2.69 (m, 2H). LC-MS m / z: 476.3[M + H] + HPLC purity (214 nm): > 99.9%; t R = 7.685 minutes.

[0474] Example 1al: Preparation of compound 39.

[0475]

[0476] Methyl 2-(6-chloropyridin-3-yl)-2-methylpropionate (39.5). 60% NaH (259 mg, 6.47 mmol) was added to a solution of 39.6 (400 mg, 2.16 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Iodomethane (673 mg, 4.74 mmol) was then added to the mixture at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane / EtOAc = 3:1) to give 39.6 (260 mg, 56.5% yield) as a yellow solid. LC-MS m / z: 214.2 [M+ H] + LCMS purity (214 nm): 97.99%; t R = 0.802 minutes.

[0477] 2-(6-chloropyridin-3-yl)-2-methylpropionic acid (39.4). A mixture of 39.5 (260 mg, 1.22 mmol), NaOH (97 mg, 2.43 mmol), MeOH (15 mL), and H₂O (15 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water (20 mL) and acidified to pH 5–6 with 2 N HCl. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to give 39.4 (180 mg, 74.1% yield) as a yellow oil. LC-MS m / z: 200.2 [M + H] + LCMS purity (254 nm): 97.60%; t R =0.393 minutes.

[0478] (2-(6-chloropyridin-3-yl)propyl-2-yl)carbamate (39.3). A mixture of 39.4 (650 mg, 3.26 mmol), phenylmethanol (704 mg, 6.51 mmol), DPPA (1348 mg, 4.90 mmol), TEA (988 mg, 9.77 mmol), and toluene (20 mL) was stirred at 110 °C for 2 hours. The mixture was then poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 5) to give 39.3 (500 mg, 50.4% yield) as a yellow solid. LC-MS m / z: 305.2 [M+ H]+. LCMS purity (254 nm): 87.77%; tR = 2.036 min.

[0479] (2-(6-((6-((2-(methanesulfonyl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)propyl-2-yl)carbamate (39.2). 39.3 (300 mg, 0.98 mmol), N 4A suspension of 1,4-dioxane (30 mL) containing 312 mg (312 mg, 1.18 mmol), Brettphos-Pd-G3 (91 mg, 0.10 mmol), Xantphos (116 mg, 0.20 mmol), and Cs2CO3 (641 mg, 1.97 mmol) was stirred overnight at 110 °C under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 80%) to give 39.2 mg (330 mg, 62.8% yield) as a yellow solid. LC-MS m / z: 533.2 [M+1] + LCMS purity (254 nm): 87.32%; t R = 2.032 minutes.

[0480] N 4 -(5-(2-aminopropyl-2-yl)pyridin-2-yl)- N 6 -(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (39.1). A mixture of 39.2 (330 mg, 0.62 mmol) and Pd / C (10% wt, 30 mg) in MeOH (30 mL) was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2 10%) to give 39.1 (150 mg, 60.8% yield) as a white solid. LC-MS m / z: 399.3 [M+ H] + LCMS purity (254 nm): 98.07%; t R = 1.480 minutes.

[0481] N 4 -(2-(methylsulfonyl)phenyl)- N 6-(5-(2-(oxetane-3-ylamino)propyl-2-yl)pyridin-2-yl)pyrimidin-4,6-diamine (39). A mixture of 39.1 (150 mg, 0.38 mmol), oxetane-3-one (54 mg, 0.75 mmol), NaBH3CN (71 mg, 1.13 mmol), AcOH (0.1 mL), and MeOH (10 mL) was stirred overnight at 60 °C. The reaction mixture was then poured into water (20 mL) and the pH was adjusted to 7–8 with 2 M NaOH solution. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC to give 39 (29 mg, 16.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 9.91 (s, 1H), 8.78 (s, 1H), 8.31 (d, J = 0.8 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.91 (dd, J = 8.0, 1.6Hz, 1H), 7.77-7.71 (m, 2H), 7.46-7.44 (m, 2H), 7.38-7.34 (m, 1H), 4.44 (dd, J = 7.2, 6.0 Hz, 2H), 4.29 (dd, J = 6.8, 6.8 Hz, 2H), 3.74-3.64 (m, 1H), 3.23(s, 3H), 3.00 (d, J = 9.2 Hz, 1H), 1.31 (s, 6H). LC-MS m / z: 455.2 [M+ H] + HPLC purity (214 nm): 97.84%; t R = 7.060 minutes.

[0482] Example 1am: Preparation of compound 40.

[0483]

[0484] 1-(6-(6-(2-(methanesulfonyl)phenylamino)pyrimidin-4-ylamino)pyridin-3-yl)acetone (40.2). 6-Chloro-N-(2-(methanesulfonyl)phenyl)pyrimidin-4-amine (1C) was prepared as described in Example 1aa. 1-(6-aminopyridin-3-yl)acetone (288 mg, 2.11 mmol), Cs₂CO₃ (919 mg, 2.82 mmol), Xantphos (81 mg, 0.14 mmol), and Brettphos Pd G₃ (63 mg, 0.070 mmol) were added to a solution of 1C (400 mg, 1.41 mmol) in dioxane (15 mL). The mixture was then stirred at 110 °C for 2 h under a nitrogen atmosphere. After the initial material consumption (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (60 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 4) to give 40.2 (415 mg, 77% yield) as a yellow solid. LC-MS m / z: 384.2 [M + 1] + LCMS purity (254 nm): 91.05%; t R =0.470 minutes.

[0485] ( R )- N 4 -(2-(methylsulfonyl)phenyl)- N 6-(5-(1-(oxetane-3-ylamino)ethyl)pyridin-2-yl)pyrimidine-4,6-diamine (40). Oxetane-3-amine (146 mg, 2.00 mmol) and AcOH (12 mg, 0.20 mmol) were added to a solution of 40.2 (255 mg, 0.66 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then, NaBH3CN (84 mg, 1.33 mmol) was added. The mixture was stirred overnight at 80 °C. After the initial material was consumed (monitored by LCMS), the reaction mixture was concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) to obtain 40.1, and purified by reversed-phase preparative HPLC and preparative SFC to obtain 40 (34 mg, 11.6% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 9.92 (s, 1H), 8.79 (s, 1H), 8.32 (d, J = 0.4 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (dd, J = 8.4, 1.6Hz, 1H), 7.77-7.70 (m, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 1H), 7.51-7.41 (m,2H), 7.39-7.31 (m, 1H), 4.57 (t, J = 6.4 Hz, 1H), 4.41-4.25 (m, 2H), 4.12 (t, J = 6.4 Hz, 1H), 3.83-3.55 (m, 2H), 3.22 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H). LC-MS m / z: 441.2 [M + 1] + HPLC purity (214 nm): 98.85%; t R = 6.651 minutes.

[0486] Example 1an: Preparation of compound 41.

[0487]

[0488] Synthesis of 1-(6-chloropyridin-3-yl)cyclopropane carboxylate (41.5). NaH (60% wt, 862 mg, 21.55 mmol) was added to a solution of methyl 2-(6-chloropyridin-3-yl)acetate (1 g, 5.39 mmol) in THF (30 mL), and the resulting mixture was stirred at room temperature for 0.5 h. Then, 1,2-dibromoethane (1.01 g, 5.39 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 10 / 1) to give 41.5 (500 mg, 43.9% yield) as a yellow solid. LC-MS m / z: 212.1 [M + 1] + LCMS purity (254 nm): 90.53%; t R =1.623 minutes.

[0489] Synthesis of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid (41.4). A mixture of 41.5 (500 mg, 2.36 mmol), NaOH (189 mg, 4.73 mmol), MeOH (5 mL), and H₂O (5 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water (20 mL) and acidified to pH 5–6 with 2 N HCl. The mixture was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated to give 41.4 (450 mg, 96.4% yield) as a yellow oil. LC-MS m / z: 198.1 [M + H] + LCMS purity (214 nm): 99.77%; t R = 1.407 minutes.

