Chemical compounds

Abstract

The present disclosure describes novel compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their medical uses. The compounds of the present disclosure have activity as dual modulators of Janus kinase (JAK), either alone or in combination with one or more additional mechanisms involving tyrosine kinases, such as TrkA or Syk, and PDE4, and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions in which modulation of JAK is desirable. Also described herein are methods for treating inflammation, autoimmune diseases, cancer, and other conditions susceptible to inhibition of JAK and PDE4 by administering the compounds described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 870537, filed July 3, 2019, U.S. Provisional Patent Application No. 62 / 916697, filed October 17, 2019, U.S. Provisional Patent Application No. 62 / 916700, filed October 17, 2019, U.S. Provisional Patent Application No. 62 / 949280, filed December 17, 2019, and U.S. Provisional Patent Application No. 62 / 949301, filed December 17, 2019, each of which is incorporated by reference herein in its entirety.

[0002] The present disclosure describes novel boron-containing compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and medical uses thereof. In one embodiment, the compounds of the present disclosure have activity as inhibitors of Janus kinase (JAK), alone or in combination with at least one additional mechanism of inhibition of another tyrosine kinase, including, for example, a tropomyosin receptor kinase A (TrkA) inhibitor or a spleen tyrosine kinase (Syk) inhibitor, and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions in which modulation of JAK, optionally in conjunction with one or more other mechanisms of inhibition, including tyrosine kinases including TrkA and Syk, is desirable. Also described herein are methods of treating inflammation, autoimmune diseases, cancer, and other conditions amenable to inhibition of JAK, optionally in conjunction with one or more other mechanisms of inhibition, including tyrosine kinases including TrkA and Syk, by administering the compounds of the present disclosure. In one embodiment, the compounds of the present disclosure have activity as dual inhibitors of Janus kinase (JAK) and phosphodiesterase-4 (PDE4), and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions in which modulation of JAK in conjunction with PDE4 is desirable. Also described herein are methods for treating inflammation, autoimmune diseases, cancer, and other conditions susceptible to inhibition of JAK in conjunction with PDE4 by administering the compounds of the present disclosure. Similarly, if the compounds of the present disclosure have additional inhibitory mechanisms, the present disclosure includes methods for treating other conditions susceptible to such inhibition. [Background technology]

[0003] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease affecting approximately 20% of children and up to 10% of adults. It poses a significant economic and societal burden due to direct medical costs and lost productivity in individuals with AD. The burden of AD appears to be primarily related to limited treatment options. Furthermore, no standard of care exists according to AD treatment guidelines, and treatment can be tailored to individual needs. Local interventions are the mainstay of AD therapy. To date, topical corticosteroids have been the primary treatment. However, their use can be limited by potential local and systemic adverse effects. Topical calcineurin inhibitors are classified as second-line anti-inflammatory therapies for AD, with advantages in long-term maintenance and specific site application. Topical calcineurin inhibitors inhibit calcineurin-dependent T cell activation, but a black box warning regarding the potential for malignant neoplasm progression with the use of topical calcineurin inhibitors reduces patient adherence to treatment.

[0004] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine / threonine kinases. Inappropriate kinase activity resulting from mutation, overexpression, or improper regulation, dysregulation, or deregulation, as well as overproduction or underproduction of growth factors or cytokines, has been implicated in numerous diseases, including, but not limited to, cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders, such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell motility, which have been implicated in the aforementioned and related diseases. Therefore, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention.

[0005] In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2) plays a central role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology, 2004, 5, 253). Upon binding to their receptors, cytokines activate JAKs, which then phosphorylate cytokine receptors, thereby creating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family, which ultimately result in gene expression and stimulate biological responses, such as itch signals. Activation of the JAK-STAT pathway also leads to several other ancillary biological activities that contribute to inflammatory and pruritic processes, which contribute to acute allergies in animals but may also exacerbate clinical symptoms and contribute to chronic allergies. Selectivity between JAK subtypes may prove useful in the treatment of certain diseases or disorders.

[0006] The TrkA family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) are involved in various intracellular signaling pathways implicated in psoriasis and related pruritus, pain signaling, and cancer. TrkA receptor activity is initiated upon binding of a family of neurotrophin ligands, including nerve growth factor (NGF) (Roblin et al., Acta Derm Venereol, 2015, 95, 542). Increased expression of NGF and TrkA in the epidermis has been associated with the formation of psoriatic lesions. Furthermore, NGF stimulates the expression and sensitivity of its co-receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), and NGF-TrkA-TRPV1 signaling is thought to be involved in these dermatological conditions.

[0007] The phosphodiesterase (PDE) family of enzymes plays a role in the degradation of cyclic adenosine monophosphate, an important intracellular second messenger at the center of multiple signaling pathways. PDE inhibitors have been developed and evaluated for the treatment of various conditions, including asthma, chronic obstructive pulmonary disease, erectile dysfunction, Alzheimer's disease, and chronic inflammatory skin diseases. Phosphodiesterase type 4 inhibitors, commonly referred to as PDE4 inhibitors, are drugs used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). The PDE4 family of enzymes is the most prevalent PDE in immune cells and is primarily responsible for the hydrolysis of cAMP both within immune cells and within cells of the central nervous system.

[0008] As mentioned above, phosphodiesterase-4 (PDE4) is mainly present in immune cells, epithelial cells, and brain cells, and is an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects due to the increase in cyclic adenosine monophosphate (cAMP) levels and subsequent regulation of a wide range of genes and proteins. Therefore, PDE4 may be a promising therapeutic target for the treatment of various pulmonary diseases, dermatological diseases, and serious neurological diseases. Many PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole are indicated for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. However, the dramatic effects of drugs may be accompanied by adverse effects such as nausea, vomiting, and gastrointestinal reactions.

[0009] In addition to dermatological usefulness, PDE4 inhibitors can have potential as treatment for a diverse group of different diseases, including central nervous system disorders, such as major depressive disorder, depression, anxiety disorder, schizophrenia, Parkinson's disease, Alzheimer's disease, multiple sclerosis, attention deficit hyperactivity disorder, Huntington's disease, stroke, autism, and inflammatory conditions, such as chronic obstructive pulmonary disease (COPD), asthma, and rheumatoid arthritis.PDE4 inhibition is also known to reduce the ethanol seeking and consumption in rats, and can be useful in treating alcohol dependence.

[0010] Inflammation underlies the pathogenesis of various human diseases, including infectious diseases, immune-mediated disorders, metabolic disorders, neurodegeneration, and cancer. Inflammatory diseases affect a significant proportion of the global population and have highly complex pathogenic mechanisms (Kazatchkine and Kaveri, 2001). To date, many therapeutic strategies have emerged for the treatment of inflammatory diseases (Tabas and Glass, 2013; Siebert et al., 2015). Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have made significant contributions to inflammatory intervention, but serious long-term adverse effects and multiple manifestations of disease have led some patients to abandon these treatment options (Hart and Huskisson, 1984). Therefore, there remains a great need for the discovery of novel therapeutic agents to control inflammation with a broad anti-inflammatory spectrum (Uguccioni et al., 2017). Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) function as fundamental second messengers in the regulation of multiple cellular metabolism. Phosphodiesterases (PDEs) consist of 11 families (PDE1-PDE11) and are available for the degradation of cyclic nucleotides (Kumar et al., 2013). The distribution of PDE subfamilies is diverse in different cells and tissues, which may provide substantial support for their pharmacological studies in the fields of inflammation, cognition, adipogenesis, proliferation, apoptosis, and differentiation. The cAMP-specific PDE4 is highly expressed in the brain, cardiovascular tissues, smooth muscle, keratinocytes, and immune cells (including T cells, monocytes, macrophages, neutrophils, dendritic cells, and eosinophils) (Chiricozzi et al., 2016). Inhibition of PDE4 increases intracellular levels of cAMP, which may subsequently modulate inflammatory responses and maintain immune balance (Maurice et al., 2014). Targeting PDE4 has been proven to be an effective therapeutic strategy for inflammatory conditions, including asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis (AD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, and neuroinflammation.Several products, such as roflumilast, apremilast, and crisaborole, have been approved successively for the treatment of inflammatory airway or skin diseases. Furthermore, a series of novel PDE4 inhibitors have also been developed for the regulation of inflammation and have shown satisfactory therapeutic effects. Increasing evidence demonstrates that patients suffering from inflammatory diseases exhibit higher PDE4 expression than healthy individuals (Schafer et al., 2016). There are four subtypes of PDE4, namely, PDE4A-PDE4D, which are highly specific for cAMP degradation but not for cGMP degradation. Inhibition of PDE4 leads to the accumulation of intracellular cAMP, which subsequently activates PKA, cyclic nucleotide-gated ion channels, and Epac1 / 2. These are involved in the regulation of pro- and anti-inflammatory cytokine synthesis, T cell activation, neutrophil degranulation, antigen presentation, and epithelial integrity through the initiation of multiple downstream factors. Release of the catalytic subunit from the regulatory subunit upon PKA activation subsequently increases the phosphorylation of cAMP response element binding protein (CREB), activating transcription factor 1 (ATF-1), and cAMP response element modulator (CREM), and recruits CREB-binding protein (CBP) or the homologous protein p300, which can lead to a reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines (Schafer, 2012).Previous studies have demonstrated that the transcriptional activity of classical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) can be stimulated upon phosphorylation of p65 at Ser276 by PKA (Christian et al., 2016). CBP / p300 is closely associated with NF-kB p65, and PKA activation can regulate the transcriptional activity of NF-kB through modulation of its interaction with CBP / p300 without IkBa degradation or NF-kB DNA binding activity, which leads to downregulation of inflammatory responses ( Zhong et al., 1998 ; Schafer, 2012 ).Additionally, PKA activation may interfere with B-cell lymphoma 6 (Bcl-6)-mediated synthesis of proinflammatory cytokines and immune cell proliferation (Page, 2014; Hernandez-Florez and Valor, 2016). Activation of Epac1 / 2 as a result of cAMP elevation serves as a promising alternative mechanism for targeting inflammation and proliferation (Lehrke et al., 2015). The spatial and temporal compartmentalization of intracellular cAMP contributes to the transcription factor Epac signalosome, a small GTPase (Rap1), which is beneficial for optimizing the treatment of inflammatory airway diseases, renal failure, vasculature disorders, and neuroinflammation (Schmidt et al., 2013). Because cAMP plays a role in diverse physiological metabolism in various cell types, cAMP elevation after PDE4 inhibition is closely related to the suppression of immune responses or the overactivity of intermediates. Accumulating research has shown that PDE4 inhibition may modulate both innate and adaptive responses. PDE4 inhibition has demonstrated regulatory activity in macrophages, neutrophils, monocytes, and dendritic cells (Crilly et al., 2011; Schafer, 2012). In addition, PDE4 inhibition has shown a significant effect on T cell receptor (TCR)-induced activation of T cells, manifested as a reduction in cytokine and chemokine release from T helper 1 (Th1), Th2, and Th17 cells (Sakkas et al., 2017), whereas PDE4 inhibition may have little effect on B cell phenotype and function (Schafer et al., 2014). Furthermore, elevation of cAMP in keratinocytes and epithelial cells may also inhibit inflammatory responses and regulate cell growth and barrier function (Page, 2014). See Li H, et al., Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 9:1048 (2018), which cites subreferences therein, all of which are incorporated by reference herein for their background biological teachings.

[0011] Therefore, PDE4 is an anti-inflammatory target upstream of JAK, which regulates cytokines through the JAK-STATS pathway.Therefore, PDE4 inhibitors have complementary biological effects to JAK inhibitors.The combination of the inhibitory activity of both JAK and PDE4 in one molecule provides a drug with a unique and attractive anti-inflammatory profile and spectrum for the treatment of inflammatory diseases with highly complex pathogenic mechanisms.So far, such a drug has not been reported in the literature.

[0012] The central role played by Syk (spleen tyrosine kinase) in the immune system in mediating inflammatory responses, coupled with its more recently identified association with malignancies, has made this kinase a popular target for the development of therapeutic agents for the treatment of multiple disease states, ranging from arthritis and asthma to leukemia and lymphoma. Syk is a cytoplasmic protein tyrosine kinase well-known for its ability to link immune cell receptors to intracellular signaling pathways that regulate cellular responses to extracellular antigens and antigen-immunoglobulin complexes, which are particularly important for the initiation of inflammatory responses. Therefore, Syk is an attractive target for therapeutic kinase inhibitors designed to ameliorate the symptoms and consequences of acute and chronic inflammation. Given SYK's central role in transmitting activation signals in B cells, inhibition of this tyrosine kinase may aid in the treatment of B cell malignancies and autoimmune diseases.

[0013] Syk inhibition has been proposed as a treatment for both lymphoma and chronic lymphocytic leukemia. Syk inhibitors, including cerdulatinib and entospletinib, are in clinical development. Other inhibitors of B-cell receptor (BCR) signaling, including ibrutinib (PCI-32765), which inhibits BTK, and idelalisib (a PI3K inhibitor—CAL-101 / GS-1101), have also shown activity in the disease. Fostamatinib (R788), an orally active SYK inhibitor, is being developed for the treatment of rheumatoid arthritis. Nilvadipine, a Syk inhibitor, has been shown to modulate amyloid-β production and tau phosphorylation and has therefore been proposed as a treatment for Alzheimer's disease.

[0014] Thus, JAK inhibitors, with or without additional tyrosine kinase activity and with or without a dual PDE4 inhibition mechanism, may provide novel therapeutic strategies for a variety of immune and inflammatory diseases, including rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), psoriasis, alopecia areata, atopic dermatitis, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer. See Schwartz et al., JAK inhibition as a therapeutic strategy for immune and inflammatory diseases, Nat Rev Drug Discov., 2017 Dec 28., 17(1):78, which is incorporated herein by reference for a rationale for targeting JAK.

[0015] Psoriasis and psoriatic arthritis are associated with abnormal inflammation and the production of pro-inflammatory mediators.Psoriasis and psoriatic arthritis are inflammatory diseases that share common characteristics and share common immunological mechanisms.Psoriasis is a systemic disease, meaning that it primarily affects the skin, but up to 40% of individuals with psoriasis may progress to psoriatic arthritis.Psoriatic arthritis typically affects peripheral joints, and sometimes affects the spine and sacroiliac joint area.Enthesitis, dactylitis, and nail changes, such as pitting and discoloration, are also common signs of psoriatic disease in patients with joint involvement. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Kisseleva et al, Gene, 2002, 285, 1 [Non-patent document 2] Yamaoka et al. Genome Biology 2004, 5, 253 [Non-patent document 3] Roblin et al., Acta Derm Venereol, 2015, 95, 542 [Non-patent document 4] Kazatchkine and Kaveri, 2001 [Non-Patent Document 5] Tabas and Glass, 2013 [Non-patent document 6] Siebert et al., 2015 [Non-Patent Document 7] Hart and Huskisson, 1984 [Non-patent document 8] Uguccioni et al., 2017 [Non-Patent Document 9] Kumar et al., 2013 [Non-Patent Document 10] Chiricozzi et al., 2016 [Non-Patent Document 11] Maurice et al., 2014 [Non-Patent Document 12] Schafer et al., 2016 [Non-Patent Document 13] Schafer, 2012 [Non-Patent Document 14] Christian et al., 2016 [Non-Patent Document 15] Zhong et al., 1998 [Non-Patent Document 16] Page, 2014 [Non-Patent Document 17] Hernandez-Florez and Valor, 2016 [Non-Patent Document 18] Lehrke et al., 2015 [Non-Patent Document 19] Schmidt et al., 2013 [Non-Patent Document 20] Crilly et al., 2011 [Non-Patent Document 21] Sakkas et al., 2017 [Non-Patent Document 22] Schafer et al., 2014 [Non-Patent Document 23] Li H, et al., Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 9:1048 (2018) [Non-Patent Document 24] Schwartz et al., JAK inhibition as a therapeutic strategy for immune and inflammatory diseases, Nat Rev Drug Discov., 2017 Dec 28., 17(1):78 [Summary of the Invention] [Problem to be solved by the invention]

[0017] Therefore, there is a need for therapeutic methods that target and modulate JAK alone, or JAK and one or more of the tyrosine kinases, including additional mechanisms, such as inhibition of TrkA and Syk, and optionally in combination with PDE4, for the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions for which modulation is desirable.In addition, compounds with additional activity that modulates one of the additional tyrosine kinases, including inhibition of tropomyosin receptor kinase A (TrkA) or spleen tyrosine kinase (Syk), are also desirable. [Means for solving the problem]

[0018] One embodiment of the present disclosure is a compound of formula (I): [ka] [In the formula, A is, [ka] is selected from the group consisting of X is selected from the group consisting of NH, O, and S; If present, R 1 teeth, selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl), and O(C1-C3 haloalkyl); If present, each R 1bare independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl), and O(C1-C3 haloalkyl); If present, R 2 and R 3 each is independently selected from the group consisting of C1-C3 alkyl, C2-C3 alkenyl, and C2-C3 alkynyl, and when present, R 2 and R 3 together form a three-membered cycloalkyl ring, If present, R 2a and R 3a are independently selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C3 alkenyl, and C2-C3 alkynyl; 2a and R 3a together form a three-membered cycloalkyl ring, R B is selected from the group consisting of substituted phenyl, unsubstituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkenyl, substituted C1-C6 alkenyl, unsubstituted C1-C6 alkynyl, substituted C1-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, and unsubstituted arylalkyl, substituted arylalkyl; R C is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -CHO, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, and partially or fully halogenated cyclopropyl. or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0019] In one aspect, when present, R 1is selected from the group consisting of hydrogen and fluorine, or is selected from the group consisting of chlorine, bromine, iodine, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl), and O(C1-C3 haloalkyl).

[0020] One embodiment of the present disclosure is a compound of formula (IA): [ka] [In the formula, X is selected from the group consisting of NH, O, and S; R 1 is selected from the group consisting of hydrogen and fluorine; R B is selected from the group consisting of substituted phenyl, unsubstituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkenyl, substituted C1-C6 alkenyl, unsubstituted C1-C6 alkynyl, substituted C1-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted arylalkyl, and substituted arylalkyl; R C is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -CHO, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, and partially or fully halogenated cyclopropyl] or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0021] In one aspect, R C is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. C is selected from the group consisting of CH3, CF3, F, and Cl. In one aspect, X is NH. In one aspect, R Bis selected from the group consisting of unsubstituted phenyl, substituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted arylalkyl, and substituted arylalkyl. B is selected from the group consisting of unsubstituted phenyl, substituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted benzyl, and substituted benzyl. In one aspect, each of the substituted phenyl, substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, or substituted benzyl is independently substituted with one or more substituents selected from the group consisting of —C(O)O(C1-C3), OH, CH2OH, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, halogen, O(C1-C3 alkyl), and O(C1-C3 haloalkyl). In one aspect, R B is selected from the group consisting of unsubstituted C1-C6 alkyl, and unsubstituted C3-C6 cycloalkyl. 1 is hydrogen. In one aspect, R 1 is fluorine.

[0022] One embodiment of the present disclosure comprises: [ka] a compound selected from the group consisting of TIFF0007597781000005.tif202163TIFF0007597781000006.tif212160TIFF0007597781000007.tif216161TIFF0007597781000008.tif201159TIFF0007597781000009.tif226161TIFF0007597781000010.tif229162TIFF0007597781000011.tif133165 or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0023] One embodiment of the present disclosure comprises: [ka] a compound selected from the group consisting of: TIFF0007597781000013.tif207160TIFF0007597781000014.tif229158TIFF0007597781000015.tif181163; or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0024] One embodiment of the present disclosure is a compound of formula (IB): [ka] [In the formula, A is, [ka] is selected from the group consisting of X is selected from the group consisting of NH, O, and S; R B is selected from the group consisting of unsubstituted phenyl, substituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, substituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, substituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, and unsubstituted arylalkyl, substituted arylalkyl; R C is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, and partially or fully halogenated cyclopropyl; Each R 1when present, is selected from the group consisting of chlorine, bromine, iodine, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl), and O(C1-C3 haloalkyl); Each R 1b if present, is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl), and O(C1-C3 haloalkyl); R 2 and R 3 each, when present, is independently selected from the group consisting of C1-C3 alkyl, C2-C3 alkenyl, and C2-C3 alkynyl; 2 and R 3 together form a three-membered cycloalkyl ring, R 2a and R 3a each, when present, is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C3 alkenyl, and C2-C3 alkynyl; R 2a and R 3a together form a three-membered cycloalkyl ring] or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0025] In one aspect, A is [ka] is selected from the group consisting of:

[0026] In one aspect, A is [ka] is selected from the group consisting of:

[0027] In one aspect, when present, R 1 is selected from the group consisting of chlorine, bromine, iodine, C1-C3 alkyl, and C1-C3 haloalkyl. 1b is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, and C1-C3 haloalkyl. 1b is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0028] In one aspect, when present, R 2 and R 3 Each of A is methyl. [ka] is.

[0029] In one aspect, X is NH. In one aspect, R B is unsubstituted phenyl, substituted phenyl, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, or substituted C3-C6 cycloalkyl. B is unsubstituted phenyl, unsubstituted C1-C6 alkyl, or unsubstituted C3-C6 cycloalkyl. B is unsubstituted C1-C6 alkyl or unsubstituted C3-C6 cycloalkyl. B is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, substituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, substituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, or substituted C3-C6 cycloalkyl. In one aspect, the substitution is selected from one or more of CH2OH, C1-C3 alkyl, C1-C3 haloalkyl, and SO2(C1-C3 alkyl). In one aspect, R Cis selected from the group consisting of halogen, C1-C3 alkyl, and partially or fully halogenated C1-C3 alkyl. C is selected from the group consisting of CH3, CF3, F, and Cl.

[0030] One embodiment of the present disclosure comprises: [ka] a compound selected from the group consisting of: TIFF0007597781000022.tif198158TIFF0007597781000023.tif199157TIFF0007597781000024.tif216161TIFF0007597781000025.tif37159; or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharmaceutically acceptable salt thereof.

[0031] One embodiment of the present disclosure comprises: [ka] The compound includes a compound selected from the group consisting of TIFF0007597781000027.tif200160TIFF0007597781000028.tif164164.

[0032] One embodiment of the present disclosure includes a method for treating a patient with a disease or disorder susceptible to modulation of one or more of (i) JAK and (ii) JAK and an additional enzyme, comprising administering a therapeutically effective amount of a compound of the present disclosure. In one aspect, the additional enzyme is also a tyrosine kinase. In one aspect, the additional tyrosine kinase is one or more of TrkA and Syk. In one aspect, the additional enzyme is PDE4.

[0033] One embodiment of the present invention includes a method for treating a patient with a disease or disorder susceptible to modulation of JAK, either alone or in combination with dual or multiple modulation by one or more additional enzyme inhibitors, comprising administering a therapeutically effective amount of a compound of the present disclosure. In one aspect, the additional enzyme inhibitor is a tyrosine kinase inhibitor. In one aspect, the additional tyrosine kinase inhibitor inhibits one or more of TrkA and Syk. In one aspect, the additional enzyme inhibitor is a PDE4 inhibitor. In one embodiment, the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behçet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer. In one embodiment, the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis. In one embodiment, the compound is administered in an amount that perturbs an immunomodulatory pathway in the cell. In one embodiment, the perturbation results in an effect on the JAK-STAT pathway.

[0034] One embodiment of the present invention includes a method for inhibiting JAK in mammalian cells, alone or in combination with the inhibition of one or more additional mechanisms, comprising contacting mammalian cells with a compound of the present disclosure. In one aspect, the additional mechanism is also the inhibition of tyrosine kinase. In one aspect, the tyrosine kinase is one or more of TrkA and Syk. In one aspect, the additional mechanism is the inhibition of PDE4.

[0035] One embodiment of the present invention includes a method of treating a patient having a disease or disorder susceptible to modulation of JAK, either alone or in dual modulation with PDE4, comprising administering a therapeutically effective amount of a compound of the present disclosure. In one embodiment, the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behçet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer. In one embodiment, the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis. In one embodiment, the compound is administered in an amount that perturbs an immunomodulatory pathway in the cell. In one embodiment, the perturbation results in an effect on the JAK-STAT pathway.

[0036] One embodiment of the present invention includes a method of inhibiting JAK in combination with PDE4 in a mammalian cell, comprising contacting the mammalian cell with a compound of the present disclosure. In one aspect, the JAK is JAK-1. In one aspect, the inhibition is selective for JAK-1. In one aspect, the mammalian cell is a cell from a subject with an inflammatory condition. In one aspect, the method further includes modulating one or more of TrkA and Syk.

[0037] One embodiment of the present invention includes a method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis. In one aspect, the subject is a mammal. In one aspect, the mammal is selected from a human, a livestock mammal, a domestic mammal, or a companion mammal. In one aspect, the mammal is a human. In one aspect, the mammal is one or more of a cow, sheep, goat, llama, alpaca, pig, horse, donkey, dog, and cat.

[0038] One embodiment of the present invention includes a composition comprising a compound of the present disclosure and a pharmaceutically or veterinarily acceptable carrier.

[0039] One embodiment of the present invention includes a combination comprising a compound of the present disclosure and one or more other pharmaceutically or veterinarily active substances.

[0040] One embodiment of the present invention includes a compound of the present disclosure for use in medicine.

[0041] One embodiment of the present invention includes a compound of the present disclosure for the manufacture of a medicament for the treatment of one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

[0042] One embodiment of the present invention includes the use of a compound of the present disclosure for the treatment of one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

[0043] Surprisingly, when structural modifications are made to the core pyrimidine shown, including the number and arrangement of one or more nitrogen atoms in its ring, but other variables are consistent with the compounds of the present disclosure, the modified core is characterized by substantially different biological activity.Such compounds appear to have no JAK activity or have significantly reduced JAK activity compared with the compounds of the present disclosure.However, interestingly, such compounds maintain the level of PDE4 activity.

[0044] In addition, unexpectedly, when the compound is the compound of formula (IA) and the NH linker shown is alkylated, for example, N-CH3, the compound does not have JAK activity or has significantly reduced JAK activity.In addition, the alkylated NH linker also reduces the PDE4 activity of the compound.A non-limiting hypothesis is that the alkylation of NH group abolishes hydrogen bonding, thereby reducing its binding affinity to JAK1.Examples include the comparative compounds A and B described herein.

[0045] Additionally, unexpectedly, when the compound is of formula (I) and X is N-alkyl, e.g., N-CH3, the compound has significantly reduced JAK activity. A non-limiting hypothesis is that NH is a key pharmacophore that provides a critical hydrogen bond donor to the hinge domain of the kinase.

[0046] Additionally, unexpectedly, when the regiochemistry of (IA) is modified as shown in the compound of formula (III) shown below, JAK and PDE4 activity is decreased, as exemplified in the data shown below:

[0047] [ka] TIFF0007597781000030.tif181160

[0048] One or more aspects and embodiments may be combined in different embodiments even if not specifically stated, i.e., all aspects and embodiments may be combined in any way or combination. [Brief explanation of the drawings]

[0049] [Figure 1-1] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-2] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-3] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-4] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-5] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-6] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-7] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-8] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-9] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-10] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-11] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-12]1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-13] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-14] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-15] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-16] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-17] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-18] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-19] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 1-20] 1 is a table showing the results of biological testing for compounds of the present disclosure, as described in more detail herein. [Figure 2] 1 shows the results of a docking model with a compound of the present disclosure in the active site of JAK1, showing NH(X) forming hydrogen bonds with Gly1020 and Asp1021 through crystal water. Alkylation of the NH group abolishes the hydrogen bond and reduces its binding affinity to JAK1. DETAILED DESCRIPTION OF THE INVENTION

[0050] definition Any reference herein to "one embodiment" or "an embodiment" or "another embodiment" or similar phrases means that a particular feature, structure, characteristic, operation, or function described is included in at least one embodiment. Thus, any appearance of the phrase "in one embodiment" or "in an embodiment" herein does not necessarily refer to the same embodiment. Furthermore, particular features, structures, characteristics, operations, or functions may be combined in any suitable manner in one or more embodiments, and embodiments of the described subject matter can and are intended to cover modifications and variations of the described embodiments. Particular aspects should be treated in a similar manner when used herein.

[0051] The terms "at least one," "one or more," and "and / or" are open-ended expressions that are both conjunctive and disjunctive in operation. For example, the expressions "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C," and "A, B, and / or C" each mean A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together.

[0052] The term "a" or "an" entity refers to one or more of that entity. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the terms "comprising," "including," and "having" can be used interchangeably.

[0053] The compounds of the present disclosure include those generally described and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, "Handbook of Chemistry and Physics", 75th Ed., CRC Press, New York, NY (1995). In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, CA (1999), and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York, NY (2001), the entire contents of which are hereby incorporated by reference herein.

[0054] When referring to the compounds disclosed herein, the following terms have the following meanings unless otherwise indicated. The following definitions are intended to clarify the defined terms, but are not intended to be limiting. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms are used within their generally accepted meanings.

[0055] As used herein, "alkyl" refers to a substituted or unsubstituted monovalent saturated aliphatic hydrocarbyl group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and preferably 1 to 6 carbon atoms. The hydrocarbon chain can be either straight or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. Similarly, an "alkenyl" group refers to an alkyl group having one or more double bonds within the chain, and an "alkynyl" group refers to an alkyl group having one or more triple bonds within the chain. An alkyl group can be substituted or unsubstituted. An alkenyl group can be substituted or unsubstituted. An alkynyl group can be substituted or unsubstituted.

[0056] As used herein, "aryl" refers to a substituted or unsubstituted carbocyclic aromatic ring system, either pendent or fused, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indane, or biphenyl. A preferred aryl is phenyl.

[0057] As used herein, "cycloalkyl" refers to a substituted or unsubstituted, unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and partially saturated versions thereof, such as cyclohexenyl and cyclohexadienyl. Cycloalkyl groups can be substituted or unsubstituted.

[0058] As used herein, "halogen" or "halo" refers to a halogen. In some embodiments, the halogen is preferably Cl (chlorine) or F (fluorine).

[0059] As used herein, "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and preferably 1 to 6 carbon atoms, in which at least one hydrogen atom has been replaced with a halogen, including, but not limited to, perhalo groups in which all hydrogen atoms have been replaced with halogen atoms. A preferred perhalo group is a perfluoro group. The haloalkyl chain can be either linear or branched. Exemplary haloalkyl groups include trifluoromethyl, trichloromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a "haloalkenyl" group refers to a haloalkyl group having one or more double bonds within the chain, and a "haloalkynyl" group refers to a haloalkyl group having one or more triple bonds within the chain.

[0060] As used herein, the term "heterocyclyl" refers to a substituted or unsubstituted unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms in which one or more carbon atoms are replaced by a heteroatom selected from O, N, S, or Si, and each N, S, or Si is optionally oxidized and each N is optionally quaternized. The heterocyclyl group can be attached to the remainder of the molecule through a heteroatom.

[0061] As used herein, the terms "heteroaryl" or "heteroaromatic" refer to a substituted or unsubstituted aromatic ring group having 5 to 14 ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, sulfur, or silicon). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), and pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl). Examples of monocyclic 6-membered nitrogen-containing heteroaryl groups include pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of monocyclic 6-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridinyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.

[0062] The term "arylalkyl" refers to a group in which an aryl group, such as phenyl (Ph), is linked via an alkyl group. Examples include benzyl, phenethyl, and the like. The term "benzyl," as used herein, refers to a group in which a phenyl group is bonded to a CH group, thus a CHPh group. The term substituted benzyl refers to a group in which the benzyl group contains one or more substituents. In a preferred embodiment, the phenyl group has one substituent. In another preferred embodiment, the phenyl group has zero substituents (is unsubstituted). In one embodiment, the phenyl group can have 1 to 5 substituents, or in another embodiment, 2 to 3 substituents. Additionally, the alkylene linking group can also have at least one substituent.

[0063] As used herein, "substituted" or "optionally substituted" refers to the replacement of a hydrogen atom that would otherwise be present in place of a substituent. When discussing ring systems, optional substitution is typically with one, two, or three substituents replacing hydrogen atoms that are normally present. However, when referring to straight-chain and branched moieties, the number of substitutions may be greater and may occur wherever hydrogen is present. The substitutions may be the same or different.

[0064] As used herein, "selectivity" with respect to the activity of a compound of the present invention refers to a greater than 10-fold difference in activity. In one embodiment, a compound of the present disclosure can be characterized as being selective for JAK1 over other JAK subtypes. In one embodiment, a compound of the present disclosure can be characterized as having a JAK2:JAK1 ratio of about 10 to about 1000. In one embodiment, a compound of the present disclosure can be characterized as having a JAK3:JAK1 ratio of about 0.5 to about 800. In one embodiment, upon administration to a subject in need thereof, a compound of the present disclosure preferentially inhibits Jak1 activity over Jak2 activity, Jak3 activity, and Tyk2 activity, inhibiting one or more of Jak2, Jak3, or Tyk2 activity in the subject by less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, or 5%. In certain embodiments, Jak1 activity is preferentially inhibited over Jak2 activity, Jak3 activity, and Tyk2 activity. In certain embodiments, greater than 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of Jak1 activity is inhibited in a mammalian subject. In certain embodiments, Jak1 activity is preferentially inhibited over Jak2 activity. For example, preferential inhibition can be achieved by an IC of Jak1 inhibition. 50 and IC of Jak2 inhibition 50 The IC of Jak1 inhibition can be measured by the Jak1 / Jak2 potency ratio, which is defined as the reciprocal of the ratio of Jak1 to Jak2. In certain embodiments, the Jak1 / Jak2 potency ratio is at least about 30, 35, 40, 45, 50, 55, 60, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 85, or more. In certain embodiments, the IC of Jak1 inhibition can be measured by the Jak1 / Jak2 potency ratio, which is defined as the reciprocal of the ratio of Jak1 to Jak2. In certain embodiments, the IC of Jak1 inhibition can be measured by the Jak1 / Jak2 potency ratio, which is defined as the reciprocal of the ratio of Jak1 to J 50 is measured by inhibition of IL6-stimulated STAT3 phosphorylation ex vivo, for example, using a sample (e.g., a blood sample) from a subject administered a compound of the present disclosure. In certain embodiments, the IC of Jak2 inhibition 50is measured by the inhibition of EPO-stimulated STAT5 phosphorylation ex vivo, for example, using a sample (e.g., a blood sample) from a subject administered a compound of the present disclosure. In certain embodiments, the activity of Jak1 is preferentially inhibited over the activity of Jak3. For example, preferential inhibition can be measured by the IC of Jak1 inhibition. 50 and IC of Jak3 inhibition 50 The IC of Jak1 inhibition can be measured by the Jak1 / Jak3 potency ratio, which is defined as the reciprocal of the ratio of Jak1 to Jak3. In certain embodiments, the Jak1 / Jak3 potency ratio is at least about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 56, 57, 58, 59, 60, 65, 70, or more. In certain embodiments, the IC of Jak1 inhibition can be measured by the Jak1 / Jak3 potency ratio, which is defined as the reciprocal of the ratio of Jak1 to Jak3 ... 50 is measured, for example, by inhibition of IL6-stimulated STAT3 phosphorylation ex vivo using a sample (eg, a blood sample) from a subject administered a compound of the present disclosure.