[0490] Synthesis of 1-(6-chloropyridin-3-yl)cyclopropylcarbamate (41.3). A mixture of 41.4 (450 mg, 2.28 mmol), phenylmethanol (492 mg, 4.55 mmol), DPPA (940 mg, 3.42 mmol), TEA (691 mg, 6.83 mmol), and toluene (20 mL) was stirred at 110 °C for 2 h. The reaction mixture was then poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 5) to give 41.3 as a yellow solid (300 mg, 44.5% yield). LC-MS m / z: 303.1 [M + 1] + LCMS purity (214 nm): 98.53%; t R = 1.752 minutes.

[0491] Synthesis of 1-(6-(6-(2-(methanesulfonyl)phenylamino)pyrimidin-4-ylamino)pyridin-3-yl)cyclopropylcarbamate benzyl ester (41.2). 41.3 (300 mg, 0.99 mmol), N 4 A mixture of 2-(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (262 mg, 0.99 mmol), Brettphos Pd G3 (90 mg, 0.099 mmol), XantPhos (115 mg, 0.20 mmol), Cs₂CO₃ (646 mg, 1.99 mmol), and dioxane (10 mL) was stirred overnight at 110 °C under nitrogen. The reaction mixture was then poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 41.2 (350 mg, 66.6% yield) as a yellow solid. LC-MS m / z: 531.2 [M + 1] + LCMS purity (214 nm): 70.21%; t R = 1.609 minutes.

[0492] N 4 -(5-(1-aminocyclopropyl)pyridin-2-yl)- N 6Synthesis of 4,6-(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (41.1). A solution of 41.2 (200 mg, 0.38 mmol) in AcOH (3 mL) containing 33% HBr was stirred overnight at 70 °C. The reaction mixture was then poured into water (20 mL) and neutralized to pH 7–8 with 2 M NaOH. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 41.1 as a yellow solid (110 mg, 73.6% yield). LC-MS m / z: 397.2 [M + H] + LCMS purity (214 nm): 73.40%; t R = 1.322 minutes.

[0493] N 4 -(2-(methylsulfonyl)phenyl)- N 6 Synthesis of 4,6-(5-(1-(oxetane-3-ylamino)cyclopropyl)pyridin-2-yl)pyrimidine-4,6-diamine (41). A mixture of 41.1 (110 mg, 0.28 mmol), oxetane-3-one (40 mg, 0.55 mmol), NaBH3CN (44 mg, 0.69 mmol), AcOH (0.2 mL), and MeOH (5 mL) was stirred overnight at 60 °C. The reaction mixture was then poured into water (20 mL) and neutralized to pH 7–8 with 2 M NaOH. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) and reversed-phase preparative HPLC to give 41 (55 mg, 43.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.92 (s, 1H), 8.79 (s, 1H), 8.31 (d, J = 0.8 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (dd, J= 8.0, 1.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.65 (dd, J = 8.4,2.4 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 1H), 4.43-4.39 (m, 2H), 4.11(dd, J = 6.4, 6.4 Hz, 2H), 3.97-3.91 (m, 1H), 3.58 (d, J = 9.6 Hz, 1H), 3.22 (s, 3H), 0.86-0.83 (m, 2H), 0.80-0.77 (m, 2H). LC-MS m / z: 453.3 [M + H] + HPLC purity (214 nm): > 99.9%; t R = 7.364 minutes.

[0494] Example 1ao: Preparation of compound 42.

[0495]

[0496] 4-(6-Nitropyridin-3-yl)morpholine (42.2). Morpholine (322 mg, 3.69 mmol) and DIEA (635 mg, 4.92 mmol) were added to a solution of 5-bromo-2-nitropyridine (500 mg, 2.46 mmol) in DMSO (20 mL), and the reaction mixture was stirred overnight at 100 °C. After the starting material was consumed, the mixture was diluted with water (100 mL) and extracted with EtOAc (70 mL × 2). The organic extract was washed with brine (150 mL × 4), dried over Na2SO4, and concentrated to give crude product 42.2 (505 mg, 98% yield) as a brown solid. LC-MS m / z: 210.4 [M+1] + LCMS purity (214 nm): 71.43%; t R = 1.402 minutes.

[0497] 5-Morpholinopyridine-2-amine (42.1). 10% Pd / C (10 mg) was added to a solution of 42.2 (50 mg, 0.24 mmol) in MeOH (20 mL), and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give crude product 42.1 (35 mg, 81.4% yield) as an orange oil. LC-MS m / z: 180.4 [M+1]+ LCMS purity (214 nm): 55.49%; t R = 1.353 minutes.

[0498] N 4 -(2-(methylsulfonyl)phenyl)- N 6 -(5-morpholinopyridin-2-yl)pyrimidine-4,6-diamine (42). A mixture of 42.1 (130 mg, 0.73 mmol), 1C (205 mg, 0.73 mmol), Brettphos-Pd-G3 (132 mg, 0.145 mmol), Xphos (138 mg, 0.290 mmol), and Cs2CO3 (710 mg, 2.178 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 42 (65.56 mg, 21.2% yield) as a light gray solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.71 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.90 (dd, J = 8.0, 1.6Hz, 1H), 7.75-7.01 (m, 1H), 7.48-7.41 (m, 2H), 7.36-7.32 (m, 1H), 7.30 (s,1H), 3.75 (t, J = 5.2 Hz, 4H), 3.22 (s, 3H), 3.08 (t, J = 5.2 Hz, 1H). LC-MS m / z: 427.1 [M+1] + HPLC purity (214 nm): 98.40%; t R = 7.375 minutes.

[0499] Example 1ap: Preparation of compound 43.

[0500]

[0501] 6-Chloro- N -(tetrahydrofuran-3-yl)nicotinamide (43.1). Tetrahydrofuran-3-amine (276 mg, 3.17 mmol), HATU (1801 mg, 4.74 mmol), and DIEA (1223 mg, 9.48 mmol) were added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol) in DMF (50 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL × 4), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 6: 4) to give 43.1 (400 mg, 55.6% yield). LC-MS: m / z = 227.2 [M+1] + LCMS purity (214 nm): 48.84%; t R =1.067 minutes.

[0502] 6-(6-(2-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)- N -(tetrahydrofuran-3-yl)nicotinamide (43). N 4 A mixture of 1,4-dioxane (30 mL) containing 233 mg (233 mg, 0.88 mmol), 43.1 (200 mg, 0.88 mmol), Brettphos Pd G3 (120 mg, 0.13 mmol), X-phos (124 mg, 0.26 mmol), and Cs2CO3 (858 g, 2.64 mmol) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 20: 1) and then by reversed-phase preparative HPLC to give 43 (7.4 mg, 1.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 10.29 (s, 1H), 8.88 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.52 (d,J = 6.4 Hz 1H), 8.37 (d, J = 0.8 Hz, 1H), 8.12 (dd, J = 8.8, 2.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0, 1.6 Hz, 1H), 7.77-7.73 (m,1H), 7.63 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.41-7.37 (m, 1H), 4.48-4.43 (m,1H), 3.89-3.83 (m, 2H), 3.74-3.69 (m, 1H), 3.58 (dd, J = 8.8, 4.4 Hz, 1H), 3.23 (s, 3H), 2.20-2.11 (m, 1H), 1.95-1.88 (m, 1H). LC-MS m / z=455.2 [M+1] + HPLC purity: > 99.9% (214 nm), t R = 6.657 minutes.

[0503] Example 1aq: Preparation of compound 44.

[0504]

[0505] N 4 -(4-methylpyridin-2-yl)- N 6-(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (44). 4-Methylpyridin-2-amine (38 mg, 0.35 mmol), Cs₂CO₃ (230 mg, 0.70 mmol), Brettphos Pd G₃ (16 mg, 0.018 mmol), and Xantphos (20 mg, 0.035 mmol) were added to a solution of 1C (100 mg, 0.35 mmol) in dioxane (5 mL). The mixture was microwave-irradiated at 130 °C for 1 h under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 44 (55 mg, 44% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.88 (s, 1H), 8.80 (s, 1H), 8.32 (d, J =0.8 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.91 (dd, J = 8.0, 1.2 Hz, 1H), 7.77-7.69 (m, 1H), 7.49 (s, 1H), 7.41-7.29 (m, 2H), 6.80(d, J = 5.2 Hz, 1H), 3.22 (s, 3H), 2.28 (s, 3H). LC-MS m / z: 356.2 [M + 1] + HPLC purity (254 nm): > 99.9%; t R = 8.171 minutes.

[0506] Example 1ar: Preparation of compound 45.

[0507]

[0508] N 4 -(4-methylpyridin-2-yl)pyrimidine-4,6-diamine (45.2).A mixture of 2-chloro-4-methylpyridine (2.0 g, 15.68 mmol), pyrimidine-4,6-diamine (2.59 g, 23.52 mmol), Cs₂CO₃ (10.26 g, 31.50 mmol), Xantphos (914 mg, 1.58 mmol), and Pd₂(dba)₃ (723 mg, 0.79 mmol) in dioxane (60 mL) was stirred overnight at 110 °C under nitrogen. After the reaction was complete and cooled to room temperature, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂ / MeOH / TEA = 15 / 1 / 0.01) to give 45.2 g (1.10 g, 35% yield) as a pale green solid. LC-MS m / z: 202.3 [M+1] + LCMS purity (254 nm): 98.67%; t R =1.320 minutes.

[0509] 2-((6-((4-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)benzonitrile (45.1). A mixture of 45.2 (300 mg, 1.49 mmol), 2-bromobenzonitrile (271 mg, 1.49 mmol), BrettPhos-Pd-G3 (136 mg, 0.15 mmol), X-phos (72 mg, 0.15 mmol), and Cs2CO3 (971 mg, 2.98 mmol) in dioxane (10 mL) was stirred at 110 °C for 3 hours under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and washed with water (30 mL × 2) and then with brine (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The target product was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 10 / 1) to give 45.1 mg (90 mg, 20% yield) of a yellow solid. LC-MS m / z: 303.3 [M+1] + LCMS purity (254 nm): 89.14%; t R = 0.755 minutes.

[0510] 2-((6-((4-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)benzamide (45).To a stirred solution of 45.1 (90 mg, 0.30 mmol) in DMSO (3 mL), K₂CO₃ (124 mg, 0.90 mmol) and H₂O₂ (30% wt, 102 mg, 0.90 mmol) were added. The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The final product was purified by reversed-phase preparative HPLC to give 45 (50 mg, 52% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08(s, 1H), 9.84 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.24 (br, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.69 (br, 1H), 7.52-7.46 (m, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 7.05-7.00 (m, 1H), 6.80 (d, J = 4.4 Hz, 1H), 2.28 (s, 3H). LC-MS m / z: 321.3 [M+ 1] + HPLC purity (214 nm): >99.9%; t R = 7.364 minutes.

[0511] Example 1as: Preparation of compound 46.

[0512]

[0513] 6-Chloro- N-(6-methylpyridin-2-yl)pyrimidin-4-amine (46.2). 4,6-Dichloropyrimidine (1.38 g, 9.25 mmol), Pd2(dba)3 (842 mg, 0.92 mmol), Xantphos (532 mg, 0.92 mmol), and Cs2CO3 (6.03 g, 18.49 mmol) were added to a stirred solution of 6-methylpyridin-2-amine (1.00 g, 9.25 mmol) in dioxane (20 mL). The mixture was stirred overnight at 80 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give 46.2 g (0.60 g, 29% yield) as a yellow solid. LC-MS m / z: 221.3 [M+H] + LCMS purity (214 nm): 53.54%; t R = 1.703 minutes.

[0514] 2-(6-(6-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzonitrile (46.1). 2-Aminobenzonitrile (161 mg, 1.36 mmol), Brettphos-Pd-G3 (127 mg, 0.14 mmol), Xantphos (81 mg, 0.14 mmol), and Cs2CO3 (886 mg, 2.72 mmol) were added to a stirred solution of 46.2 (300 mg, 1.36 mmol) in dioxane (10 mL). The mixture was microwave-irradiated at 130 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 3) and reversed-phase preparative HPLC to give 46.1 mg (170 mg, 41% yield) as a white solid. LC-MS m / z: 303.4 [M + H] + LCMS purity (254 nm): 81.02%; t R = 1.821 minutes.

[0515] 2-(6-(5-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzamide (46). K₂CO₃ (233 mg, 1.69 mmol) and H₂O₂ (30% w / w, 191 mg, 1.69 mmol) were added to a stirred solution of 46.1 (170 mg, 0.56 mmol) in DMSO (5 mL). The mixture was stirred overnight at room temperature under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was poured into ice water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 46 (44 mg, 24% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.00 (br, 1H), 9.87 (br, 1H), 8.36 (s, 1H),8.29 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.83-7.65 (m, 3H), 7.58 (dd, J = 7.8, 7.8 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.05 (dd, J = 7.6, 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 2.41 (s, 3H). LC-MS m / z:321.3 [M + H] + HPLC purity (254 nm): 97.09%; t R = 7.374 minutes.

[0516] Example 1at: Preparation of compound 47.

[0517]

[0518] 2-((6-((5-methylpyridazin-3-yl)amino)pyrimidin-4-yl)amino)benzonitrile (47.1). 2-((6-aminopyrimidin-4-yl)amino)benzonitrile (1E) was prepared as described in Example 1au. A mixture of 1E (150 mg, 0.71 mmol), 3-bromo-5-methylpyridazine (135 mg, 0.78 mmol), Brettphos-Pd-G3 (64 mg, 0.071 mmol), Xphos (68 mg, 0.142 mmol), and Cs₂CO₃ (692 mg, 2.13 mmol) in 1,4-dioxane (40 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was filtered by suction filtration. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc) to give 47.1 (70 mg, 32.6% yield) as a yellow solid. LC-MS m / z: 304.4 [M+ H] + LCMS purity (254 nm): 70.04%; t R = 1.558 minutes.

[0519] 2-((6-((5-methylpyridazin-3-yl)amino)pyrimidin-4-yl)amino)benzamide (47). NaOH (9 mg, 0.23 mmol) and 30% H2O2 (131 mg, 1.16 mmol) were added to a solution of 47.1 (70 mg, 0.23 mmol) in DMSO (15 mL), EtOH (7.5 mL), and water (1.0 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The organic extract was washed successively with water (50 mL × 4) and brine (60 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 47 (15 mg, 20.3% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.14 (s, 1H), 10.18 (s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.44-8.42 (m, 2H), 8.23 ​​(s, 1H), 7.77 (d, J =7.6 Hz, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.36 (s,1H), 7.05 (t,J = 7.6 Hz, 1H), 2.30 (s, 3H). LC-MS m / z: 322.2 [M+ H] + HPLC purity (214 nm): > 99.9%; t R = 6.223 minutes.

[0520] Example 1au: Preparation of compound 48.