[0065] Exemplary substitutions, which may be the same or different, include halogen, such as fluoro, chloro, bromo, or iodo; haloalkyl, such as -CF, -CFCF, -CHF, -CHF, R', OR', OH, SH, SR', NO, CN, C(O)R', C(O)OR', OC(O)R', CON(R'), OC(O)N(R'), NH, NHR', N(R'), NHCOR', NHCOH, NHCONH, NHCONHR', NHCON(R'), NRCOR' , NRCOH, NHCOH, NHCOR', NHC(S)NH, NHC(S)NHR', NHC(S)N(R'), COR', COH, CHO, CONH, CONHR', CON(R'), S(O)H, S(O)R', SONHR', SON(R'), NHS(O)H, NR'S(O)H, NHS(O)R', NR'S(O)R', and Si(R'), each of which is an alkylene linker, i.e., (CH) xwhere x is 1, 2, or 3. In embodiments in which the saturated carbon atom is optionally substituted with one or more substituents, the substituents may be the same or different and may also include =O, =S, =NNHR', =NNH, =NN(R'), =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCOR', =NNHCOH, =NNHSOR', =NNHSOH, =N-CN, =NH, or =NR'. Each occurrence of R' is the same or different and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, or heteroaryl, or, when two R' are each attached to a nitrogen atom, they can form a saturated or unsaturated heterocyclic ring containing 4 to 6 ring atoms.

[0066] In some embodiments of the present disclosure, particularly preferred embodiments of substituents include —C(O)O(C1-C3), OH, CH2OH, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, halogen, O(C1-C3 alkyl), and O(C1-C3 haloalkyl).

[0067] As used herein, the phrases veterinary or veterinarily, or pharmaceutical or pharmaceutically acceptable salts refer to any salt of a compound disclosed herein that retains its biological properties and is not toxic or otherwise undesirable for veterinary or pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include those derived from organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid. , 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, and the like.

[0068] Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as halides, e.g., chlorides and bromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanolates, ethanolamines ... Examples of suitable salts include benzenesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, and muconate.

[0069] Examples of inorganic bases that can be used to form base addition salts include, but are not limited to, metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides, such as lithium amide and sodium amide; metal carbonates, such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases, such as ammonium hydroxide and ammonium carbonate.

[0070] Examples of organic bases that can be used to form base addition salts include, but are not limited to, metal alkoxides, such as lithium, sodium, and potassium alkoxides, including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium hydroxides, such as choline hydroxide; and amines, including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.

[0071] According to embodiments of the present disclosure, the base may be a quaternary ammonium hydroxide, in which one or more of the alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that can be used according to the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, and tetramethylammonium hydroxide, with choline hydroxide being preferred. According to embodiments of the present disclosure, the alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that can be used according to the present disclosure include methylamine, ethylamine, diethylamine, and triethylamine. Preferably, the substituted alkylamine base is substituted with one or more hydroxyl groups, preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that can be used according to the present disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (deanol), tromethamine, ethanolamine, and diolamine.

[0072] In certain cases, the substituents shown may contribute to optical isomerism and / or stereoisomerism. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Molecules with at least one stereogenic center can be characterized by the absolute configuration of that asymmetric center, and are governed by the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: Chiral compounds are designated as (R) or (S) according to the International Standards for Chiral Compounds (ISC), 1996, pp. 657-668, or can be characterized by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0073] In certain embodiments, the compounds disclosed herein may have one or more asymmetric centers, and therefore, such compounds may be produced as racemic mixtures, enantiomerically enriched mixtures, or individual enantiomers. Unless otherwise indicated, for example, by designating the stereochemistry at any position in the formula, the description or naming of a particular compound in the specification and claims is intended to include both the individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0074] In certain embodiments, the compounds disclosed herein are "stereochemically pure." A stereochemically pure compound has a level of stereochemical purity that would be recognized as "pure" by one of ordinary skill in the art. Of course, this level of purity can be less than 100%. In certain embodiments, "stereochemically pure" refers to a compound that is substantially free of other isomers, i.e., at least about 85% or more free. In certain embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% free from other isomers.

[0075] As used herein, the terms "subject" and "patient" may be used interchangeably herein. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal, e.g., a dog or cat. In a further embodiment, the subject is an animal, e.g., a sheep, cow, horse, goat, fish, pig, or poultry (e.g., chicken, turkey, duck, or goose). In another embodiment, the subject is a primate, e.g., a monkey, e.g., a cynomolgus monkey or a chimpanzee.

[0076] In addition, pharmaceutically acceptable prodrugs of the compounds represented by Formula (I) are also included in the present disclosure. A pharmaceutically acceptable prodrug refers to a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198. The term prodrug is used throughout this specification to describe any pharmaceutically acceptable form of a compound that yields an active compound upon administration to a patient. A pharmaceutically acceptable prodrug refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form a compound of the present disclosure. Typical examples of prodrugs include compounds having biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deamined, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.

[0077] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the present disclosure in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in compounds of the present disclosure include isotopes of hydrogen, e.g. 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C and 14 C, an isotope of chlorine, e.g. 36 Cl, an isotope of fluorine, e.g. 18 F, an isotope of iodine, e.g. 123 I and 125 I, isotopes of nitrogen, e.g. 13 N and 15N, isotopes of oxygen, e.g. 15 O. 17 O and 18 O, isotopes of phosphorus, e.g. 32 P, as well as sulfur isotopes, e.g. 35 Certain isotopically labeled compounds of the present disclosure, for example those incorporating a radioactive isotope, may be useful in drug or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and rapid means of detection. Heavier isotopes, such as deuterium, i.e. 2 Substitution with H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution with N may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples, substituting appropriate isotopically labeled reagents for previously employed non-labeled reagents.

[0078] Compositions and Methods of Administration The compounds of the present disclosure used in the methods disclosed herein can, in certain embodiments, be administered as veterinary or pharmaceutical compositions comprising at least one compound of the present disclosure, in the form of a salt, if appropriate, either alone or in combination with one or more compatible veterinarily or pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent. Compositions are provided that include a derivative of the present disclosure or a salt thereof and an acceptable excipient, carrier, or diluent. The compositions may also be in a variety of forms, including, but not limited to, oral formulations, injectable formulations, and topical, transdermal, or subcutaneous formulations.

[0079] The composition may be in a form suitable for oral use, such as a dietary supplement, troche, lozenge, chewable tablet, tablet, hard or soft capsule, emulsion, aqueous or oily suspension, aqueous or oily solution, dispersible powder or granules, syrup, or elixir. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of veterinary or pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preservatives in order to provide an elegant and palatable preparation.

[0080] Lozenges are solid compositions containing one or more active ingredients that are intended to slowly dissolve or disintegrate in the oral cavity by passive incubation in the oral cavity or by active inhalation or chewing. They can be used for systemic effect when the drug is absorbed through the lining of the cheek or esophagus or swallowed. In particular, soft lozenges can be chewed or slowly dissolved in the mouth. These dosage forms have the advantage of being flavored, making them easy to administer to both human and animal patients; they have easily modifiable formulas and can be patient-specific; they can deliver precise amounts of active ingredients to the oral cavity and digestive system; and they can maintain prolonged contact with the oral cavity or esophageal cavity.

[0081] Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.

[0082] Formulations for oral use may be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.Capsules may also be soft gelatin capsules in which the active ingredient is mixed with water or a miscible solvent such as propylene glycol, PEG, and ethanol, or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0083] The composition may also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phosphatides, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The emulsion may also contain sweeteners, bittering agents, flavoring agents, and preservatives.

[0084] In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are highly suitable as liquid carrier vehicles. Microemulsions are quaternary systems containing an aqueous phase, an oil phase, a surfactant, and a cosurfactant. They are translucent, isotropic liquids. Microemulsions consist of a stable dispersion of microdroplets of an aqueous phase in an oil phase, or vice versa. The size of these microdroplets is less than 200 nm (1000-100,000 nm for emulsions). The interfacial membrane is composed of alternating surfactant (SA) and cosurfactant (Co-SA) molecules, which reduce the interfacial tension, thereby allowing the spontaneous formation of microemulsions. In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, unsaturated polyglycosylated glycerides, triglycerides, or mixtures of such compounds. In one embodiment of the oil phase, the oil phase is comprised of triglycerides, and in another embodiment of the oil phase, the triglycerides are medium chain triglycerides, e.g., C8-C 10 The oil phase is caprylic / capric triglyceride. In another embodiment, the oil phase will comprise a % v / v range selected from the group consisting of about 2 to about 15%, about 7 to about 10%, and about 8 to about 9% v / v of the microemulsion. The aqueous phase can be, for example, water or a glycol derivative, such as propylene glycol, glycol ether, polyethylene glycol, or glycerol. In one glycol derivative embodiment, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Typically, the aqueous phase will comprise about 1 to about 4% v / v of the microemulsion. Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolized C8-C8. 10Examples of surfactants include glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, co-surfactants include short-chain alcohols, such as ethanol and propanol. Some compounds are common to the three components mentioned above, such as the aqueous phase, surfactant, and co-surfactant. However, different compounds may be substituted for each component in the same formulation. In one embodiment, the ratio of surfactant / co-surfactant amount to surfactant may be about 1 / 7 to about 1 / 2.

[0085] Another embodiment for the amount of co-surfactant will be from about 25 to about 75% v / v surfactant and from about 10 to about 55% v / v co-surfactant in the microemulsion.

[0086] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil (atachis oil), olive oil, sesame oil, or coconut oil, or a mineral oil, such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as sucrose, saccharin, or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants, such as ascorbic acid, or other known preservatives.

[0087] Aqueous suspensions may contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening and / or bittering agents, such as those described herein.

[0088] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening agents, bittering agents, flavoring agents, and coloring agents, may also be present.

[0089] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and coloring agent(s).

[0090] The composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol, or polyethylene glycol may also be used. Preservatives such as phenol or benzyl alcohol may also be used.

[0091] In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, find use in the preparation of injectables.

[0092] Topical, transdermal and subcutaneous formulations may include emulsions, creams, ointments, gels or pastes.

[0093] Organic solvents that may be used in the present disclosure include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl esters, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

[0094] As a vehicle or diluent, the compositions of the present disclosure may be selected from vegetable oils, such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, and the like; mineral oils, such as, but not limited to, petrolatum, paraffin, silicones, and the like; aliphatic or cyclic hydrocarbons, or alternatively, for example, medium chain (e.g., C8-C9) 12 ) triglycerides.

[0095] Dosage forms may contain from about 0.5 mg to about 5 g of active agent.

[0096] In one embodiment of the present disclosure, the active agent is present in the formulation at a concentration of about 0.05-10% weight / volume.

[0097] The compounds of the present disclosure may be used as they are, or in the form of their preparations or formulations as a combination.

[0098] The compounds of the present disclosure may be combined with one or more agents having the same activity spectrum, for example, to increase activity, or with substances having a different activity spectrum, for example, to broaden the activity range. For example, the combination of a compound of the present disclosure with one or more additional JAK inhibitors or JAK / signal transducer and activator of transcription (JAK / STAT) modulators may provide therapeutic benefits. Examples of JAK inhibitors that may be useful as combination agents include baricitinib, ruxolitinib, filgotinib, CYT387, upadacitinib, fedratinib, peficitinib, lestaurtinib, pacritinib, oclacitinib, cerdulatinib, and tofacitinib.

[0099] The compounds of the present disclosure according to the present disclosure may be combined with one or more additional active agents.Further additional active agents that can be used in the methods provided herein in combination with the compounds of the present disclosure include, but are not limited to, disease-modifying antirheumatic drugs (DMARDs, for example, cyclosporin A and methotrexate), anti-inflammatory agents, for example, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, mycophenolate mofetil, biological agents, TNF-α inhibitors (for example, etanercept), Cox-2 inhibitors, and analgesics. These agents may include, but are not limited to, cyclosporin A, e.g., Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate, e.g., Cellcept®, azathioprine, e.g., Imuran®, daclizumab, e.g., Zenapax®, OKT3, e.g., Orthocolone®, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids, e.g., prednisolone or dexamethasone.

[0100] In some embodiments, the second active agent can include, but is not limited to, an anti-inflammatory agent, such as an NSAID, including, but not limited to, diclofenac (e.g., ARTHROTEC®), diflunisal (e.g., DOLOBID®), etodolac (e.g., LODINE®), fenoprofen (e.g., NALFON®), ibuprofen (e.g., ADVIL®, CHILDREN'S ADVIL / MOTRIN®, MEDIPREN®, MOTRIN®, NUPRIN®, or PEDIACARE®). FEVER®), indomethacin (e.g., ARTHREXIN®), ketoprofen (e.g., ORUVAIL®), ketorolac (e.g., TORADOL®), fosfomycin tromethamine (e.g., MONURAL®), meclofenamic acid (e.g., MECLOMEN®), nabumetone (e.g., RELAFEN®), naproxen (e.g., ANAPROX®, ANAPROX® DS, EC-NAPROSYN®, NAPRELAN®, or NAPROSYN®), oxaprozin (e.g., DAYPRO®), piroxicam (e.g., FELDENE®), sulindac (e.g., CLINORIL®), and tolmetin (e.g., TOLECTIN® DS or TOLECTIN®).

[0101] In other embodiments, the second active agent can include, but is not limited to, a disease-modifying antirheumatic drug (e.g., a DMARD) or an immunosuppressant, such as, but not limited to, methotrexate (e.g., RHEUMATREX®), sulfasalazine (e.g., AZULFIDINE®), and cyclosporine (e.g., SANDIMMUNE® or NEROAL®; and cyclosporine A).

[0102] In other embodiments, the second active agent may include, but is not limited to, mycophenolate mofetil (e.g., CellCept®), an immunosuppressant that is widely used in organ transplantation and is gaining acceptance in the treatment of autoimmune and inflammatory skin disorders.

[0103] In further embodiments, the second active agent can include, but is not limited to, biologic agents such as etanercept (ENBREL®), infliximab (REMICADE®), and adalimumab (HUMIRA®).

[0104] In further embodiments of interest, the second active agent can include, but is not limited to, Cox-2 inhibitors, such as celecoxib (CELEBREX®), valdecoxib (BEXTRA®), and meloxicam (MOBIC®).

[0105] These one or more additional active agents may be administered as part of the same or different dosage forms, via the same or different routes of administration, and on the same or different dosing schedules according to standard pharmaceutical practice.

[0106] The pharmaceutical preparations containing the compounds of the present disclosure for delivery to humans or other mammals are preferably in unit-dosage form, where the preparation is further divided into unit doses containing appropriate amounts of active ingredients.The unit-dosage form may be a packaged preparation containing individual amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules.The unit-dosage form may also be a capsule, tablet, or lozenge itself, or it may be an appropriate number of any of these in packaged form.

[0107] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000 mg according to the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0108] In therapeutic use for the treatment or alleviation of inflammation, autoimmune diseases, and cancer in humans or other mammals, the compounds utilized in the treatment methods are administered at an initial dosage of about 0.1 mg / kg to about 100 mg / kg per interval, about 0.1 mg / kg to about 50 mg / kg per interval, about 0.1 mg / kg to about 10 mg / kg per interval, about 0.1 mg / kg to about 5 mg / kg per interval, about 0.1 mg / kg to about 2.5 mg / kg per interval, about 0.1 mg / kg to about 2.0 mg / kg per interval, about 0.1 mg / kg to about 1.0 mg / kg per interval, about 0.4 mg / kg to about 1.0 mg / kg per interval, or about 0.4 mg / kg to about 0.6 mg / kg per interval. Preferred intervals can be daily, weekly, monthly, quarterly, semi-annually, or annually. Dosage can vary depending on patient requirements, such as the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the efficacy of the compound(s) used. Determining the appropriate dosage and route of administration for a particular situation is within the skill of a person skilled in the art. Generally, treatment will be initiated with a smaller dosage that is less than the optimal dose of the compound, which can be increased by small increments until the optimal effect under the specific circumstances of the condition is achieved. For convenience, the total daily dosage can be divided and administered in smaller amounts throughout the day if desired.

[0109] In therapeutic use, embodiments of the disclosed compounds are useful in the manufacture of a medicament for a method of treating any condition in which inhibition of JAK, optionally in dual PDE4 modulation, and optionally together with one or more of TykA and Syk, is desirable, including, but not limited to, cancer, neuroinflammation, inflammatory airway disease, ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, and atopic dermatitis. In one or more embodiments, the compounds of the present disclosure are useful in treating one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behcet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, the mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer.

[0110] In therapeutic use, the compounds of the present disclosure are useful in the manufacture of a medicament for a method of treating any condition, including, but not limited to, cancer, neuroinflammation, inflammatory airway disease, ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or atopic dermatitis. In one or more embodiments, the compounds of the present disclosure are useful in treating one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behcet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, the mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer.

[0111] The present disclosure expressly encompasses the compounds presented in the following compound list, including their salt forms. Compositions comprising any of these compounds in a therapeutically acceptable amount are also within the scope of the present disclosure. The compositions may further comprise a pharmaceutically or veterinarily acceptable excipient, diluent, carrier, or mixture thereof. Such compositions may be administered alone or in combination with inhibition of tropomyosin receptor kinase A (TrkA) or spleen tyrosine kinase (Syk), optionally in combination with inhibition of PDE4, to a subject in need thereof to treat or control a disease or disorder mediated in whole or in part, directly or indirectly, by JAK. The compositions may further comprise an additional active agent, as described herein.