[0521]

[0522] 2-((6-aminopyrimidin-4-yl)amino)benzonitrile (1E). Pyrimidine-4,6-diamine (3.63 g, 32.96 mmol), Cs₂CO₃ (21.48 g, 65.93 mmol), Pd₂(dba)₃ (1.51 g, 1.65 mmol), and Xantphos (1.91 g, 3.30 mmol) were added to a solution of 2-bromobenzonitrile (6.00 g, 32.96 mmol) in dioxane (100 mL). The mixture was heated to 100 °C and stirred at 100 °C for 2 h under a nitrogen atmosphere. After the initial material consumption (monitored by LCMS), the reaction mixture was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 2 / 1) to give 1E as a red solid (1.20 g, 17% yield). LC-MS m / z: 212.2 [M+ H] + LCMS purity (214 nm): 78.98%; t R = 1.283 minutes.

[0523] 2-((6-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)amino)benzonitrile (48.1). A mixture of 1E (150 mg, 0.71 mmol), 4-bromo-2-methylpyrimidin (135 mg, 0.78 mmol), Brettphos-Pd-G3 (64 mg, 0.071 mmol), Xphos (68 mg, 0.142 mmol), and Cs2CO3 (692 mg, 2.13 mmol) in 1,4-dioxane (40 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was filtered by suction filtration. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc:hexane = 7:3) to give 48.1 (115 mg, 53.5% yield) as a yellow solid. LC-MS m / z: 304.2 [M+ H] +LCMS purity (214 nm): 83.62%; t R = 1.541 minutes.

[0524] 2-((6-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)amino)benzamide (48). NaOH (15 mg, 0.38 mmol) and 30% H2O2 (215 mg, 1.90 mmol) were added to a solution of 48.1 (115 mg, 0.38 mmol) in DMSO (15 mL), EtOH (7.5 mL), and water (1.5 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL × 2). The organic extract was washed successively with water (60 mL × 4) and brine (60 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 48 (25 mg, 20.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.31 (s,1H), 8.43 (s, 1H), 8.37 (d, J = 6.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.23(s, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.54-7.50 (m, 1H), 7.39 (d, J = 6.0 Hz, 1H), 7.10-7.06 (m, 1H), 2.51 (s, 3H). LC-MSm / z: 322.3 [M+ H] + HPLC purity (214 nm): 99.09%; t R = 6.119 minutes.

[0525] Example 1av: Preparation of compound 49.

[0526]

[0527] 2-(6-(6-methylpyrazin-2-ylamino)pyrimidin-4-ylamino)benzonitrile (49.1). A mixture of 1E (100 mg, 0.47 mmol), 2-chloro-6-methylpyrazine (60 mg, 0.47 mmol), Brettphos Pd G3 (43 mg, 0.047 mmol), X-phos (22 mg, 0.047 mmol), and Cs2CO3 (306 mg, 0.94 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 19:1) to give compound 49.1 (80 mg, 56% yield) as a yellow solid. LC-MS m / z: 304.2 [M+1] + LCMS purity (214 nm): 87.4%; t R = 1.352 minutes.

[0528] 2-(6-(6-methylpyrazin-2-ylamino)pyrimidin-4-ylamino)benzamide (49). To a solution of 49.1 (100 mg, 0.33 mmol) in DMSO (10 mL), EtOH (2 mL), and H2O (0.2 mL), NaOH (20 mg, 0.49 mmol) and 30% H2O2 (187 mg, 1.65 mmol) were added, and the mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 49 (35.81 mg, 33.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.05 (s, 1H), 10.22 (s, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.78 (d, J = 7.6 Hz, 1 H), 7.73 (s, 1H), 7.54-7.50 (m, 2H), 7.07 (t, J = 7.6Hz, 1H), 2.42 (s, 3H). LC-MS m / z: 322.3[M+1]+ HPLC purity (214 nm): > 99.9%; t R =6.518 minutes.

[0529] Example 1aw: Preparation of compound 50.

[0530]

[0531] N 4 -(6-methylpyridin-2-yl)pyrimidine-4,6-diamine (50.2). A mixture of 2-chloro-6-methylpyridine (1.27 g, 10.0 mmol), pyrimidine-4,6-diamine (1.10 g, 10.0 mmol), Pd2(dba)3 (0.915 g, 1.0 mmol), Xantphos (1.15 g, 2.0 mmol), and Cs2CO3 (9.75 g, 30 mmol) in 1,4-dioxane (70 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The organic extract was washed with brine (100 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (CH₂Cl₂: MeOH = 15:1) to give 50.2 g (720 mg, 35.8% yield) as a green solid. LC-MS m / z: 202.3 [M+1] + LCMS purity (214 nm): 90.90%; t R = 1.331 minutes.

[0532] 3-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)pyridinecarboxylonitrile (50.1). A mixture of 50.2 (50 mg, 0.25 mmol), 3-bromopyridinecarboxylonitrile (46 mg, 0.25 mmol), Brettphos-Pd-G3 (23 mg, 0.025 mmol), Xphos (24 mg, 0.05 mmol), and Cs2CO3 (245 mg, 0.75 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give crude product 50.1 (60 mg, 80% yield) as an orange solid. LC-MS m / z: 304.3 [M+1]+ LCMS purity (214 nm): 24.37%; t R = 1.608 minutes.

[0533] 3-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)pyridine amide (50). 30% H2O2 (68 mg, 0.6 mmol) was added to a solution of 50.1 (36 mg, 0.12 mmol) and NaOH (4.75 mg, 0.12 mmol) in DMSO (6 mL) and EtOH (3 mL), and the reaction mixture was stirred overnight at room temperature. After the starting material was consumed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 50 (3.18 mg, 8.4% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.89 (s, 1H), 9.96 (s, 1H), 9.08 (dd, J = 8.4, 1.2 Hz, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.21 (dd, J = 4.4, 1.2 Hz,1H), 9.78 (s, 1H), 7.62-7.57 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 6.83 (d, J =7.2 Hz, 1H), 2.44 (s, 3H). LC-MS m / z: 322.3 [M+1] + HPLC purity (214 nm): 94.19%; t R =8.143 minutes.

[0534] Example 1ax: Preparation of compound 51.

[0535]

[0536] 4-Aminonicotinonitrile (51.2). A solution of 4-chloronicotinonitrile (138 mg, 1.0 mmol) in MeCN (10 mL) and NH3·H2O (5 mL) was stirred overnight at 65 °C in a sealed tube. After cooling to room temperature, the mixture was evaporated under reduced pressure to give crude product 52.1 (105 mg, 88.2% yield) as a gray oil. LC-MS m / z: 120.2 [M+1] + LCMS purity (214 nm): 72.58%; t R = 0.851 minutes.

[0537] 4-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)nicotinonitrile (51.1). A mixture of 51.2 (100 mg, 0.84 mmol), 6-chloro-N-(6-methylpyridin-2-yl)pyrimidin-4-amine (185 mg, 0.84 mmol), Brettphos-Pd-G3 (77 mg, 0.084 mmol), Xphos (80 mg, 0.0168 mmol), and Cs2CO3 (821 mg, 2.52 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 110 °C under an argon atmosphere. The mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated to give crude compound 51.1 (100 mg, 39.2% yield) as a green solid. LC-MS m / z: 304.2 [M+1] + LCMS purity (254 nm): 16.98%; t R = 1.669 minutes.

[0538] 4-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)nicotinamide (51). 30% H2O2 (108 mg, 0.96 mmol) was added to a solution of 51.1 (58 mg, 0.19 mmol) and NaOH (7.65 mg, 0.19 mmol) in DMSO (4 mL) and EtOH (2 mL). The reaction mixture was stirred overnight at room temperature. After the starting material was consumed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 51 as a white solid (14.72 mg, 24.1% yield). 1H NMR (400 MHz, DMSO- d 6) δ 11.65 (s, 1H), 10.06 (s, 1H), 8.88 (s, 1H),8.52-8.48 (m, 3H), 8.45 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.61 (t, J = 4.0Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H). LC-MSm / z: 322.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R = 8.639 minutes.