[0112] Compound List

[0113] It should be understood that when in aqueous media, some contemplated compounds of the present disclosure may exist in reversible equilibrium with water due to the Lewis acidic nature of the trigonal planar boron center. This dynamic equilibrium may be important for the biological activity of the compounds of the present disclosure. Compounds of the present disclosure in this dynamic equilibrium are another aspect of the present disclosure.

[0114] Embodiments of the present disclosure are provided in the following lists, where aspects of compound activity are noted. For each list, the present disclosure includes stereoisomers, enantiomers, or tautomers of each compound, and veterinarily or pharmaceutically acceptable salts thereof. The (+) symbol identifies compounds of the present disclosure that have the noted target activity. The (*) symbol indicates preferential activity, with the increasing number identifying the most preferred compound.

[0115] [Table 1] TIFF0007597781000032.tif243159TIFF0007597781000033.tif226162TIFF0007597781000034.tif223158TIFF0007597781000035.t if224158TIFF0007597781000036.tif228165TIFF0007597781000037.tif231164TIFF0007597781000038.tif242166TIFF00075977810 00039.tif239158TIFF0007597781000040.tif214159TIFF0007597781000041.tif224158TIFF0007597781000042.tif220160TIFF000 7597781000043.tif230161TIFF0007597781000044.tif238158TIFF0007597781000045.tif231158TIFF0007597781000046.tif114161

[0116] Additional Compound List A1: Additional embodiments of the present disclosure include: [ka] The compound includes a compound selected from the group consisting of:

[0117] Additional Compound List B1: Additional embodiments of the present disclosure include: [ka] The compound includes a compound selected from the group consisting of: [Example]

[0118] The numbering of the examples is adjusted within each designated section and is not consecutive between sections. In addition, different naming conventions may be used throughout this disclosure. Thus, compounds may be referred to by different chemical names depending on the convention used. Those skilled in the art will recognize the differences, and the different chemical names will be clear. The variables provided in the following exemplary schemes may not match the variables in other parts of this disclosure. However, the description remains clear in context.

[0119] Part 1-1: General synthetic instructions for compounds of formula (IB)

[0120] General synthetic scheme A:

[0121] [ka]

[0122] Detailed procedures are as shown in the preparation of 7-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol.

[0123] [ka]

[0124] A.1 Preparation of 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine

[0125] [ka]

[0126] A mixture of pentan-3-amine (1.3 g, 15 mmol), 2,4-dichloro-5-methylpyrimidine (3.67 g, 22.5 mmol), and DIPEA (3.87 g, 30 mmol) in 1,4-dioxane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography eluting with PE / EA:8 / 1 to give 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine (1.45 g, 45% yield) as a white powder. MS: m / z = 214.0 (M+H). + .

[0127] A.2 Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate

[0128] [ka]

[0129] To a mixture of 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine (1 g, 4.68 mmol, 1 equiv.) and methyl 5-amino-2-bromo-3-methylbenzoate (1.14 g, 4.68 mmol, 1 equiv.) in dioxane (30 mL), TsOH.HO (1.34 g, 7.02 mmol, 1.5 equiv.) was added in one portion at room temperature under a N atmosphere. The resulting mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then poured into saturated NaHCO solution (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (1.5 g, 3.56 mmol, 76.08% yield) as a brown solid. 1H NMR (DMSO, 400 MHz) δ 9.10 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 6.17 (d, J =8.4 Hz, 1H), 4.08~4.05 (m, 1H), 3.83 (s, 3H), 2.33 (s, 3H), 1.94 (s, 3H), 1.62-1.51 (m, 4H), 0.85 (t, J = 7.6 Hz, 6H).

[0130] A.3 Preparation of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate

[0131] [ka]

[0132] To a mixture of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (500 mg, 1.19 mmol, 1 equiv) in dioxane (10 mL) was added KOAc (291 mg, 2.97 mmol, 2.5 equiv), Pd(PPh3)2Cl2 (83.30 mg, 118.67 μmol, 0.1 equiv), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (600 mg, 2.66 mmol, 2.24 equiv) in one portion under a N2 atmosphere at 25 °C, and the resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1-ethylpropylamino)-5-methylpyrimidin-2-yl]amino]-3-methyl-benzoate (700 mg, crude) as a brown oil, which was used directly in the next step without further purification. MS (ESI): C 24 H 25 Calculated mass of BN4O4: 454.28, measured m / z: 455.2 [M+H] + .

[0133] A.4 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine

[0134] [ka]

[0135] To a mixture of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (700 mg, crude, 1 equiv.) and MeOH (0.1 mL) in THF (8 mL) was added NaBH (174 mg, 4.62 mmol, 3 equiv.) in portions at 0 °C, and the resulting mixture was stirred at 0–25 °C for 30 min. The mixture was then poured into ice-water (w / w = 1 / 1) (8 mL), and the pH of the aqueous phase was adjusted to 3–4 with aqueous HCl (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-45%, 10.5 min). After lyophilization, the TFA salt was poured into ice-water (w / w = 1 / 1) (8 mL), and the pH of the aqueous phase was adjusted to 6-7 with aqueous NaHCO3 (2 N), followed by extraction with EtOAc (3 x 5 mL). The combined organic phase was washed with brine (2 x 5 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give N-(1-ethylpropyl)-N-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine (46 mg, 116.46 μmol, 7.56% yield, 86.14% purity) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.89 (s, 1H), 8.58 (s, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 6.11 (d, J = 8.4 Hz, 1H), 4.86 (s, MS (ESI): C 18 H 25 Calculated mass of BN4O2: 340.21, measured m / z: 341.1 [M+H] +. HPLC: 86.14% (220 nm), 93.84% (254 nm).

[0136] General synthetic scheme B:

[0137] [ka]

[0138] The detailed procedure is as shown in the preparation of 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol.

[0139] [ka]

[0140] To a solution of 5-amino-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol (450 mg, 2.8 mmol) in EtOH (10 mL) was added 2-chloro-N-cyclopentyl-5-methylpyrimidin-4-amine (591 mg, 2.8 mmol), and two drops of concentrated HCl were added at room temperature. The resulting reaction mixture was stirred overnight at room temperature. It was then neutralized by the addition of aqueous NaHCO and extracted with EtOAc. The combined organic phases were washed with brine and concentrated in vacuo to give a residue that was purified by silica chromatography eluting with DCM / MeOH (100 / 1 to 10 / 1) to give the crude product, which was then triturated with MeCN and water to give 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol (69 mg, 7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.59 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 6.37 (d, J = 6.8 Hz, 1H), 4.86 (s, HPLC purity: 98.51% / 210 nm and 98.35% / 254 nm. MS: (M+H)+: m / z = 339.2. HPLC purity: 98.51% / 210 nm and 98.35% / 254 nm. MS: (M+H) + : m / z = 339.2.

[0141] General synthetic scheme C:

[0142] [ka]

[0143] The detailed procedure is as shown in the preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine.

[0144] [ka]

[0145] C.1 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol

[0146] [ka]

[0147] Methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate (500 mg, 1.17 mmol, 1 equiv.) was added to MeMgBr (3 M, 7.80 mL, 20 equiv.) at 0 °C over 30 min, and the resulting mixture was stirred at 25 °C for 6.5 h. The reaction mixture was then poured into saturated aqueous NH Cl (15 mL), and the aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 0-100% ethyl acetate / petroleum ether gradient elution, 36 mL / min) to give 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol (250 mg, 585 μmol, 49.99% yield) as a yellow solid.

[0148] C.2 Preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0149] [ka]

[0150] To a solution of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol (50 mg, 117 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (66.1 mg, 293 μmol, 2.5 equiv.) in dioxane (3 mL) was added KOAc (23.0 mg, 234 μmol, 2 equiv.) and Pd(PPh)Cl (8.21 mg, 11.7 μmol, 0.1 equiv.) under a N atmosphere at 25° C., and the resulting mixture was stirred at 120° C. for 5 h. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 15% to 35%, 12 min) to give N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine (8.4 mg, 19.18% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 9.49 (s, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.58-7.56 (m, 2H), 7.42-7.38 (m, 2H), 7.26-7.25 (m, 2H), 7.23-7.16 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 3.83 (s, 6H). MS (ESI): C 21 H 23 Calculated mass of BN4O2: 374.19, measured m / z: 375.1 [M+H] + . HPLC: 100.00% (220 nm), 100.00% (254 nm).

[0151] General synthetic scheme D:

[0152] [ka]

[0153] Detailed procedures are as shown in the preparation of 3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol.

[0154] [ka]

[0155] D.1 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone

[0156] [ka]

[0157] To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.5 g, 7.02 mmol, 1 equiv.) and 1-(5-amino-2-bromo-phenyl)ethanone (1.50 g, 7.02 mmol, 1 equiv.) in dioxane (50 mL) was added TsOH.HO (2.00 g, 10.5 mmol, 1.5 equiv.) at 25 °C, and the resulting mixture was heated to 80 °C and stirred for 12 h. HO (30 mL) was poured into the above mixture, and the pH was adjusted to 9 with saturated aqueous NaHCO and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-100% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone (1.3 g, 3.32 mmol, 47.33% yield) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.73 (dd, J = 8.8, 2.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 8.8 Hz, 1H), 4.08-4.04 (m, 1H), 2.54 (s, 3H), 1.94 (m, 3H), 1.62-1.49 (m, 4H), 0.85 (t, J = 7.6 Hz, 6H).

[0158] D.2 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol

[0159] [ka]

[0160] To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone (700 mg, 1.79 mmol, 1 equiv.) and MeOH (1.79 mmol, 72.4 μL, 1 equiv.) in THF (5 mL) was added NaBH (102 mg, 2.69 mmol, 1.5 equiv.) at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into HO (10 mL), the pH was adjusted to 5 with 2 N HCl, and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by a short column to give 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (400 mg, 1.02 mmol, 56.98% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J = 8.8, 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.06 (d, J = 8.8 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H), 4.93-4.88 (m, 1H), 4.26-4.13 (m, 1H), 1.93 (s, 3H), 1.62-1.53 ​​(m, 4H), 1.28 (d, J = 6.4 Hz, 3H), 0.87 (q, J = 7.6 Hz, 6H)

[0161] D.3 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine

[0162] [ka]

[0163] To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (300 mg, 763 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (431 mg, 1.91 mmol, 2.5 equiv.) in dioxane (10 mL) under a N atmosphere at 25 °C, Pd(PPh3)2Cl2 (53.5 mg, 76.3 μmol, 0.1 equiv.) and KOAc (150 mg, 1.53 mmol, 2 equiv.) were added, and the resulting mixture was stirred at 80 °C for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was dissolved in HO (10 mL), the pH of which was adjusted to 5 with 2 N HCl, and extracted with EtOAc (3×8 mL). The combined organic layers were washed with brine (3×5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 40%–60%, 12 min) to give N-(1-ethylpropyl)-N-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine (96 mg, 211 μmol, 27.65% yield, 99.80% purity, TFA) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 12.06 (s, 1H), 10.19 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 7.72 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, MS (ESI): C 20 H 26 Calculated mass of BF3N4O4: 454.20, measured m / z: 341.0 [M+H]+ . HPLC: 99.80% (220 nm), 99.74% (254 nm).

[0164] Part 1-2: Example of synthesis of compounds of formula (IB)

[0165] [Example 1] 7-Methoxy-5-((5-methyl-4-(methylthio)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0166] [ka]

[0167] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.60 (s, 1H), 8.58 (br, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 4.87 (s, 2H), 3.78 (s, 3H), 2.59 (s, 3H), 2.06 (s, 3H). MS (ESI): m / z actual value 318.0 [M+H] + Purity by HPLC: 98.8% (220 nm), 98.93% (254 nm).

[0168] [Example 2] 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0169] [ka]

[0170] This material was prepared according to general synthetic scheme D below. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.05 (s, 1H), 8.77 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.50-7.48 (m, 2H), 6.36 (d, J = 7.2 Hz, 1H), 5.11 (q, J = 6.4 Hz, 1H), 4.45-4.43 (m, 1H), 2.01-1.99 (m, 2H), 1.93 (s, 3H), 1.74-1.73 (m, 2H), 1.60-1.57 (m, 4H),1.37 (d, J = 6.4 Hz, 1H). MS (ESI): m / z Measured value: 339.2 [M+H] + Purity by HPLC: 97.16% (220 nm), 97.78% (254 nm).

[0171] [Example 3] 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0172] [ka]

[0173] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.09 (s, 1H), 8.73 (s, 1H), 8.12 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.0, 1.6 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 4.53-4.47 (m, 1H), 2.03-2.01 (m, 2H), 1.93 (s, 3H), 1.76-1.73 (m, 2H), 1.61-1.57 (m, 4H),1.42 (s, 6H). MS (ESI): m / z Measured value: 353.2 [M+H] +Purity by HPLC: 95.93% (220 nm), 94.50% (254 nm).

[0174] [Example 4] 6-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-1-ol

[0175] [ka]

[0176] This material was prepared according to the following general synthetic scheme B. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.95 (s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.51 (s, 2H), 6.35 (d, J = 7.2 Hz, 1H), 4.44-4.38 (m, 1H), 4.04 (t, J = 5.6 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.01-1.99 (m, 2H), 1.92 (s, 3H), 1.75-1.73 (m, 2H), 1.59-1.57 (m, 4H). MS (ESI): m / z actual value 339.2 [M+H] + Purity by HPLC: 96.64% (220 nm), 98.79% (254 nm).

[0177] [Example 5] 7-Methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0178] [ka]

[0179] This material was prepared according to the following general synthetic scheme A.1 H NMR (DMSO-d6, 400 MHz) δ 8.89 (s, 1H), 8.58 (s, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 6.11 (d, J = 8.4 Hz, 1H), 4.86 (s, HPLC purity: 86.14% / 210 nm and 93.84% / 254 nm.MS: (M+H) + : m / z = 341.1.

[0180] [Example 6] 3,3-Dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0181] [ka]

[0182] This material was prepared according to the following general synthetic scheme B. 1 H NMR (DMSO-d6, 400 MHz) δ 11.86 (br, 1H), 10.13 (br, 1H), 8.99 (br, 1H), 7.91-7.86 (m, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 4.16-4.11 (m, 1H), 2.03 (s, 3H), 1.64-1.58 (m, 4H), 1.45 (s, 6H), 0.84 (t, J = 7.2 Hz, 6H) ppm. HPLC purity: 99.8% / 210 nm and 99.99% / 254 nm.MS: (M+H) + : m / z = 355.2.

[0183] [Example 7] 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0184] [ka]

[0185] This material was prepared according to the following general synthetic scheme B. 1 H NMR (DMSO-d6, 400 MHz) δ 8.97 (s, 1H), 8.59 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 6.37 (d, J = 6.8 Hz, 1H), 4.86 (s, HPLC purity: 98.51% / 210 nm and 98.35% / 254 nm. MS: (M+H) + : m / z = 339.2.

[0186] [Example 8] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0187] [ka]

[0188] This material was prepared according to the following general synthetic scheme A. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.33 (s, 1H), 8.65 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1H) 6.87 (d, J = 7.2 Hz, 1H), 4.88 (s, 2H), 4.42-4.36 (m,1H), 2.37 (s, 3H), 2.01-1.98 (m, 2H), 1.74-1.73 (m, 2H), 1.61-1.56 (m, 4H). MS (ESI): m / z actual value 359.1 [M+H] + Purity by HPLC: 93.73% (220 nm), 94.52% (254 nm).

[0189] [Example 9] 6-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-8-methyl-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-1-ol

[0190] [ka]

[0191] This material was prepared according to the following general synthetic scheme B. This material was obtained as the TFA salt. 1 H NMR (DMSO-d6, 400 MHz) δ 11.78 (br s, 1H), 9.40 (br s, 1H), 8.36 (s, 1H), 8.06 (br s, 1H), 7.74 (s, 1H), 7.41-7.39 (m, 2H), 4.03-4.01 (m, 3H), 2.83 (t, J = 6 Hz, 2H), 2.50 (s, 3H), 2.12 (s, 3H), 1.96-1.90 (m, 2H), 1.68-1.69 (m, 2H), 1.55-1.52 (m, 4H) ppm. HPLC purity: 98.72% / 210 nm and 95.12% / 254 nm. MS: (M+H) + : m / z = 353.2.

[0192] [Example 10] 7-chloro-3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0193] [ka]

[0194] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.63 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 4.17-4.08 (m, 1H), 2.04 (s, 3H), 1.67-1.46 (m, 4H), 1.46 (s, 6H), 0.85 (t, J = 7.4 Hz, 6H). MS (ESI): m / z actual value 389.2 [M+H] + HPLC purity: 99.84% (220 nm), 99.83% (254 nm).

[0195] [Example 11] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3,7-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0196] [ka]

[0197] This material was prepared according to general synthetic scheme C below. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.77 (br, 1H), 8.78 (br, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.51-4.45 (m, 1H), 2.39 (s, 3H), 1.99-1.97 (m, 2H), 1.77-1.75 (m, 2H), 1.68-1.66 (m, 2H), 1.56-1.54 (m, 2H), 1.43 (s, 6H). MS (ESI): m / z actual value 387.1 [M+H] + Purity by HPLC: 97.21% (220 nm), 88.55% (254 nm).

[0198] [Example 12] 7-chloro-5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0199] [ka]

[0200] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.61 (s, 1H), 8.76 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.46-4.41 (m, 1H), 2.50-1.99 (m, 2H), 1.76-1.74 (m, 2H), 1.65-1.55 (m, 4H), 1.43 (s, 6H). MS (ESI): m / z actual value 407.1 [M+H] + Purity by HPLC: 98.76% (220 nm), 98.54% (254 nm).