[0539] Example 1ay: Preparation of compound 52.

[0540]

[0541] 2-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)nicotinonitrile (52.1). N 4 A mixture of (6-methylpyridin-2-yl)pyrimidine-4,6-diamine (201 mg, 1.0 mmol), 2-bromopyridinium carboxynitrile (275 mg, 1.5 mmol), Brettphos-Pd-G3 (91 mg, 0.1 mmol), Xphos (95 mg, 0.2 mmol), and Cs₂CO₃ (980 mg, 3.0 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (EtOAc:hexane = 7:13) to give 52.1 g (150 mg, 49.5% yield) as a yellow solid. LC-MS m / z: 304.2 [M+1] + LCMS purity (214 nm): 97.65%; t R = 1.664 minutes.

[0542] 2-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)nicotinamide (52). 30% H2O2 (56 mg, 2.5 mmol) was added to a solution of 52.1 (152 mg, 0.5 mmol) and NaOH (20 mg, 0.5 mmol) in DMSO (6 mL) and EtOH (3 mL), and the reaction mixture was stirred overnight at room temperature. After the starting material was consumed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 52 as a white solid (63.99 mg, 39.9% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 11.59 (s, 1H), 9.96 (s, 1H), 9.17 (s, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 8.24 (dd, J =8.0,1.6 Hz, 1H), 7.89 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 7.6, 4.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 2.48 (s, 3H). LC-MS m / z: 322.3 [M+1] + HPLC purity (214 nm): > 99.9%; t R = 7.158 minutes.

[0543] Example 1az: Preparation of compound 53.

[0544]

[0545] N1,(2-Aminophenyl)methanesulfonamide (53.1). DIEA (774 mg, 5.99 mmol) and Ms2O (522 mg, 3.00 mmol) were added to a solution of phenyl-1,2-diamine (216 mg, 2.00 mmol) in MeCN (10 mL). The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was diluted with water (20 mL) and the pH was adjusted to 8–9 with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give 53.1 (165 mg, 44% yield) as a yellow solid. LC-MS m / z: 187.2 [M+1] + LCMS purity (214 nm): 93.87%; t R = 0.449 minutes.

[0546] N -(2-(6-(6-methylpyridin-2-ylamino)pyrimidin-4-ylamino)phenyl)methanesulfonamide (53). 6-chloro-N-(6-methylpyridin-2-yl)pyrimidin-4-amine (195 mg, 0.89 mmol), Cs₂CO₃ (577 mg, 1.77 mmol), Xantphos (51 mg, 0.089 mmol), and Brettphos Pd G₃ (40 mg, 0.044 mmol) were added to a solution of 53.1 (165 mg, 0.89 mmol) in dioxane (15 mL). The mixture was then stirred at 110 °C for 5 hours under a nitrogen atmosphere. After the initial material was consumed (monitored by LCMS), the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with water (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 53 (36 mg, 11.0% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ9.79 (s, 1H), 9.04 (br, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.55 (dd, J = 8.0, 8.0 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H),7.35-7.23 (m, 2H), 7.20 (dd, J = 7.6, 7.6 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 2.89 (s, 3H), 2.33 (s, 3H). LC-MS m / z: 369.2 [M-1] + HPLC purity (254 nm): 98.94%; t R = 5.795 minutes.

[0547] Example 1ba: Preparation of compound 54.

[0548]

[0549] ( S )-3-methyl-4-(6-nitropyridin-3-yl)morpholine (54.2). Add ( ) to a solution of 5-bromo-2-nitropyridine (1.0 g, 4.93 mmol) in DMSO (40 mL). S 3-Methylmorpholine (746 mg, 7.92 mmol) and DIEA (1.27 g, 9.84 mmol) were added, and the reaction mixture was stirred overnight at 100 °C. After the starting material was consumed, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (70 mL × 2). The organic extract was washed with brine (150 mL × 4), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (CH2Cl2: MeOH = 10: 1) to give 54.2 g (240 mg, 21.8% yield) of a brown oil. LC-MS m / z: 224.4 [M+1] + LCMS purity (214 nm): 78.20%; t R = 1.836 minutes.

[0550] ( S5-(3-methylmorpholino)pyridine-2-amine (54.1). 10% Pd / C (40 mg) was added to a solution of 54.2 (120 mg, 0.54 mmol) in MeOH (30 mL), and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give crude product 54.1 (97 mg, 93.3% yield). LC-MS m / z: 194.4 [M+1] + LCMS purity (214 nm): 44.23%; t R = 1.302 minutes.

[0551] ( S )- N 4 -(5-(3-methylmorpholino)pyridin-2-yl)- N 6 -(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (54). A mixture of 54.1 (110 mg, 0.57 mmol), 1C (162 mg, 0.57 mmol), Brettphos-Pd-G3 (104 mg, 0.114 mmol), Xphos (109 mg, 0.23 mmol), and Cs2CO3 (557 mg, 1.71 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 54 (15.79 mg, 6.3% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.53 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 0.8 Hz, 1H), 7.92-7.88 (m, 2H), 7.73-7.68 (m,2H), 7.36-7.32 (m, 1H), 6.77 (d, J = 9.2 Hz, 1H), 6.10 (d, J = 0.8 Hz, 1H),4.26-4.24 (m, 1H), 3.92 (dd, J= 11.2, 3.6 Hz, 1H), 3.76-3.70 (m, 2H), 3.63(dd, J = 11.2, 2.8 Hz, 1H), 3.51-3.45 (m, 1H), 3.19 (s, 3H), 3.06-2.98 (m,1H). LC-MS m / z: 441.3 [M+1] + HPLC purity (254 nm): 99.38%; t R = 7.630 minutes.

[0552] Example 1bb: Preparation of compound 55.

[0553]

[0554] (4,6-Dichloropyrimidin-2-yl)carbamate di-tert-butyl ester (55.3). Boc₂O (5.32 g, 24.39 mmol) was added to a stirred solution of 4,6-dichloropyrimidin-2-amine (2.00 g, 12.20 mmol) and DMAP (1.79 g, 14.63 mmol) in THF (40 mL). The mixture was stirred at room temperature for 1 hour. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1) to give 55.3 (1.70 g, 38.3% yield) as a grayish-white solid. LC-MS m / z: 208.1 [M - 156 +1] + LCMS purity (254 nm): 99.32%; t R = 2.174 minutes.

[0555] (4-Chloro-6-((6-methylpyridin-2-yl)amino)pyrimidin-2-yl)carbamate di-tert-butyl ester (55.2). 6-methylpyridin-2-amine (238 mg, 2.20 mmol), Cs₂CO₃ (1.43 g, 4.39 mmol), Xantphos (127 mg, 0.22 mmol), and Pd₂(dba)₃ (201 mg, 0.22 mmol) were added to a stirred solution of 55.3 (800 mg, 2.20 mmol) in dioxane (40 mL). The mixture was stirred at 90 °C for 3 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1) to give 55.2 mg (800 mg, 83.6% yield) as a grayish-white solid. LC-MS m / z: 436.2 [M + 1] + LCMS purity (254 nm): 98.58%; t R = 2.503 minutes.

[0556] 2-((2-amino-6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)benzonitrile (55.1). 2-aminobenzonitrile (136 mg, 1.15 mmol), Cs₂CO₃ (747 mg, 2.29 mmol), Xantphos (69 mg, 0.12 mmol), and Brettphos Pd G₃ (109 mg, 0.12 mmol) were added to a stirred solution of 55.2 (500 mg, 1.15 mmol) in dioxane (30 mL). The mixture was stirred at 100 °C for 2 days under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10 / 1) to give 55.1 mg (200 mg, 54.9% yield) as a light brown solid. LC-MS m / z: 318.3 [M + 1] + LCMS purity (254 nm): 44.16%; t R = 1.830 minutes.

[0557] 2-((2-amino-6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)benzamide (55). K₂CO₃ (131 mg, 0.94 mmol) and H₂O₂ (30% wt, 107 mg, 0.94 mmol) were added to a stirred solution of 55.1 (100 mg, 0.32 mmol) in DMSO (4 mL). The mixture was stirred overnight at room temperature. After the reaction was indicated to be complete by LCMS (monitored by LCMS), the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water (20 mL × 3) and then with brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by reversed-phase preparative HPLC to give 55 (11 mg, 10.4% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 10.69 (s, 1H), 9.35 (s, 1H), 8.40-8.31 (m, 1H), 8.16(br, 1H), 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.66-7.56 (m, 2H), 7.54-7.47 (m,1H), 7.45-7.39 (m, 1H), 6.99-6.91 (m, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 6.10 (s, 2H), 2.37 (s, 3H). LC-MS m / z: 336.3 [M + 1] + HPLC purity (254 nm): 97.69%; t R = 8.525 minutes.

[0558] Example 1bc: Preparation of compound 56.

[0559]

[0560] 6-Chloro-2-methyl- N-(2-(methylthio)phenyl)pyrimidine-4-amine (56.2). 4,6-Dichloro-2-methylpyrimidine (5.85 g, 35.91 mmol), Cs₂CO₃ (23.40 g, 71.82 mmol), Xantphos (521 mg, 0.90 mmol), and Pd₂(dba)₃ (824 mg, 0.90 mmol) were added to a stirred solution of 2-(methylthio)aniline (5.00 g, 35.91 mmol) in dioxane (50 mL). The mixture was stirred at 80 °C for 5 h under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane / EtOAc = 5 / 1) to give 56.2 (2.00 g, 21% yield) as a grayish-white solid. LC-MS m / z: 266.1 [M+ H] + LCMS purity (254 nm): 97.51%; t R = 1.833 minutes.

[0561] 6-Chloro-2-methyl- N -(2-(methanesulfonyl)phenyl)pyrimidine-4-amine (56.1). A potassium persulfate complex salt (1.39 g, 2.26 mmol) was added to a stirred solution of 56.2 (300 mg, 1.13 mmol) in CH₂Cl₂ (8 mL). The mixture was stirred overnight at room temperature. After the initial material was consumed (monitored by LC-MS), the mixture was filtered and the filtrate was concentrated under vacuum to give 56.1 (320 mg, 95% yield) as a grayish-white solid. LC-MS m / z: 298.1 [M +H] + LCMS purity (254 nm): 91.94%; t R = 1.655 minutes.

[0562] 2-Methyl- N 4 -(6-Methylpyridin-2-yl)- N 6-(2-(methanesulfonyl)phenyl)pyrimidine-4,6-diamine (56). 6-methylpyridin-2-amine (109 mg, 1.01 mmol), Cs₂CO₃ (656 mg, 2.02 mmol), X-phos (48 mg, 0.10 mmol), and Brettphos PdG₃ (91 mg, 0.10 mmol) were added to a stirred solution of 56.1 (300 mg, 1.01 mmol) in dioxane (8 mL). The mixture was stirred overnight at 110 °C under nitrogen. After the initial material was consumed (monitored by LCMS), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane / EtOAc = 2 / 3) and reversed-phase preparative HPLC to give 56 as a white solid (196 mg, 53% yield). 1 H NMR (400 MHz, DMSO-) d 6) δ 9.88 (s, 1H), 8.64 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.80-7.72 (m, 1H), 7.62 (s, 1H), 7.55 (dd, J =8.0, 8.0 Hz, 1H), 7.39-7.32 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.77 (d, J =7.6 Hz, 1H), 3.23 (s, 3H), 2.38 (s, 3H), 2.34 (s, 3H). LC-MS m / z: 370.1 [M +H] + HPLC purity (254 nm): 99.70%; t R = 8.599 minutes.

[0563] Example 1bd: Preparation of compound 57.

[0564]

[0565] 6-Chloro- N 4-(2-(methylthio)phenyl)pyrimidine-2,4-diamine (57.2). A suspension of 4,6-dichloropyrimidine-2-amine (800 mg, 4.88 mmol), 2-(methylthio)aniline (814 mg, 5.85 mmol), Pd2(bda)3 (458 mg, 0.50 mmol), Xantphos (579 mg, 1.00 mmol), and Cs2CO3 (3180 mg, 9.76 mmol) in dried 1,4-dioxane (50 mL) was stirred at 80 °C for 3 hours under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 30%) to give 57.2 (190 mg, 14.6% yield) as a white solid. LC-MS m / z: 267.4 [M+ H] + LCMS purity (214 nm): 52.21%; t R = 0.713 minutes.

[0566] 6-Chloro- N 4 -(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine (57.1). Add 57.2 (190 mg, 0.71 mmol) to a solution of CH2Cl2 (10 mL). m -CPBA (579 mg, 2.85 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc / hexane 60%) to give 57.1 mg (110 mg, 51.7% yield) as a colorless oil. LC-MS m / z: 299.1 [M+ H] + LCMS purity (254 nm): 77.02%; t R = 0.618 minutes.

[0567] N 4 -(6-Methylpyridin-2-yl)- N 6-(2-(methylsulfonyl)phenyl)pyrimidine-2,4,6-triamine (57). A suspension of 57.1 (140 mg, 0.47 mmol), 6-methylpyridin-2-amine (62 mg, 0.57 mmol), Pd2(bda)3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.10 mmol), and Cs2CO3 (306 mg, 0.94 mmol) in dried 1,4-dioxane (20 mL) was stirred at 80 °C for 3 h under nitrogen. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (EtOAc / hexane 80%) to give a crude product, which was further purified by reversed-phase preparative HPLC to give 57 (6 mg, 3.4% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.45 (br, 1H), 8.35 (br,1H), 8.09 (d, J = 6.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.71-7.61 (m, 2H),7.54-7.51 (m, 1H), 7.29-7.24 (m, 1H), 6.76-6.74 (m, 2H), 6.19-6.17 (m, 2H), 3.22 (s, 3H), 2.36 (s, 3H). LC-MS m / z: 371.1 [M+ H] + HPLC purity (214 nm): 99.28%; t R = 7.784 minutes.

[0568] Example 1be: Preparation of compound 58.

[0569]

[0570] 2-(6-(4-methylpyrimidin-2-ylamino)pyrimidin-4-ylamino)benzonitrile (58.1). A mixture of 1E (100 mg, 0.47 mmol), BrettPhos Pd G3 (43 mg, 0.047 mmol), 2-chloro-4-methylpyrimidin (60 mg, 0.47 mmol), X-phos (23 mg, 0.048 mmol), and Cs2CO3 (306 mg, 0.94 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 19:1) to give compound 58.1 (110 mg, 76.6% yield) as a yellow solid. LC-MS m / z: 304.2 [M+1] + LCMS purity (214 nm): 48.81%; t R = 1.368 minutes.

[0571] 2-(6-(4-methylpyrimidin-2-ylamino)pyrimidin-4-ylamino)benzamide (58). NaOH (20 mg, 0.49 mmol) and 30% H2O2 (186 mg, 1.64 mmol) were added to a solution of 58.1 (100 mg, 0.33 mmol) in DMSO (5 mL), EtOH (1 mL), and H2O (0.1 mL). The reaction mixture was then stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, it was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 58 as a white solid (11.15 mg, 10.5% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 11.13 (s, 1H), 10.02 (s, 1H), 8.48 (d, J = 5.2 Hz, 1 H), 8.40-8.38 (m, 2 H), 8.23 ​​(s, 1H), 7.94 (s,1H), 7.78 (dd, J = 8.0, 1.2 Hz, 1 H), 7.71 (s, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 6.8 Hz, 1 H), 6.95 (d,J = 4.8 Hz, 1 H), 2.42 (s, 3 H). LC-MSm / z: 322.1[M+1] + HPLC purity (214 nm): 91.45%; t R = 6.772 minutes.