[0201] [Example 13] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0202] [ka]

[0203] This material was prepared according to general synthetic scheme D below. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.74 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46-7.41(m, 2H), 5.15 (q, J = 6.4 Hz, 1H), 4.45-4.40 (m, 1H), 1.97-1.96 (m, 2H), 1.74-1.73 (m, 2H), 1.64-4.63 (m, 2H), 1.55-1.53 ​​(m, 2H), 1.38 (d, J = 6.4 Hz, 3H). MS (ESI): m / z actual value 359.1 [M+H] + Purity by HPLC: 98.84% (220 nm), 97.83% (254 nm).

[0204] [Example 14] 3-Methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0205] [ka]

[0206] This material was prepared according to general synthetic scheme D below. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 12.06 (br, 1H), 10.19 (s, 1H), 9.06 (s, 1H), 7.82 (br, 1H), 7.72 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 5.20 (q, J = 6.4 Hz, 1H), 4.12-4.03 (m, 1H), 2.03 (s, 3H), 1.64-1.59 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H), 0.88-0.82 (m, 6H). MS (ESI): m / z Measured value: 341.1 [M+H] + Purity by HPLC: 99.8% (220 nm), 99.74% (254 nm).

[0207] [Example 15] 3,3-Dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0208] [ka]

[0209] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.18 (s, 1H), 9.64 (s, 1H), 8.91 (br, 1H), 7.93 (s, 1H), 7.56-7.51 (m, 3H), 7.43-7.38 (m, 4H), 7.27-7.25 (m, 1H), 2.18 (s, 3H), 1.29 (s, 6H). MS (ESI): m / z actual value 361.0 [M+H] + Purity by HPLC: 100% (220 nm), 99.77% (254 nm).

[0210] [Example 16] 5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0211] [ka]

[0212] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.52 (s, 1H), 9.13 (s, 1H), 8.23 ​​(s, 1H), 7.81 (br, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 5.06 (s, 2H), 4.11-4.06 (m, 1H), 2.04 (s, 1H), 1.65-1.55 (m, 4H), 0.83 (t, J = 7.4 Hz, 6H). MS (ESI): m / z actual value 395.1 [M+H] + Purity by HPLC: 98.77% (220 nm), 99.23% (254 nm).

[0213] [Example 17] 7-Methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0214] [ka]

[0215] This material was prepared according to the following general synthetic scheme A. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.78 (br, 1H), 9.01 (br, 1H), 8.70 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.42-7.38 (m, 2H), 7.22-7.17 (m, 2H), 6.54 (br, 1H), 4.76 (s, 2H), 2.30 (s, 3H), 2.14 (s, 3H). MS (ESI): m / z actual value 347.1 [M+H] + Purity by HPLC: 90.25% (220 nm), 88.74% (254 nm).

[0216] [Example 18] 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0217] [ka]

[0218] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.71 (br, 1H), 8.91 (s, 1H), 8.66 (br, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.40-7.36 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 4.86 (s, 2H), 2.15 (s, 3H). MS (ESI): m / z actual value 401.1 [M+H] + Purity by HPLC: 99.28% (220 nm), 99.8% (254 nm).

[0219] [Example 19] 3-Methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0220] [ka]

[0221] This material was prepared according to general synthetic scheme D below. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.26 (s, 1H), 9.69 (s, 1H), 8.98 (br, 1H), 7.93 (s, 1H), 7.56-7.53 (m, 4H), 7.45-7.41 (m, 2H), 7.32-7.31 (m, 2H), 5.02 (q, J = 6.4 Hz, 1H), 2.18 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H). MS (ESI): m / z actual value 347.1 [M+H] + Purity by HPLC: 94.91% (220 nm), 93.77% (254 nm).

[0222] [Example 20] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0223] [ka]

[0224] This material was prepared according to the following general synthetic scheme C. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.75 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.49 (br, 1H), 7.38 (d, J = 8.0 Hz, MS (ESI): m / z Actual value 373.1 [M+H] + Purity by HPLC: 96.66% (220 nm), 95.82% (254 nm).

[0225] [Example 21] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0226] [ka]

[0227] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.92 (s, 1H), 8.98 (br, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 5.01 (s, 2H), 4.43-4.38 (m, 1H), 1.98-1.96 (m, 2H), 1.74-1.72 (m, 2H), 1.63-1.55 (m, 4H). MS (ESI): m / z actual value 413.0 [M+H] + HPLC purity: 98.46% (220 nm), 98.87% (254 nm).

[0228] [Example 22] 7-chloro-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0229] [ka]

[0230] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.47 (s, 1H), 9.10 (s, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.78 (s, 1H), 7.45 (s, 1H), 4.99 (s, 2H), 4.09-4.02 (m, 1H), 2.03 (s, 3H), 1.68-1.56 (m, 4H), 0.87 (t, J = 7.4 Hz, 6H). MS (ESI): m / z actual value 361.1 [M+H] + HPLC purity: 99.83% (220 nm), 99.82% (254 nm).

[0231] [Example 23] 7-Ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0232] [ka]

[0233] This material was prepared according to the following general synthetic scheme A. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.25 (s, 1H), 8.89 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 4.95 (s, 2H), 4.12-4.07 (m, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.03 (s, 3H), 1.64-1.57 (m, 4H), 1.19 (t, J = 6.8 Hz, 3H), 0.85 (t, J = 7.4 Hz, 6H). MS (ESI): m / z actual value 355.1 [M+H] + Purity by HPLC: 93.05% (220 nm), 95.97% (254 nm).

[0234] [Example 24] 3,3,7-trimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0235] [ka]

[0236] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.93 (s, 1H), 8.45 (s, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.25 (s, 1H), 6.17 (d, J = 8.8 Hz, 1H), 4.23-4.21 (m, 1H), 2.35 (s, 3H), 1.96 (s, 3H), 1.68-1.54 (m, 4H), 1.42 (s, 6H), 0.88 (t, J = 7.4 Hz, 6H). MS (ESI): m / z actual value 369.2 [M+H] + Purity by HPLC: 98.87% (220 nm), 99.07% (254 nm).

[0237] [Example 25] 7-chloro-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0238] [ka]

[0239] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.98 (br, 1H), 9.31 (br, 1H), 8.98 (br, 1H), 7.94 (s, 1H), 7.56-7.54 (m, 3H), 7.45-7.41 (m, 3H), 7.27-7.25 (m, 1H), 4.80 (s, 2H), 2.17 (s, 3H). MS (ESI): m / z actual value 367.1 [M+H] + Purity by HPLC: 96% (220 nm), 98.16% (254 nm).

[0240] [Example 26] 7-chloro-3,3-dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0241] [ka]

[0242] This material was prepared according to the following general synthetic scheme C. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.03 (br, 1H), 9.30 (br, 1H), 8.83 (br, 1H), 7.95 (s, 1H), 7.59-7.57 (m, 3H), 7.42-7.38 (m, 2H),7.35 (s, 1H), 7.23-7.19 (m, 1H), 2.17 (s, 3H), 1.32 (s, 6H). MS (ESI): m / z actual value 395.1 [M+H] + Purity by HPLC: 96.13% (220 nm), 98.95% (254 nm).

[0243] [Example 27] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0244] [ka]

[0245] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.77 (s, 1H), 8.77 (br, 1H), 8.05 (s, 1H), 7.53-7.50 (m, 3H), 4.91 (s, 2H), 4.46-4.37 (m, 1H), 2.73 (q, J = 7.4 Hz, 2H), 1.98-1.96 (m, 2H), 1.74-1.72 (m, 2H), 1.64-1.54 (m, 4H), 1.17 (t, J = 7.8 Hz, 3H). MS (ESI): m / z actual value 373.1 [M+H] + Purity by HPLC: 98.74% (220 nm), 98.68% (254 nm).

[0246] [Example 28] 7-chloro-5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0247] [ka]

[0248] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.65 (s, 1H), 8.90 (br, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.01 (d, J = 7.2 Hz, 1H), 4.93 (s, 2H), 4.41-4.35 (m, 1H), 2.01-1.99 (m, 2H), 1.74-1.73 (m, 2H), 1.62-1.57 (m, 4H). MS (ESI): m / z actual value 379.1 [M+H] + Purity by HPLC: 94.64% (220 nm), 97.36% (254 nm).

[0249] [Example 29] 3,7-Dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0250] [ka]

[0251] This material was prepared according to general synthetic scheme D below. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.92 (s, 1H), 8.54 (s, 1H), 7.50 (s, 1H), 7.67 (s, 1H), 7.37 (s, 1H), 6.16 (d, J = 8.4 Hz, 1H), 5.09 (q, J = 6.4 Hz, 2H), 4.17-4.14 (m, 1H), 2.36 (s, 3H), 1.95 (s, 3H), 1.64-1.54 (m, 4H), 1.37 (d, J = 6.4 Hz, 3H), 0.91-0.86 (m, 6H). MS (ESI): m / z actual value 355.2 [M+H] + Purity by HPLC: 97.41% (220 nm), 96.99% (254 nm).

[0252] [Example 30] 3,3,7-trimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0253] [ka]

[0254] This material was prepared according to the following general synthetic scheme C. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.99 (br, 1H), 9.5 (br, 1H), 8.67 (s, 1H), 7.91 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.42-7.38 (m, 2H), 7.27-7.23 (m, 2H), 7.15 (s, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.30 (s, 6H). MS (ESI): m / z actual value 375.1 [M+H] + HPLC purity: 99.84% (220 nm), 99.82% (254 nm).

[0255] [Example 31] 5-((4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0256] [ka]

[0257] This material was prepared according to the following general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.43 (br, 1H), 8.98 (br, 1H), 8.90 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.44-7.42 (m, 2H), 6.19 (d, J = 7.2 Hz, 2H), 4.98 (s, 2H), 4.30-4.25 (m, 1H), 2.77 (q, J =7.2 Hz, 2H), 1.99-1.97 (m, 2H), 1.72-1.71 (m, 2H), 1.59-1.55 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H). MS (ESI): m / z Measured value 339.2 [M+H] + HPLC purity: 98.52% (220 nm), 98.84% (254 nm).

[0258] [Example 32] 7-Ethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0259] [ka]

[0260] This material was prepared according to the following general synthetic scheme A. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.13 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.35 MS (ESI): m / z actual value 361.1 [M+H] + Purity by HPLC: 92.87% (220 nm), 94.53% (254 nm).

[0261] [Example 34] 6-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0262] [ka]

[0263] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.83 (s, 1H), 8.03 & 8.00 (2 s, 1H), 7.86 (s, 1H), 7.64 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 4.8 Hz, partial 1H), 6.01 (s, partial 1H), 4.91 (s, 2H), 4.08 (s, partial 1H), 3.97 (d, J = 4.0 Hz, partial 1H), 1.98-1.90 (m, 4H), 1.80-1.50 (m, 4H), 1.50-1.30 (m, 3H), 1.20-1.05 (m, 1H), 0.97 & 0.91 (two s, 3H) ppm. HPLC purity: 97.30% at 210 nm and 98.22% at 254 nm. MS: m / z = 353.2 (M+H) + .

[0264] [Example 51] 6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0265] [ka]

[0266] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (br s, 1H), 9.67 (br s, 1H), 9.24 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.03-8.02 (m, 1H), 7.95 (s, 1H), 7.71-7.67 (m, 2H), 7.64-7.56 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 3.18 (s, 3H), 2.19 (s, 3H) ppm. HPLC purity: 98.73% / 210 nm and 99.38% / 254 nm. MS: (M+H) + : m / z = 411.1.

[0267] [Example 52] 3,3-Dimethyl-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0268] [ka]

[0269] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1 H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.84 (s, 1H), 9.11 (br s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.95 (s, HPLC purity: 98.30% / 210 nm and 99.14% / 254 nm. MS: m / z =438.9 (M+H) + .

[0270] [Example 55] 7-methyl-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0271] [ka]

[0272] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1 H NMR (400 MHz, DMSO-d6): δ 9.74 (br s, 1H), 9.66 (br s, 1H), 9.07 (s, 1H), 8.05 (s, 2H), 7.84 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 5.00 (s, 2H), 3.18 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H) ppm. HPLC purity: 99.60% / 210 nm and 99.63% / 254 nm. MS: m / z =425.1 (M+H) + .

[0273] [Example 59] 6-((4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0274] [ka]

[0275] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1H NMR (400 MHz, DMSO-d6): δ 12.11 (br s, 1H), 10.20 (s, 1H), 9.20 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.72 - 7.61 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 5.00 (s, 2H), 4.40 (br s, 1H), 4.02-3.90 (m, 1H), 3.22 (d, J = 6.3 Hz, 2H), 1.99 (s, 3H), 1.88 (d, J = 11.4 Hz, 2H), 1.79 (d, HPLC purity: 94.70% / 210 nm and 94.29% / 254 nm. MS: m / z = 369.2 (M+H) + .

[0276] [Example 62] 7-Fluoro-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0277] [ka]

[0278] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1H NMR (300 MHz, DMSO-d6): δ 9.64 (br s, 1H), 9.58 (brs, 1H), 9.36 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.67-7.64 (m, 2H), 7.47-7.43 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 3.18 (s, 3H), 2.18 (s, 3H) ppm; HPLC purity: 98.33% / 210 nm and 98.04% / 254 nm; MS: m / z = 429.1 [M+H] + .

[0279] [Example 63] 6-((5-methyl-4-((1-methylpiperidin-4-yl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0280] [ka]

[0281] This material was prepared according to the following general synthetic scheme B. The analytical data for this compound are shown below. 1H NMR (400 MHz, DMSO-d6): δ 9.01 (br s, 1H), 8.81 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.0 & 2.0 Hz, 1H), 7.64 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 4.92 (s, 2H), 4.05-3.90 (m, 1H), 2.78 (d, J = 11.2 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 7.8 Hz, 2H), 1.91 (s, 3H), 1.84 (d, J = 7.8 Hz, 2H), 1.70-1.50 (m, 2H) ppm. HPLC purity: 94.22% / 210 nm and 97.13% / 254 nm. MS: m / z = 354.2 (M+H) + .

[0282] [Example 64] 6-((5-methyl-4-(piperidin-4-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0283] [ka]

[0284] This material was prepared according to the following general synthetic scheme B. This material was obtained as the 2·HCl salt. The analytical data for this compound are shown below. 1H NMR (400 MHz, DMSO-d6): δ 12.61 (br s, 1H), 10.85 (br s, 1H), 9.60 (br s, 1H), 9.41 (s, 1H), 9.34 (br s, 1H), 8.34 (br s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.67 (dd, J = 8.4 & 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.30-4.20 (m, 1H), 3.31-3.28 (m, 2H), 2.95-2.80 (m, 2H), 2.03 (s, 3H), 2.01-1.98 (m, 4H) ppm. HPLC purity: 99.46% / 210 nm and 99.18% / 254 nm. MS: m / z = 340.2 (M+H) + .

[0285] [Example 65] 6-((4-(cyclohexylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0286] [ka]

[0287] The title compound was prepared according to the scheme and procedures shown below.

[0288] [ka]

[0289] A mixture of cyclohexamine (1.5 g, 15 mmol), 2,4-dichloro-5-methylpyrimidine (3.67 g, 22.5 mmol), and DIPEA (3.87 g, 30 mmol) in 1,4-dioxane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography eluting with PE / EA:8 / 1 to give 2-chloro-N-cyclohexyl-5-methylpyrimidin-4-amine (1.4 g, 41% yield) as a white powder. MS: m / z = 225.9 (M+H). + A mixture of 2-chloro-N-cyclohexyl-5-methylpyrimidin-4-amine (562.5 mg, 2.5 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (372.5 mg, 2.5 mmol) in AcOH (10 mL) was stirred under microwave for 20 min at 145° C. The reaction mixture was concentrated and purified by preparative HPLC to give 6-((4-(cyclohexylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (40 mg) as a white powder. 1 H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.15 (s, 1H), 8.00-7.99 (d, 1H), 7.90 (dd, J = 8 & 4 Hz, 1H), 7.64 (d, 1H), 7.24 (d, J = 12.0 Hz, 1H), 6.19 (d, J= 8.0 Hz, 1H). 4.92 (s, 2H), 4.02-4.00 (m, 1H), 1.93-1.91 (m, 2H), 1.91 (s, 3H), 1.76-1.73 (m, 2H), 1.66-1.62 (m, 1H), 1.37-1.27 (m, 4H), 1.18-1.12 (m, 1H) ppm. HPLC purity: 96.2% / 214 nm and 95.4% / 254 nm. MS: m / z = 339.1 [M + H] + .

[0290] [Example 66] 6-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0291] [ka]

[0292] The title compound was prepared according to the scheme and procedures shown below.

[0293] [ka]

[0294] A mixture of pentan-3-amine (1.3 g, 15 mmol), 2,4-dichloro-5-methylpyrimidine (3.67 g, 22.5 mmol), and DIPEA (3.87 g, 30 mmol) in 1,4-dioxane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography eluting with PE / EA:8 / 1 to give 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine (1.45 g, 45% yield) as a white powder. MS: m / z = 214.0 (M+H). + A mixture of 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine (213 mg, 1.0 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (150 mg, 1.0 mmol) in AcOH (5 mL) was stirred under microwave heating for 20 min at 145° C. The reaction mixture was concentrated and purified by preparative TLC and preparative HPLC to give 6-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (8 mg) as a white powder. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.61 (s, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.05 (d, J= 9.0 Hz, 1H), 4.90 (s, 2H), 4.10-4.04 (m, 1H), 1.93 (s, 3H), 1.61-1.54 (m, 4H), 0.88 (t, J= 7.5 Hz, 6H) ppm. HPLC purity: 96.1% / 214 nm and 95.3% / 254 nm. MS: m / z = 327.1 [M+H] + .