[0572] Example 1bf: Preparation of compound 59.

[0573]

[0574] N 4 -(6-Methylpyridin-2-yl)- N 6 -(2-(methylthio)pyridin-3-yl)pyrimidine-4,6-diamine (59.1). 3-bromo-2-(methylthio)pyridine (300 mg, 1.47 mmol), N 4 A mixture of (6-methylpyridin-2-yl)pyrimidine-4,6-diamine (354 mg, 1.76 mmol), Brettphos-Pd-G3 (136 mg, 0.15 mmol), Xphos (138 mg, 0.29 mmol), and Cs₂CO₃ (1.44 g, 4.41 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (CH₂Cl₂: MeOH = 15: 1) to give 59.1 g (260 mg, 54.5% yield) as a yellow solid. LC-MS m / z: 325.4 [M+1] + Purity (at 214 nm) 91.0%; t R = 1.482 minutes.

[0575] N 4 -(6-Methylpyridin-2-yl)- N 6-(2-(methylsulfonyl)pyridin-3-yl)pyrimidine-4,6-diamine (59). A mixture of 59.1 (210 mg, 0.65 mmol) and 30% H2O2 (3.5 mL) in AcOH (5 mL) and H2O (5 mL) was stirred at 60 °C for 2 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 59 (6 mg, 2.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ9.99 (s, 1H), 9.14 (s, 1H), 8.70 (dd, J = 8.8, 1.2 Hz, 1H), 8.40 (dd, J =4.4, 1.6 Hz, 1H), 8.37 (s, 1H), 7.73 (dd, J = 8.8, 4.4 Hz, 1H), 7.61-7.57 (m,2H), 7.35 (d, J = 8.0, 1H), 6.83 (d, J = 7.6 Hz, 1H), 3.43 (s, 3H), 2.41 (s, 3H). LC-MS m / z: 357.2 [M+ H] + HPLC purity (214 nm): > 99.9%; t R = 7.758 minutes.

[0576] Example 1bg: Preparation of compound 60.

[0577]

[0578] 3-(Methylsulfonyl)pyridine-4-amine (60.3). A mixture of 3-iodo-4-aminopyridine (5.0 g, 22.73 mmol), CH3SOONa (2.30 g, 22.73 mmol), and CuI (4.32 g, 22.73 mmol) in DMSO (50 mL) was stirred overnight at 120 °C under an argon atmosphere. After the reaction was complete, the mixture was filtered and the filtrate was evaporated under reduced pressure to give crude product 60.3 (3.70 g, 94.5% yield) as a yellow solid. LC-MS m / z = 173.2 [M+1] +LCMS purity (254 nm): 61.94%; t R =0.599 minutes.

[0579] 4-Bromo-3-(methylsulfonyl)pyridine (60.2). Slowly add 60.3 (1.0 g, 5.81 mmol) and CuBr (1.25 mg, 8.76 mmol) to a mixture in MeCN (30 mL). t -BuONO (1.2 mL, 11.60 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then stirred overnight at 70 °C. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (MeOH: CH2Cl2 = 1: 9) to give 60.2 (700 mg, 51.1% yield) as a brown solid. LC-MS m / z = 236.2 [M+1] + LCMS purity: 69.20% (214 nm), t R = 1.205 minutes.

[0580] N 4 -(3-(methylsulfonyl)pyridin-4-yl)pyrimidine-4,6-diamine (60.1). A mixture of 60.2 (300 mg, 1.27 mmol), 4,6-diaminopyrimidine (140 mg, 1.28 mmol), Pd2(dba)3 (50 mg, 0.054 mmol), Xantphos (62 mg, 0.108 mmol), and Cs2CO3 (832 mg, 2.56 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL), dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (MeOH:CH₂Cl₂ = 1:9) to give 60.1 (200 mg, 59.3% yield) as a yellow solid. LC-MS m / z = 266.2 [M+1] + LCMS purity: 60.87% (254 nm), t R = 1.107 minutes.

[0581] N 4 -(6-Methylpyridin-2-yl)- N 6-(3-(methylsulfonyl)pyridin-4-yl)pyrimidine-4,6-diamine (60). A mixture of 60.1 (180 mg, 0.68 mmol), 2-bromo-6-methylpyridine (117 mg, 0.68 mmol), Brettphos-Pd-G3 (93 mg, 0.102 mmol), X-phos (97 mg, 0.204 mmol), and Cs2CO3 (663 mg, 2.04 mmol) in 1,4-dioxane (25 mL) was stirred overnight at 110 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 60 (7.18 mg, 3.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 10.17 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.66 (d, J =6.0 Hz, 1H), 8.51 (s, 1H), 8.40 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 3.44 (s, 3H), 2.44 (s, 3H). LC-MS m / z=357.3 [M+1] + HPLC purity: 96.69% (254 nm), t R =7.662 minutes.

[0582] Example 1bh: Preparation of compound 61.

[0583]

[0584] 3-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)isonicotinonitrile (61.1). N 4A mixture of (6-methylpyridin-2-yl)pyrimidine-4,6-diamine (201 mg, 1.0 mmol), 3-bromoisonitrile (275 mg, 1.50 mmol), Brettphos-Pd-G3 (91 mg, 0.10 mmol), Xphos (95 mg, 0.20 mmol), and Cs₂CO₃ (980 mg, 3.0 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 110 °C under an argon atmosphere. After the starting material was consumed, the mixture was filtered to remove solids, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated to give crude product 61.1 (250 mg, 82.4% yield) as an orange solid. LC-MS m / z: 304.2 [M+1] + LCMS purity (214 nm): 41.65%; t R = 1.533 minutes.

[0585] 3-((6-((6-methylpyridin-2-yl)amino)pyrimidin-4-yl)amino)isonicotinamide (61). 30% H2O2 (56 mg, 2.5 mmol) was added to a solution of 61.1 (150 mg, 0.5 mmol) and NaOH (20 mg, 0.5 mmol) in DMSO (6 mL) and EtOH (3 mL), and the reaction mixture was stirred overnight at room temperature. After the starting material was consumed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by reversed-phase preparative HPLC to give 61 as a pale yellow solid (38.63 mg, 24% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.45 (s, 1H), 9.92 (s, 1H), 9.52 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 7.99 (s, 1H), 7.65 (d, J = 4.8 Hz, 1H), 7.61 -7.57 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 6.82 (d, J= 7.2Hz, 1H), 2.42 (s, 3H). LC-MS m / z: 322.3 [M+1] + LCMS purity (214 nm): 99.20%; t R =6.193 minutes.

[0586] Example 1bi: Preparation of compound 62.

[0587]

[0588] 6-Chloro-4-methoxy- N -(3-Methyloxetane-3-yl)pyridine-3-amine (62.1). A mixture of 5-bromo-2-chloro-4-methoxypyridine (400 mg, 1.80 mmol), 3-methyloxetane-3-amine (157 mg, 1.80 mmol), Pd2(dba)3 (165 mg, 0.18 mmol), XantPhos (208 mg, 0.36 mmol), Cs2CO3 (1.17 g, 3.60 mmol), and dioxane (10 mL) was stirred overnight at 110 °C under nitrogen. The reaction mixture was then poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / hexane = 1 / 1) to give 62.1 mg (200 mg, 48.6% yield) as a yellow solid. LC-MS m / z: 229.2 [M+1] + LCMS purity (214 nm): 96.16%; t R = 0.470 minutes.