[0295] Parts 1-3: Synthesis examples of compounds of formula (IB)

[0296] 3. 5-amino-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0297] [ka]

[0298] 3.1 Preparation of 1-(2-bromo-5-nitrophenyl)ethan-1-one

[0299] [ka]

[0300] To a solution of potassium nitrate (12.5 g, 125 mmol) in concentrated sulfuric acid (100 mL) was added 1-(2-bromophenyl)ethan-1-one (20.0 g, 100 mmol) at 0 °C, and the resulting mixture was then warmed to room temperature and stirred for 1.5 h. The reaction was quenched by pouring into ice water (500 mL), and the aqueous phase was extracted with dichloromethane (2 x 150 mL). The combined organic phases were dried over anhydrous MgSO, filtered, and concentrated in vacuo to give a residue that was purified by silica gel flash chromatography (eluting with 10% EA in PE) to give 1-(2-bromo-5-nitrophenyl)ethan-1-one (13.9 g, 54%) as a white powder. 1 H NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 2.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 2.65 (s, 3H) ppm.

[0301] 3.2 Preparation of 1-(2-bromo-5-nitrophenyl)ethan-1-ol

[0302] [ka]

[0303] To a solution of 1-(2-bromo-5-nitrophenyl)ethan-1-one (4.8 g, 20 mmol) in MeOH (30 mL) was added NaBH (1.15 g, 30 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water and extracted with EA. The combined organic phase was washed with water, brine, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (PE / EA (100 / 1 to 10 / 1)) to give 1-(2-bromo-5-nitrophenyl)ethan-1-ol (3.7 g, 77% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.37 (d, J = 2.9 Hz, 1H), 8.02 (dd, J = 8.7, 2.9 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 5.80 (d, J = 4.4 Hz, 1H), 5.09-4.84 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H) ppm.

[0304] 3.3 Preparation of 1-bromo-2-(1-(methoxymethoxy)ethyl)-4-nitrobenzene

[0305] [ka]

[0306] To a solution of 1-(2-bromo-5-nitrophenyl)ethan-1-ol (3.7 g, 15 mmol) in DMC (30 mL) was added DIEA (5.2 mL, 30 mmol). MOMCl (2.4 g, 30 mmol) was then added dropwise to the mixture. The resulting mixture was heated to 40 °C for 2 h, then cooled to room temperature, washed with saturated NaHCO3, brine, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (PE / EA (30 / 1 to 10 / 1)) to give 1-bromo-2-(1-(methoxymethoxy)ethyl)-4-nitrobenzene (4.1 g, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 2.6 Hz, 1H), 7.91 (dd, J = 8.7, 2.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 5.2-5.0 (m, 1H), 4.62 (d, J = 6.4 Hz, 1H), 4.50 (dd, J = 6.8, 0.6 Hz, 1H), 3.31 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H) ppm.

[0307] 3.4. Preparation of 2-(2-(1-(methoxymethoxy)ethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0308] [ka]

[0309] To a solution of the compound 1-bromo-2-(1-(methoxymethoxy)ethyl)-4-nitrobenzene (3.1 g, 10 mmol) in dioxane (30 mL), KOAc (1.96 g, 20 mol), B2Pin2 (3.0 g, 12 mmol), and (dppf)PdCl2-DCM (816 mg, 1 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was heated to 100 °C overnight. The precipitate from the reaction mixture was then removed by filtration, and the filtrate was concentrated under vacuum to give a residue, which was purified by silica chromatography (PE / EA (20 / 1 to 5 / 1)) to give 2-(2-(1-(methoxymethoxy)ethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g, crude) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.2, 2.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 5.35 (q, J = 6.4 Hz, 1H), 4.59 (d, J = 6.8, 1.0 Hz, 1H), 4.48 (d, J = 6.8, 3.2 Hz, 1H), 3.28 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.30 (s, 12H) ppm.

[0310] 3.5 Preparation of 3-methyl-5-nitrobenzo[c][1,2]oxaborol-1(3H)-ol

[0311] [ka]

[0312] To a solution of 2-(2-(1-(methoxymethoxy)ethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g, 6.4 mmol) in THF (6 mL) was added 6 N HCl (3 mL). The reaction was stirred at room temperature overnight. The reaction mixture was then diluted with water, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, brine, and concentrated in vacuo to give a residue that was purified by preparative HPLC (eluting with water and 0.1% TFA in ACN) to give 3-methyl-5-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (1.0 g, 81% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 8.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 5.35 (q, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H) ppm.

[0313] 3.6 Preparation of 5-amino-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0314] [ka]

[0315] To a solution of 3-methyl-5-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (1.0 g, 5.1 mmol) in THF (6 mL) was added Pd / C (100 mg, 10% mmol). The reaction was degassed and flushed with H three times, then stirred at room temperature overnight. The reaction mixture was passed through a pad of Celite, and the filtrate was concentrated in vacuo to give a residue that was purified by preparative HPLC (eluting with ACN and water) to give 5-amino-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (400 mg, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.50 (dd, J = 7.9, 1.8 Hz, 1H), 6.44 (s, 1H), 5.43 (s, 2H), 4.99 (q, J = 6.5 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H) ppm.

[0316] 4. 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0317] [ka]

[0318] This material was prepared using general synthetic scheme B by following the procedure used for the synthesis of 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol as a white solid. Yield: 8%. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.05 (s, 1H), 8.77 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.50-7.48 (m, 2H), 6.36 (d, J = 7.2 Hz, 1H), 5.11 (q, J = 6.4 Hz, 1H), 4.45-4.43 (m, 1H), 2.01-1.99 (m, 2H), 1.93 (s, 3H), 1.74-1.73 (m, 2H), 1.60-1.57 (m, 4H),1.37 (d, J = 6.4 Hz, 1H). MS (ESI): m / z Measured value: 339.2 [M+H] + Purity by HPLC: 97.16% (220 nm), 97.78% (254 nm).

[0319] 5. 5-Amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0320] [ka]

[0321] 5.1 Preparation of tert-butyl(4-bromo-3-(2-hydroxypropan-2-yl)phenyl)carbamate

[0322] [ka]

[0323] To a solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)benzoate (10.0 g, 30.4 mmol) in dry THF (50 mL) was added MeMgBr (50 mL, 150 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water and extracted with EtOAc. The combined organic phases were washed with water, brine, dried over anhydrous NaSO, and concentrated in vacuo to give a residue that was purified by silica chromatography eluting with PE / EA (100 / 1 to 10 / 1) to give tert-butyl (4-bromo-3-(2-hydroxypropan-2-yl)phenyl)carbamate (7.5 g, 75% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 8.6, 2.6 Hz, 1H), 5.18 (s, 1H), 1.59 (s, 6H), 1.47 (s, 9H) ppm.

[0324] 5.2 Preparation of tert-butyl(4-bromo-3-(2-(methoxymethoxy)propan-2-yl)phenyl)carbamate

[0325] [ka]

[0326] To a solution of tert-butyl (4-bromo-3-(2-hydroxypropan-2-yl)phenyl)carbamate (7.5 g, 22.8 mmol) in DCM (80 mL) was added DIPEA (5.2 mL, 30 mmol). MOMCl (2.4 g, 30 mmol) was then added dropwise to the mixture. The resulting mixture was heated up to 40 °C for 2 h. The reaction mixture was then cooled to room temperature, washed with saturated NaHCO3, brine, and concentrated in vacuo to give a residue that was purified by silica chromatography (PE / EA (30 / 1 to 10 / 1)) to give tert-butyl (4-bromo-3-(2-(methoxymethoxy)propan-2-yl)phenyl)carbamate (6.5 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0327] 5.3 Preparation of tert-butyl(3-(2-(methoxymethoxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0328] [ka]

[0329] To a solution of tert-butyl(4-bromo-3-(2-(methoxymethoxy)propan-2-yl)phenyl)carbamate (6.5 g, 17 mmol) in dioxane (50 mL), KOAc (5.1 g, 52 mol), B2Pin2 (5.1 g, 20.4 mmol), and (dppf)PdCl2-DCM (1.4 g, 1.7 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was heated up to 100 °C for 4 h and then cooled to room temperature. The solids from the mixture were removed by filtration, and the filtrate was concentrated in vacuo to give a residue that was purified by silica chromatography (PE / EA (20 / 1 to 5 / 1)) to give tert-butyl (3-(2-(methoxymethoxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.4 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0330] 5.4 Preparation of tert-butyl(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate

[0331] [ka]

[0332] To a solution of tert-butyl (3-(2-(methoxymethoxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.4 g, 5.7 mmol) in EtOH (15 mL) was added 2N HCl (5 mL, 10 mol), and the resulting reaction mixture was stirred at room temperature for 30 min. After that, the mixture was diluted with EtOAc, and the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (PE / EtOAc = 10:1) to give tert-butyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (1.0 g, crude) as a yellow oil, which was used directly in the next step without further purification. MS: (MH) - : m / z = 276.0.

[0333] 5.5 Preparation of 5-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol HCl salt

[0334] [ka]

[0335] A solution of tert-butyl(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (1.0 g, 3.6 mmol) in dioxane (4 M HCl in dioxane, 6 mL) was stirred at room temperature for 3 hours, and the precipitate was collected by filtration and dried under vacuum to give 5-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol HCl salt (280 mg, 37%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.43 (d, J = 7.8 Hz, 1H), 6.77-6.67 (m, 2H), 1.39 (s, 6H) ppm.

[0336] 6. 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0337] [ka]

[0338] This material was prepared using general synthetic scheme B by following the procedure used for the synthesis of 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol. Yield: 26%. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.09 (s, 1H), 8.73 (s, 1H), 8.12 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.0, 1.6 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 4.53-4.47 (m, 1H), 2.03-2.01 (m, 2H), 1.93 (s, 3H), 1.76-1.73 (m, 2H), 1.61-1.57 (m, 4H),1.42 (s, 6H). MS (ESI): m / z Measured value: 353.2 [M+H] + Purity by HPLC: 95.93% (220 nm), 94.50% (254 nm).

[0339] 7. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborol-1(3H)-ol and 5-((4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0340] [ka]

[0341] 7.1 Preparation of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-hydroxy-benzoate

[0342] [ka]

[0343] To a solution of methyl 5-amino-3-ethyl-2-hydroxybenzoate (600 mg, 3.07 mmol, 1 equiv.) and 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (713 mg, 3.07 mmol, 1 equiv.) in dioxane (20 mL) was added p-TsOH (794 mg, 4.61 mmol, 1.5 equiv.) at 20° C. The reaction mixture was stirred at 100° C. for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, to which saturated NaHCO (30 mL) was added at 0° C. and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-hydroxy-benzoate (700 mg, 1.79 mmol, 58.27% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.59 (s, 1H), 9.10 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.46-4.40 (m, 1H), 3.89 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 1.99-1.85 (m, 2H), 1.73-1.61 (m, 2H), 1.60-1.45 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H).

[0344] 7.2 Preparation of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate

[0345] [ka]

[0346] To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (658 mg, 1.84 mmol, 1.2 equiv) and methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-hydroxybenzoate (600 mg, 1.54 mmol, 1 equiv) in DCM (30 mL) was added DMAP (56 mg, 461 μmol, 0.3 equiv) and TEA (311 mg, 3.07 mmol, 427 μL, 2 equiv) at 0° C. The mixture was stirred at 25° C. for 8 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate (600 mg, 1.15 mmol, 74.75% yield) as a white solid. 1 H NMR (CDCl, 400 MHz) δ 8.16 (d, J = 3.2 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J = 3.2 Hz, 1H), 7.26 (s, 1H), 5.28 (d, J = 7.2 Hz, 1H), 4.48-4.42 (m, 1H), 3.93 (s, 3H), 2.81-2.74 (q, J = 7.6 Hz, 2H), 2.21-2.08 (m, 2H), 1.85-1.65 (m, 4H), 1.61-1.47 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H).

[0347] 7.3. Preparation of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-benzoate

[0348] [ka]

[0349] A mixture of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate (150 mg, 287 μmol, 1 equiv.), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (194 mg, 860 μmol, 3 equiv.), KOAc (84 mg, 861 μmol, 3 equiv.), and Pd(PPh)Cl (20 mg, 29 μmol, 0.1 equiv.) in dioxane (10 mL) was degassed and purged with N three times, after which the mixture was stirred at 80° C. under a N atmosphere for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-benzoate (450 mg, 924 μmol, 80.57% yield) as a white solid. 1 H NMR (CDCl, 400 MHz) δ 8.19 (d, J = 2 Hz, 1H), 7.87 (s, 1H), 7.54 (d, J = 2 Hz, 1H), 7.45 (s, 1H), 5.23 (d, J = 7.2 Hz, 1H), 4.51-4.45 (m, 1H), 3.91 (s, 3H), 3.83 (s, 4H), 2.75 (q, J = 7.6 Hz, 2H), 2.16-2.05 (m, 2H), 1.78-1.47 (m, 6H), 1.30-1.25 (t, J = 7.6 Hz, 3H), 1.14 (s, 6H).

[0350] 7.4 Preparation of N4-cyclopentyl-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine and 5-chloro-N4-cyclopentyl-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0351] [ka]

[0352] To a mixture of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-benzoate (150 mg, 308 μmol, 1 equiv., 3 batches) in THF (10 mL) and MeOH (0.5 mL) was added NaBH (58 mg, 1.54 mmol, 5 equiv.) in small portions at 0° C., after which the mixture was stirred at 25° C. under a N atmosphere for 4 h. The reaction was quenched with 1 N HCl (1 mL) at 0 °C and concentrated in vacuo to give a residue that was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 30%-50%, 10 min) to give N4-cyclopentyl-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (195 mg, 577 μmol, 62.37% yield). 1 H NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 8.76 (br s, 1H), 8.05 (s, 1H), 7.53-7.50 (m, 3H), 4.91 (s, 2H), 4.47-4.36 (m, 1H), 2.73 (q, J = 7.6 Hz, MS (ESI): C 18 H 22 Calculated mass of BClN4O2: 372.15, measured m / z: 373.1 [M+H] + . HPLC: 98.74% (220 nm), 98.68% (254 nm). 5-Chloro-N4-cyclopentyl-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (51 mg, 137 μmol, 14.80% yield) was obtained as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.43 (s, 1H), 8.98 (d, J = 2.0 Hz, 1H), 8.90 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 6.19 (d, J = 7.2 Hz, 1H), 4.95 (s, 2H), 4.30-4.24 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.00-1.90 (m, 2H), 1.76-1.65 (m, 2H), 1.64-1.48 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H).MS (ESI): C 18 H 23 Calculated mass of BN4O2: 338.19, measured m / z: 339.2 [M+H] + HPLC: 98.52% (220 nm), 98.84% (254 nm).

[0353] 8. Preparation of 3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0354] [ka]

[0355] 8.1. Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate

[0356] [ka]

[0357] To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (2 g, 9.36 mmol, 1 equiv.) and methyl 5-amino-2-bromo-benzoate (2.15 g, 9.36 mmol, 1 equiv.) in EtOH (50 mL) at 25 °C was added HCl (37.4 mmol, 3.72 mL, 36% purity, 4 equiv.), and the reaction mixture was heated to 100 °C and stirred for 24 h. The solvent was then removed to give a residue, to which HO (20 mL) was added, and the pH was adjusted to 5 with saturated aqueous NaHCO and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was triturated with MTBE (10 mL) to give the crude product, which was then triturated with EtOAc (10 mL) to give methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate (2.3 g, 5.65 mmol, 60.33% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.22 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.50 (s, 1H), 7.37-7.35 (m, 1H), 3.99-3.93 (m, 1H), 3.81 (s, 3H), 1.94 (s, 3H), 1.54-1.49 (m, 4H), 0.75 (t, J = 7.2 Hz, 6H).

[0358] 8.2. Preparation of 2-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol

[0359] [ka]

[0360] To a solution of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate (500 mg, 1.23 mmol, 1 equiv.) in THF (10 mL) was added MeMgBr (3 M, 2.05 mL, 5 equiv.) dropwise over 10 min at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was then poured into HO (30 mL), and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by a short column to give 2-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol (400 mg, 982 μmol, 79.83% yield) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.05 (s, 1H), 4.19-4.12 (m, 1H),1.99 (s, 3H), 1.58-1.48 (m, 10H), 0.86 (t, J = 7.6 Hz, 6H).

[0361] 8.3. Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine

[0362] [ka]

[0363] To a solution of 2-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol (350 mg, 859 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (485 mg, 2.15 mmol, 2.5 equiv.) in dioxane (7 mL) was added Pd(PPh3)2Cl2 (60.3 mg, 85.9 μmol, 0.1 equiv.) and KOAc (169 mg, 1.72 mmol, 2 equiv.) under a N2 atmosphere at 25 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was then filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-45%, 10 min) to give N4-(1-ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine (30 mg, 65.9 μmol, 7.67% yield, 99.8% purity, TFA) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 11.86 (s, 1H), 10.13 (s, 1H), 8.99 (s, 1H), 7.91-7.86 (m, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.16-4.11 (m, 1H), 2.03 (s, 3H), 1.64-1.58 (m, 4H), 1.45 (s, 6H), 0.84 (t, J = 7.2 Hz, 6H). MS (ESI): C 21 H 28 Calculated mass of BF3N4O4: 468.22, measured m / z: 355.2 [M+H] + . HPLC: 99.80% (220 nm), 99.99% (254 nm)

[0364] 9. Preparation of 3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0365] [ka]

[0366] 9.1 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone

[0367] [ka]

[0368] To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.5 g, 7.02 mmol, 1 equiv.) and 1-(5-amino-2-bromo-phenyl)ethanone (1.50 g, 7.02 mmol, 1 equiv.) in dioxane (50 mL) was added TsOH.HO (2.00 g, 10.5 mmol, 1.5 equiv.) at 25 °C, and the resulting mixture was heated to 80 °C and stirred for 12 h. HO (30 mL) was poured into the above mixture, and the pH was adjusted to 9 with saturated aqueous NaHCO and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-100% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone (1.3 g, 3.32 mmol, 47.33% yield) as a brown oil. 1 H NMR (DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.73 (dd, J = 8.8, 2.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 8.8 Hz, 1H), 4.08-4.04 (m, 1H), 2.54 (s, 3H), 1.94 (m, 3H), 1.62-1.49 (m, 4H), 0.85 (t, J = 7.6 Hz, 6H).

[0369] 9.2 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol

[0370] [ka]

[0371] To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanone (700 mg, 1.79 mmol, 1 equiv.) and MeOH (1.79 mmol, 72.4 μL, 1 equiv.) in THF (5 mL) was added NaBH (102 mg, 2.69 mmol, 1.5 equiv.) at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into HO (10 mL), the pH was adjusted to 5 with 2 N HCl, and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by a short column to give 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (400 mg, 1.02 mmol, 56.98% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J = 8.8, 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.06 (d, J = 8.8 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H), 4.93-4.88 (m, 1H), 4.26-4.13 (m, 1H), 1.93 (s, 3H), 1.62-1.53 ​​(m, 4H), 1.28 (d, J = 6.4 Hz, 3H), 0.87 (q, J = 7.6 Hz, 6H)

[0372] 9.3 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine

[0373] [ka]

[0374] To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (300 mg, 763 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (431 mg, 1.91 mmol, 2.5 equiv.) in dioxane (10 mL) under a N atmosphere at 25 °C, Pd(PPh3)2Cl2 (53.5 mg, 76.3 μmol, 0.1 equiv.) and KOAc (150 mg, 1.53 mmol, 2 equiv.) were added, and the resulting mixture was stirred at 80 °C for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was dissolved in HO (10 mL), the pH of which was adjusted to 5 with 2 N HCl, and extracted with EtOAc (3×8 mL). The combined organic layers were washed with brine (3×5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 40%–60%, 12 min) to give N-(1-ethylpropyl)-N-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-pyrimidine-2,4-diamine (96 mg, 211 μmol, 27.65% yield, 99.80% purity, TFA) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 12.06 (s, 1H), 10.19 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 7.72 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, MS (ESI): C 20 H 26 Calculated mass of BF3N4O4: 454.20, measured m / z: 341.0 [M+H]+ . HPLC: 99.80% (220 nm), 99.74% (254 nm).

[0375] 10. Preparation of N-(7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)-1,1,1-trifluoro-N-(5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)methanesulfonamide

[0376] [ka]

[0377] 10.1 Preparation of 3-ethyl-2-hydroxy-benzaldehyde

[0378] [ka]

[0379] A mixture of 2-ethylphenol (10.0 g, 81.86 mmol, 9.62 mL, 1 equiv), MgCl (11.7 g, 122.79 mmol, 5.04 mL, 1.5 equiv), TEA (33.1 g, 327.43 mmol, 45.57 mL, 4 equiv), and (HCHO) (4.9 g, 163.71 mmol, 2 equiv) in MeCN (100 mL) was degassed and purged with N three times, and the reaction mixture was stirred under N at 80 °C for 12 h. The reaction mixture was then poured into aqueous HCl (200 mL, 1 N), and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 3-ethyl-2-hydroxy-benzaldehyde (16 g, 106.54 mmol, 65.08% yield, 2 batches) as a yellow oil. 1 H NMR (CDCl, 400 MHz) δ 11.29 (s, 1H), 9.89 (s, 1H), 7.43-7.40 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 2.71 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).

[0380] 10.2 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzaldehyde

[0381] [ka]

[0382] To a solution of 3-ethyl-2-hydroxy-benzaldehyde (10.0 g, 66.59 mmol, 1 equiv) in AcOH (100 mL) was added HNO (14.0 g, 199.97 mmol, 10 mL, 90% purity, 3.00 equiv) slowly at 0 °C. The solution was stirred at 20 °C for 2 h. The reaction mixture was poured into ice / water (250 mL) at 0 °C and the yellow solid that formed was collected by filtration and dried under vacuum to give 3-ethyl-2-hydroxy-5-nitro-benzaldehyde (8.60 g, 44.06 mmol, 66.17% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 11.91 (s, 1H), 9.99 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 2.78 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H).

[0383] 10.3 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzoic acid

[0384] [ka]

[0385] To a solution of 3-ethyl-2-hydroxy-5-nitro-benzaldehyde (5.00 g, 25.62 mmol, 1 equiv) and 2-methyl-2-butene (12.6 g, 179.33 mmol, 19.00 mL, 7 equiv) in t-BuOH (50 mL) and HO (30 mL) was added NaHPO (13.8 g, 115.28 mmol, 4.5 equiv) and NaClO (7.00 g, 76.86 mmol, 3 equiv) at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was poured into ice / water (100 mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give 3-ethyl-2-hydroxy-5-nitro-benzoic acid (5.00 g, 18.94 mmol, 73.94% yield, 80% purity) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 11.45 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 2.78 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H).

[0386] 10.4 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzoate

[0387] [ka]

[0388] To a solution of 3-ethyl-2-hydroxy-5-nitro-benzoic acid (5.00 g, 18.94 mmol, 1 equiv.) in MeOH (50 mL) was added H2SO4 (7.4 g, 75.77 mmol, 4.0 mL, 4 equiv.) dropwise at 0 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into ice / water (100 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 3-ethyl-2-hydroxy-5-nitro-benzoate (3.60 g, 14.39 mmol, 75.95% yield, 90% purity) as a yellow oil. 1 H NMR (CDCl, 400 MHz) δ 11.74 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 4.03 (s, 3H), 2.76 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0389] 10.5 Preparation of methyl 5-amino-3-ethyl-2-hydroxybenzoate

[0390] [ka]

[0391] To a solution of methyl 3-ethyl-2-hydroxy-5-nitro-benzoate (3.50 g, 15.54 mmol, 1 equiv) in EtOH (50 mL) and HO (10 mL) was added NHCl (2.50 g, 46.63 mmol, 1.63 mL, 3 equiv) and Fe (2.60 g, 46.63 mmol, 3 equiv) at 20 °C. The mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was poured into ice / water (100 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give methyl 5-amino-3-ethyl-2-hydroxy-benzoate (2.00 g, 10.25 mmol, 65.92% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 10.49 (s, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.39 (s, 2H), 2.64 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H).

[0392] 10.6 Preparation of methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-2-hydroxy-benzoate

[0393] [ka]

[0394] To a solution of methyl 5-amino-3-ethyl-2-hydroxybenzoate (600 mg, 3.07 mmol, 1 equiv.) in dioxane (20 mL) was added p-TsOH (794 mg, 4.61 mmol, 1.5 equiv.) and 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (657 mg, 3.07 mmol, 1 equiv.) at 20 °C. The mixture was stirred at 100 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was poured into saturated NaHCO (30 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-2-hydroxy-benzoate (700 mg, 1.88 mmol, 61.15% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.55 (s, 1H), 8.68 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.61 (s, 1H), 6.03 (d, J = 8.8 Hz, 1H), 4.20-4.16 (m, 1H), 3.89 (s, 3H), 2.59-2.51 (q, J = 7.6 Hz, 2H), 1.92 (s, 3H), 1.65-1.45 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.2 Hz, 6H).

[0395] 10.7 Preparation of methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]-2-(trifluoromethylsulfonyloxy)benzoate and methyl 3-ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

[0396] [ka]

[0397] To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (748 mg, 2.09 mmol, 1.3 equiv) and methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-2-hydroxy-benzoate (600 mg, 1.61 mmol, 1 equiv) in DCM (30 mL) was added DMAP (59 mg, 483 μmol, 0.3 equiv) and TEA (326 mg, 3.22 mmol, 448 μL, 2 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 8 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]-2-(trifluoromethylsulfonyloxy)benzoate (300 mg, 471 μmol, 36.91% yield) and methyl 3-ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (300 mg, 595 μmol, 29.25% yield) as a white solid. 1 H NMR (CDCl, 400 MHz) δ 11.24 (s, 1H), 7.84-7.79 (m, 4H), 7.60 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 4.41-4.35 (m, 2H), 4.05-3.97 (m, 1H), 3.93 (s, 6H), 3.87-3.83 (m, 1H), 2.82 (q, J = 7.6 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1.99 (s, 6H), 1.65-1.51 (m, 3H), 1.49-1.35 (m, 5H), 1.33-1.21 (m, 7H), 0.90-0.80 (m, 14H).

[0398] 10.8 Preparation of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]benzoate

[0399] [ka]

[0400] A mixture of methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]-2-(trifluoromethylsulfonyloxy)benzoate (100 mg, 157 μmol, 1 equiv.), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (106 mg, 471 μmol, 3 equiv.), KOAc (46 mg, 471 μmol, 3 equiv.), and Pd(PPh)Cl (11 mg, 16 μmol, 0.1 equiv.) in dioxane (10 mL) was degassed and purged with N three times, after which the mixture was stirred at 80° C. under a N atmosphere for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]benzoate (600 mg, crude) as a colorless oil.

[0401] 10.9 Preparation of N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N-[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-1,1,1-trifluoro-methanesulfonamide

[0402] [ka]

[0403] To a mixture of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)amino]benzoate (80 mg, 133.23 μmol, 1 equiv) in MeOH (0.1 mL) and THF (2 mL) was added NaBH4 (20 mg, 532.93 μmol, 4 equiv) at 0 °C, and then the mixture was stirred at 20 °C under N2 atmosphere for 2 h. The reaction was quenched with HCl (1N, 0.5 mL) and concentrated in vacuo to give a residue that was purified by preparative HPLC (Column: Nano-micro Kromasil C18 100×30 mm 8 um; Mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-60%, 10 min) to give N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N-[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-1,1,1-trifluoro-methanesulfonamide (20 mg, 41.13 μmol, 30.87% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.09 (br s, 1H), 7.77 (s, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 3.87-3.81 (m, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.97 (s, 3H), 1.50-1.39 (m, 4H), 1.15 (t, J = 7.6 Hz, 3H), 0.75 (t, J = 7.6 Hz, 6H). MS (ESI): C 20 H 26 Calculated mass of BF3N4O4S: 486.17, measured m / z: 487.1 [M+H] + . HPLC: 96.15% (220 nm), 90.95% (254 nm).

[0404] 11. Preparation of 7-ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0405] [ka]

[0406] To a mixture of N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N-[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]-1,1,1-trifluoro-methanesulfonamide (200 mg, 411 μmol, 1 equiv) in THF (10 mL) and MeOH (10 mL) was added KCO (142 mg, 1.03 mmol, 2.5 equiv) at 0 °C, and then the mixture was stirred at 20 °C under N atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Nano-micro Kromasil C18 100×30 mm 8 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 30%-50%, 10 min) to give N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine (45 mg, 127 μmol, 15.44% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.89 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 4.95 (s, 2H), MS (ESI): C 19 H 27Calculated mass of BN4O2: 354.22, measured m / z: 355.1 [M+H] + . HPLC: 93.05% (220 nm), 95.97% (254 nm).

[0407] 12. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0408] [ka]

[0409] 12.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid

[0410] [ka]

[0411] To a mixture of 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 equiv.) in concentrated H2SO4 (70 mL) was added a solution of KNO3 (4.61 g, 45.5 mmol, 0.98 equiv.) in H2SO4 (30 mL), and the resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into ice-water (w / w = 1 / 1) (200 mL), the mixture was filtered, and the filter cake was dissolved in ethyl acetate (200 mL). The resulting solution was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-bromo-3-methyl-5-nitro-benzoic acid (10.6 g, crude) as a brown solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.55 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 2.63 (s, 3H).

[0412] 12.2 Preparation of methyl 2-bromo-3-methyl-5-nitrobenzoate

[0413] [ka]

[0414] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.5 g, 32.7 mmol, 1 equiv.) in MeOH (100 mL) was added thionyl chloride (65.3 mmol, 4.7 mL, 2 equiv.) at 0 °C, and the resulting mixture was heated to 80 °C and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give methyl 2-bromo-3-methyl-5-nitro-benzoate (8.5 g, 31.0 mmol, 94.9% yield) as an off-white solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.35 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H), 2.59 (s, 3H).

[0415] 12.3 Preparation of methyl 5-amino-2-bromo-3-methyl-benzoate

[0416] [ka]

[0417] To a mixture of methyl 2-bromo-3-methyl-5-nitrobenzoate (7.5 g, 27.4 mmol, 1 equiv.) in EtOH (100 mL) and HO (20 mL), NHCl (5.86 g, 109 mmol, 4 equiv.) and Fe (6.11 g, 109 mmol, 4 equiv.) were added in one portion at 25 °C under a N atmosphere, and the resulting mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in DCM (100 mL), and the resulting solution was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give methyl 5-amino-2-bromo-3-methylbenzoate (6 g, 24.6 mmol, 89.8% yield) as a brown oil. 1 H NMR (CDCl 3, 400 MHz) δ 6.79 (s, 1H), 6.67 (s, 1H), 3.90 (s, 3H), 3.72 (br s, 2H), 2.34 (s, 3H).

[0418] 12.4 Preparation of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine

[0419] [ka]

[0420] To a mixture of 2,4,5-trichloropyrimidine (13 g, 70.8 mmol, 1 equiv.) in THF (150 mL) was added cyclopentanamine (106 mmol, 10.5 mL, 1.5 equiv.) dropwise at 0 °C, and the mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into ice-water (w / w = 1 / 1) (200 mL), the aqueous phase was extracted with ethyl acetate (100 mL x 2), and the combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (12.6 g, 54.2 mmol, 76.6% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.44-4.38 (m, 1H), 2.14-2.11 (m, 2H), 1.75-1.66 (m, 4H), 1.49-1.45 (m, 2H).

[0421] 12.5 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate

[0422] [ka]

[0423] To a mixture of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2 g, 8.62 mmol, 1 equiv.) and methyl 5-amino-2-bromo-3-methyl-benzoate (2.1 g, 8.62 mmol, 1 equiv.) in dioxane (50 mL) was added TsOH (2.23 g, 12.9 mmol, 1.5 equiv.) dropwise at 20 °C under a N atmosphere. The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was poured into saturated aqueous NaHCO (100 mL), the aqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases were washed with brine (2 x 50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate (1.5 g, 3.41 mmol, 39.6% yield) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ 9.49 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 6.92 (d, J = 7.2 Hz, 1H), 4.38-4.33 (m, 1H), 3.83 (s, 3H), 2.34 (s, 3H), 1.98-1.93 (m, 2H), 1.72-1.70 (m, 2H), 1.62-1.54 (m, 4H).

[0424] 12.6 Preparation of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate

[0425] [ka]

[0426] To a mixture of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate (500 mg, 1.14 mmol, 1 equiv.) in dioxane (15 mL), KOAc (279 mg, 2.84 mmol, 2.5 equiv.), Pd(PPh3)2Cl2 (79 mg, 113 μmol, 0.1 equiv.), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (513 mg, 2.27 mmol, 2 equiv.) were added in one portion at 25 °C under a N2 atmosphere, and the mixture was then heated to 80 °C and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate (700 mg, crude) as a brown solid. MS (ESI): C 23 H 30 Calculated mass for BClN4O4: 472.20, measured m / z: 473.2 [M+H] + .

[0427] 12.7 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0428] [ka]

[0429] To a mixture of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylbenzoate (700 mg, crude) and MeOH (0.1 mL, 1.67 equiv.) in THF (8 mL) was added NaBH (168 mg, 4.44 mmol, 3 equiv.) in portions at 0 °C, and the reaction was then stirred at 25 °C for 30 min. The reaction mixture was poured into ice-water (w / w = 1 / 1) (8 mL), the pH of the aqueous phase was adjusted to 3-4 with HCl (2 N), and extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with brine (2 x 5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 × 30 mm 8 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 20% to 50%, 10 min) to give the product with residual TFA. The product was dissolved in ice-water (w / w = 1 / 1) (8 mL), the pH of the aqueous phase was adjusted to 7 with NaHCO3 (2 N), extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (16 mg, 42 μmol, 2.82% yield, 93.73% purity) as a yellow solid. 1 H NMR (DMSO-d 6,400 MHz) δ 9.33 (s, 1H), 8.65 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.88 (s, 2H), 4.42-4.36 (m, 1H), 2.37 (s, 3H), 2.01-1.98 (m, 2H), 1.74-1.73 (m, 2H), 1.61-1.56 (m, 4H). MS (ESI): C 17 H 20 Calculated mass of BClN4O2: 358.14, measured m / z: 359.1 [M+H] + . HPLC: 93.73% (220 nm), 94.52% (254 nm).

[0430] 13. Preparation of 7-chloro-3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0431] [ka]

[0432] 13.1 Preparation of methyl 2-amino-3-chloro-5-nitro-benzoate

[0433] [ka]

[0434] To a mixture of methyl 2-amino-5-nitro-benzoate (12 g, 61.17 mmol, 1 equiv.) in DMF (120 mL) was added NCS (10.6 g, 79.5 mmol, 1.3 equiv.) in small portions at 20° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was poured into HO (200 mL), after which the yellow precipitate was collected by filtration and dried under vacuum to give methyl 2-amino-3-chloro-5-nitro-benzoate (13 g, 56.37 mmol, 92.15% yield) as a yellow solid.1 H NMR (DMSO-d6, 400 MHz) δ 8.52 (dd, J = 6.8, 2.8 Hz, 1H), 8.29 (dd, J = 7.6, 2.4 Hz, 1H), 3.88 (s, 3H).