[0589] N 4 -(5-(3,3-difluorocyclobutylamino)pyridin-2-yl)- N 6 -(3-methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (62). 62.1 (200 mg, 0.87 mmol), N 4 -(3-(methylsulfonyl)pyridin-2-yl)pyrimidine-4,6-diamine (1A, 232 mg, 0.87 mmol), Pd2(dba)3 (80 mg, 0.09 mmol), XantPhos (101 mg, 0.17 mmol), tA mixture of BuONa (168 mg, 1.75 mmol) and dioxane (10 mL) was stirred overnight at 120 °C under nitrogen. The reaction mixture was then poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) and reversed-phase preparative HPLC to give 62 (58.1 mg, 14.8% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.37 (s, 1H), 8.60 (dd, J = 4.8, 2.0 Hz, 2H), 8.33(d, J = 0.8 Hz, 1H), 8.25 (dd, J = 8.0, 2.0 Hz, 1H), 7.32 (s, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (s, 1H), 5.18 (s, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.37 (s, 3H), 1.55 (s, 3H). LC-MS m / z:458.3 [M + H] + LCMS purity (214 nm): > 99.9%; t R = 1.596 minutes. HPLC purity (214 nm): >99.9%; t R = 7.152 minutes.

[0590] Example 1bj: Preparation of compound 63.

[0591]

[0592] 6-Chloro- N-(4-Methylpyridin-2-yl)pyrimidin-4-amine (63.1). 4,6-Dichloropyrimidine (1.38 g, 9.25 mmol), Cs₂CO₃ (6.03 g, 18.49 mmol), Pd₂(dba)₃ (0.42 g, 0.46 mmol), and Xantphos (0.54 g, 0.92 mmol) ...

Claims

1. A compound of formula I: , in X 1 Selected from N and CR 1 , Where R 1 It is a member selected from the following: H, halogen, substituted or unsubstituted straight-chain or branched C1-C6 alkyl and substituted or unsubstituted straight-chain or branched C1-C6 alkoxy; X and X 2 Independently selected from N and CH; R 2 Members selected from the following: , in R 5 It is a C1-C6 alkyl group; and R 5' R 6 and R 6' It is a member independently selected from H and C1-C6 alkyl groups; X 3 Selected from N and CR 7 ; X 4 Selected from N and CR 8 ; X 5 Selected from N and CR 9 ; R 7 R 8 R 9 and R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 aminoalkyl groups, wherein R 7 and R 8 Or R 8 and R 9 It is optionally linked together with the carbon atom to form a ring selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl. in When R 7 and R 8 and R 8 and R 9 When none of them are connected together with the carbon they are attached to to form a ring, no more than one of them is selected from R. 7 R 8 and R 9 The member is not H; R 9 The following are not included: , Where z is 0 or 1; and When at least one is selected from R 7 R 8 and R 9 When the member is Me, R 2 yes: 。 2. The compound according to claim 1, wherein X 3 X 4 and X 5 CR 7 CR 8 and CR 9 .

3. The compound according to any one of the preceding claims, wherein CR 7 CR 8 and CR 9 At least one of them includes a ring system selected from monocyclic or bicyclic ring systems having one or two heteroatoms and four, five, six or seven carbon atoms.

4. The compound of claim 3, wherein the ring system comprises oxygen and nitrogen.

5. The compound according to any one of the preceding claims, wherein R 7 R 8 and R 9 Independently selected from H, , in In Formula II or Formula III, one or more carbon atoms of the ring are optionally substituted by members independently selected from halogens and substituted or unsubstituted alkyl groups; a is selected from integers 0 and 1; R 10 and R 11 Independently selected from H, halogens, and substituted or unsubstituted C1-C6 alkyl groups; c and d are independently chosen from the integers 0, 1, 2, 3 and 4, provided that the sum c + d is chosen from the integers 3, 4, 5 and 6. A is a cyclic system selected from substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocyclic alkyl groups; and X 6 Selected from O, NR 12 and CR 12 R 13 ,in R 12 and R 13 Independently selected from H and substituted or unsubstituted alkyl groups.

6. The compound according to any one of the preceding claims, wherein the compound is based on Formula IV: , in Cyclic system B is a cycloalkyl group partially substituted by at least one selected from formulas II and III.

7. The compound according to claim 6, wherein ring system B is selected from substituted or unsubstituted cyclopentylamine and substituted or unsubstituted cyclohexylamine.

8. The compound according to any one of the preceding claims, wherein R 7 R 8 and R 9 Selected independently from: 。 9. The compound according to any one of the preceding claims, wherein R 2 It is S(O)2Me.

10. The compound according to any one of the preceding claims, wherein X is N; X 1 and X 2 It is CH; and X 3 and X 4 CR 7 and CR 8 .

11. The compound according to any one of the preceding claims, wherein the compound is based on formula V: 。 12. A compound according to formula VI: , in X is selected from N and CH; R 2 Selected from: , in R 5 It is a C1-C6 alkyl group; and R 5' R 6 and R 6' It is a member independently selected from H and C1-C6 alkyl groups; X 3 and X 4 CR 7 and CR 8 , in R 7 and R 8 Independently selected from H, and , in In Formula II or Formula III, one or more carbon atoms of the ring are optionally substituted by members independently selected from halogens and substituted or unsubstituted alkyl groups; a is selected from integers 0 and 1; R 10 and R 11 Independently selected from H, halogens, and substituted or unsubstituted C1-C6 alkyl groups; c and d are independently chosen from the integers 0, 1, 2, 3 and 4, provided that the sum c + d is chosen from the integers 3, 4, 5 and 6. A is a cyclic system selected from substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocyclic alkyl groups; and X 6 Selected from O, NR 12 and CR 12 R 13 ,in R 12 and R 13 Independently selected from H and substituted or unsubstituted alkyl groups.

13. The compound according to claim 12, wherein R 10 Or R 11 One of them is CF3.

14. The compound according to any one of the preceding claims, wherein R 1 It is F.

15. The compound according to claim 12, wherein R 9 The following are not included: , Where z is selected from 0 and 1.

16. Use of a compound, a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of the preceding claims, for the preparation of a medicament for the treatment or prevention of TYK2-mediated diseases or symptoms in a subject of need.

17. A pharmaceutical formulation comprising a compound according to any one of the preceding claims, a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical formulation comprising a compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof, a tautomer, a solvate or hydrate thereof, and a pharmaceutically acceptable carrier, said formulation being prepared for parenteral or oral administration.

19. A pharmaceutical formulation comprising a compound according to any one of the preceding claims, a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier, said formulation being formulated for intravenous, subcutaneous or intraperitoneal injection.

20. A method for treating a subject with a TYK2-mediated disease, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, according to any one of claims 1 to 13, wherein the autoimmune disease is sensitive to treatment with a TYK2 inhibitor.

21. A method of treating an autoimmune disease or inflammatory disease of a subject by inhibiting TYK2 kinase in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, according to any one of claims 1 to 15, wherein the autoimmune disease is sensitive to treatment with a TYK2 inhibitor.

22. The method according to any one of claims 20 to 21, wherein the disease is selected from the group consisting of: psoriasis, plaque psoriasis, psoriatic arthritis, and irritable bowel disease (Crohn's disease, ulcerative colitis).

23. A method for inhibiting TYK2, the method comprising contacting the TYK2 with an effective amount of the compound according to any one of claims 1 to 15.

24. The method of claim 23, wherein the inhibition of the TYK2 kinase occurs in vivo or in vitro.

25. A compound having the formula in Table 1.

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