[0435] 13.2 Preparation of methyl 2-bromo-3-chloro-5-nitrobenzoate

[0436] [ka]

[0437] To a mixture of t-BuONO (8.94 g, 86.7 mmol, 10.3 mL, 2 equiv.) and CuBr (14.53 g, 65.0 mmol, 3.0 mL, 1.5 equiv.) in MeCN (100 mL) was added methyl 2-amino-3-chloro-5-nitro-benzoate (10 g, 43.4 mmol, 1 equiv.) in small portions at 65 °C. The mixture was stirred at 65 °C for 30 min. The reaction mixture was poured into HO (150 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaSO (3×100 mL), and the combined organic layers were washed with brine (2×100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0–10% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to give methyl 2-bromo-3-chloro-5-nitro-benzoate (11 g, 37.3 mmol, 86.14% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 8.43-8.42 (m, 2H), 4.01 (s, 3H).

[0438] 13.3 Preparation of methyl 5-amino-2-bromo-3-chlorobenzoate

[0439] [ka]

[0440] To a mixture of methyl 2-bromo-3-chloro-5-nitro-benzoate (11 g, 37.4 mmol, 1 equiv) in EtOH (110 mL) and HO (30 mL) was added Fe (6.26 g, 112 mmol, 3 equiv) and NH4Cl (3.00 g, 56.0 mmol, 1.5 equiv) in one portion at 20 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was dissolved in DCM (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give methyl 5-amino-2-bromo-3-chloro-benzoate (10 g, crude) as a yellow oil. 1 H NMR (CDCl, 400 MHz) δ 6.90-6.89 (m, 1H), 6.86-6.85 (m, 1H), 3.92 (s, 3H).

[0441] 13.4 Preparation of methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate

[0442] [ka]

[0443] To a mixture of methyl 5-amino-2-bromo-3-chloro-benzoate (2.72 g, 10.3 mmol, 1.1 equiv.) and 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (2 g, 9.36 mmol, 1 equiv.) in dioxane (20 mL), TsOH.HO (2.67 g, 14.0 mmol, 1.5 equiv.) was added in one portion at 20 °C. The mixture was heated up to 80 °C and stirred for 10 h. The reaction mixture was cooled to room temperature, the pH was adjusted to 7 with saturated aqueous NaHCO, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-40% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate (2.1 g, 4.75 mmol, 50.80% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.69 (s, 1H), 6.27 (d, J = 7.6 Hz, 1H), 4.09-4.00 (m, 1H), 3.86 (s, 3H), 1.95 (s, 3H), 1.63-1.52 (m, 4H), 0.86 (t, J = 7.6 Hz, 6H).

[0444] 13.5 Preparation of 2-[2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol

[0445] [ka]

[0446] To methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate (1 g, 2.26 mmol, 1 equiv.) was added MeMgBr (3 M, 11.3 mL, 15 equiv.) in small portions at 0° C., and the resulting mixture was stirred for 4 h at 0° C. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL), and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0-60% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 2-[2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol (0.6 g, 1.36 mmol, 59.99% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 8.33 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 4.28-4.26 (m, 1H), 4.20-4.16 (m, 1H), 1.97 (s, 3H), 1.78 (s, 6H), 1.71-1.68 (m, 2H), 1.57-1.53 ​​(m, 2H), 0.96 (t, J = 7.6 Hz, 6H).

[0447] 13.6 Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine

[0448] [ka]

[0449] To a mixture of 2-[2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol (0.6 g, 1.36 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (614 mg, 2.72 mmol, 2 equiv.) in dioxane (10 mL) at 20 °C, KOAc (333 mg, 3.40 mmol, 2.5 equiv.) and Pd(PPh)Cl (95 mg, 135.81 μmol, 0.1 equiv.) were added in one portion, and the resulting mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Nano-micro Kromasil C18 100×30 mm 8 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 10 min) to give N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine (202 mg, 519.68 μmol, 38.27% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.60-7.59 (m, 2H), 4.17-4.08 (m, 1H), 2.04 (s, 3H), 1.67-1.56 (m, 4H), 1.46 (s, 6H), 0.86 (t, J = 7.2 Hz, 6H). MS (ESI): C 19 H 26 Calculated mass of BClN4O2: 388.18, measured m / z: 389.2 [M+H] + . HPLC: 99.84% (220 nm), 99.83% (254 nm).

[0450] 14. Preparation of 7-chloro-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0451] [ka]

[0452] 14.1 Preparation of [2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]methanol

[0453] [ka]

[0454] To a mixture of methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate (1.5 g, 3.40 mmol, 1 equiv.) in THF (20 mL) was added DIBAL-H (1 M, 13.6 mL, 4 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. Then, NaSO.10HO (5 g) was added to the above mixture, and the resulting mixture was stirred at 25 °C for 10 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give [2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]methanol (1 g, 2.42 mmol, 71.18% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.18 (s, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.66 (s, 1H), 6.17 (d, J = 8.8 Hz, 1H), 5.46 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.18-4.09 (m, 1H), 1.94 (s, 3H), 1.64-1.52 (m, 4H), 0.87 (t, J=7.2 Hz, 6H).

[0455] 14.2 Preparation of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine

[0456] [ka]

[0457] To a mixture of [2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]methanol (0.9 g, 2.18 mmol, 1 equiv) in THF (10 mL) was added TBSOTf (863 mg, 3.26 mmol, 750 μL, 1.5 equiv) and 2,6-dimethylpyridine (396 mg, 3.70 mmol, 430 μL, 1.7 equiv) in one portion at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into HO (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0-20% ethyl acetate / petroleum ether gradient elution, 36 mL / min) to give N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine (0.7 g, 1.33 mmol, 60.95% yield) as a yellow solid. 1 H NMR (DMSO-d6, 6.19 (d, J = 8.8 Hz, 1H), 4.64 (s, 2H), 4.14-4.07 (m, 1H), 1.94 (s, 3H), 1.63-1.49 (m, 4H), 0.93 (s, 9H), 0.87 (t, J = 7.6 Hz, 6H), 0.12 (s, 6H).

[0458] 14.3 Preparation of N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine

[0459] [ka]

[0460] To a mixture of N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-N-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine (0.6 g, 1.14 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (513 mg, 2.27 mmol, 2 equiv.) in dioxane (10 mL) was added KOAc (335 mg, 3.41 mmol, 3 equiv.) and Pd(PPh)Cl (80 mg, 114 μmol, 0.1 equiv.) in one portion at 25° C. The mixture was stirred at 80° C. under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was added with HCl (2N, 1 mL) and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 150 × 30 mm × 5 μm column; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%–40%, 12 min) to give N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5-methyl-pyrimidine-2,4-diamine (103 mg, 285.60 μmol, 25.13% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.47 (s, 1H), 9.10 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 4.99 (s, 2H), 4.09-4.02 (m, 1H), 2.03 (s, 3H), 1.68-1.52 (m, 4H), 0.87 (t, J = 7.6 Hz, 6H). MS (ESI): C 17 H 22 Calculated mass of BClN4O2: 360.15, measured m / z: 361.1 [M+H] + . HPLC: 99.83% (220 nm), 99.82% (254 nm).

[0461] 15. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3,7-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol

[0462] [ka]

[0463] 15.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate

[0464] [ka]

[0465] To a mixture of methyl 5-amino-2-bromo-3-methyl-benzoate (2.31 g, 9.45 mmol, 1 equiv.) and 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2.19 g, 9.45 mmol, 1 equiv.) in dioxane (60 mL) was added TsOH (1.79 g, 10.4 mmol, 1.1 equiv.) under a N atmosphere at 25 °C, and the resulting mixture was heated to 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by recrystallization from MTBE (40 mL) at 25 °C to give methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate (3.00 g, 6.82 mmol, 72.18% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.37 (q, J = 7.6 Hz, 1H), 3.84 (s, 3H), 2.36 (s, 3H), 1.99-1.96 (m, 2H), 1.74-1.73 (m, 2H), 1.62-1.54 (m, 4H).

[0466] 15.2 Preparation of 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-phenyl]propan-2-ol

[0467] [ka]

[0468] To a mixture of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-benzoate (1.00 g, 2.27 mmol, 1 equiv.) in THF (6 mL) under N2 atmosphere at 0 °C, MeMgBr (3 M, 4.60 mL, 6 equiv.) was added in one portion, and the resulting mixture was stirred at 25 °C for 2 h. Saturated NH4Cl (50 mL) was added to the above mixture, and the aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO and concentrated in vacuo to give 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-phenyl]propan-2-ol (0.85 g, 1.93 mmol, 84.99% yield) as a yellow oil, which was used directly in the next step without further purification.

[0469] 15.3 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0470] [ka]

[0471] To a mixture of 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl-phenyl]propan-2-ol (0.85 g, 1.93 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (1.09 g, 4.83 mmol, 2.5 equiv.) in dioxane (20 mL), KOAc (0.474 g, 4.83 mmol, 2.5 equiv.) and Pd(PPh)Cl (0.135 g, 193.28 μmol, 0.1 equiv.) were added in one portion under a N atmosphere at 25 °C, and the resulting mixture was heated to 100 °C and stirred for 7 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 5-chloro-N-cyclopentyl-N-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (0.09 g, 232.75 μmol, 12.04% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.48 (q, J = 6.8 Hz, 1H), 2.39 (s, MS (ESI): C 19 H 24 Calculated mass of BClN4O2: 386.17, measured m / z: 387.1 [M+H] + . HPLC: 97.21% (220 nm), 88.55% (254 nm).

[0472] 16. Preparation of 2-(2-bromo-3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)phenyl)propan-2-ol and 1-(2-bromo-3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)phenyl)ethanone

[0473] [ka] To a mixture of methyl 2-bromo-3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzoate (2.00 g, 4.75 mmol, 1 equiv) in THF (6 mL) under N was added MeMgBr (3 M, 9.50 mL, 6 equiv) in one portion at 0 °C and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH Cl (50 mL) and the aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by silica gel column chromatography (PE: EtOAc = 5:1 to 1:1) to give 2-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-phenyl]propan-2-ol (1.30 g, 3.09 mmol, 64.99% yield) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 8.78 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 6.06 (d, J = 8.8 Hz, 1H), 5.03 (s, 1H), 4.22-4.16 (m, 1H), 2.33 (s, 3H), 1.94 (s, 3H), 1.64-1.51 (m, 10H), 0.87 (t, J = 7.2 Hz, 6H). 1-[2-Bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-phenyl]ethenone (0.400 g, 987 μmol, 20.79% yield) was obtained as a yellow oil.

[0474] 17. Preparation of 3,3,7-trimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0475] [ka]

[0476] To a mixture of 2-[2-bromo-5-[[5-chloro-4-(1-ethylpropylamino)pyrimidin-2-yl]amino]-3-ethyl-phenyl]propan-2-ol (1.00 g, 2.26 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)5,5-dimethyl-1,3,2-dioxaborinan (1.28 g, 5.66 mmol, 2.5 equiv.) in dioxane (20 mL), KOAc (0.555 g, 5.66 mmol, 2.5 equiv.) and Pd(PPh)Cl (0.159 g, 226 μmol, 0.1 equiv.) were added in one portion under a N atmosphere at 25 °C, and the resulting mixture was heated to 100 °C and stirred for 7 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeOH]; B%: 65%-85%, 12 min) to give 3,3,7-trimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (0.111 g, 286 μmol, 12.62% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 8.44 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.27 (s, 1H), 6.16 (d, J = 8.8 Hz, 1H), 4.24-4.21 (m, 1H), 2.34 (s, 3H), 1.95 (s, 3H), 1.68-1.54 (m, 4H), 1.42 (s, 6H), 0.88 (t, J = 7.2 Hz, 6H). MS (ESI): C 20 H 29 Calculated mass of BN4O2: 368.24, measured m / z: 369.2 [M+H] + . HPLC: 98.87% (220 nm), 99.07% (254 nm).

[0477] 18. Preparation of 3,7-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0478] [ka]

[0479] 18.1 Preparation of 1-[5-[[5-chloro-4-(1-ethylpropylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-phenyl]ethanone

[0480] [ka]

[0481] To a mixture of 1-[2-bromo-5-[[5-chloro-4-(1-ethylpropylamino)pyrimidin-2-yl]amino]-3-methyl-phenyl]ethanone (400 mg, 940 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (531 mg, 2.35 mmol, 2.5 equiv.) in dioxane (20 mL), KOAc (231 mg, 2.35 mmol, 2.5 equiv.) and Pd(PPh)Cl (66 mg, 94.0 μmol, 0.1 equiv.) were added in one portion under a N atmosphere at 25 °C, and the resulting mixture was heated to 100 °C and stirred for 7 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 1-[5-[[5-chloro-4-(1-ethylpropylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-phenyl]ethanone (350 mg, 763 μmol, 81.20% yield) as a yellow oil, which was used directly in the next step.

[0482] 18.2 Preparation of 3,7-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0483] [ka]

[0484] To a mixture of 1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-phenyl]ethanone (300 mg, 684 μmol, 1 equiv.) in THF (10 mL) and MeOH (1 mL) was added NaBH (65 mg, 1.71 mmol, 2.5 equiv.) in one portion at 25 °C under a N atmosphere, and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (10 mL), the pH adjusted to 5 with 2 N HCl, and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeOH]; B%: 60%-80%, 12 min) to give 3,7-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (23 mg, 64.9 μmol, 9.49% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 8.53 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.36 (s, 1H), 6.16 (d, J = 8.4 Hz, 1H), 5.08 (q, J = MS (ESI): C 19 H 27 Calculated mass of BN4O2: 354.22, measured m / z: 355.2 [M+H] + HPLC: 97.41% (220 nm), 96.99% (254 nm).

[0485] 19. Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine

[0486] [ka]

[0487] 19.1 Preparation of methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate

[0488] [ka]

[0489] To a mixture of methyl 5-amino-2-bromo-3-chlorobenzoate (2.13 g, 8.06 mmol, 1.1 equiv.) and 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (1.7 g, 7.32 mmol, 1 equiv.) in dioxane (20 mL) was added TsOH.HO (2.09 g, 10.99 mmol, 1.5 equiv.) in one portion at 20 °C, and the resulting mixture was stirred at 80 °C for 10 h. The reaction mixture was cooled to room temperature, and its pH was adjusted to 7 with saturated aqueous NaHCO. The mixture was filtered, and the filter cake was dried under vacuum to give methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate (3 g, 6.52 mmol, 89.02% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 8.28 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 5.30 (d, J = 6.8 Hz, 1H), 4.42-4.33 (m, 1H), 3.94 (s, 3H), 2.18-2.15 (m, 2H), 1.81-1.71 (m, 4H), 1.55-1.53 ​​(m, 2H).

[0490] 19.2 Preparation of [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]methanol

[0491] [ka]

[0492] To a mixture of methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate (2 g, 4.35 mmol, 1 equiv.) in THF (20 mL) was added DIBAL-H (1 M, 22 mL, 5 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into HO (150 mL), NaSO.10HO (5 g) was added to the above mixture, and the resulting mixture was filtered to remove insoluble material. The filtrate was dried under vacuum to give [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]methanol (1.1 g, 2.55 mmol, 58.56% yield) as a yellow solid. 1 H NMR (DMSO-d6, 6.94 (d, J = 7.2 Hz, 1H), 5.50 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.43 (t, J = 8.0 Hz, 1H), 2.04-2.01 (m, 2H), 1.76-1.68 (m, 2H), 1.63-1.58 (m, 4H).

[0493] 19.3 Preparation of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-chloro-N4-cyclopentyl-pyrimidine-2,4-diamine

[0494] [ka]

[0495] To a mixture of [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]methanol (1 g, 2.31 mmol, 1 equiv) in THF (12 mL) was added TBSOTf (918 mg, 3.47 mmol, 800 μL, 1.5 equiv) and 2,6-dimethylpyridine (422 mg, 3.93 mmol, 460 μL, 1.7 equiv) in one portion at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into HO (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, filtered, and concentrated under vacuum to give the crude product, which was triturated with EtOAc at 25 °C for 10 min, then the crude product was collected by filtration and dried under vacuum to give N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-chloro-N-cyclopentyl-pyrimidine-2,4-diamine (0.0, 1.28 mmol, 55.36% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.72 (s, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.40-4.38 (m, 1H), 1.98-1.97 (m, 2H), 1.74-1.71 (s, 2H), 1.64-1.59 (m, 4H), 0.94 (s, 9H), 0.12 (s, 6H).

[0496] 19.4 Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine

[0497] [ka]

[0498] To a mixture of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-chloro-N4-cyclopentyl-pyrimidine-2,4-diamine (0.6 g, 1.10 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (496 mg, 2.20 mmol, 2 equiv.) in dioxane (10 mL) was added KOAc (323 mg, 3.29 mmol, 3 equiv.) and Pd(PPh3)2Cl2 (77 mg, 109.81 μmol, 0.1 equiv.) in one portion at 25 °C. The mixture was stirred at 80 °C under a N2 atmosphere for 16 h. The reaction mixture was filtered, and HCl (2 N, 1 mL) was added to the filtrate. The resulting mixture was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 um; mobile phase: [water (0.1% TFA)-MeOH]; B%: 45%-65%, 12 min) to give 5-chloro-N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine (25 mg, 65.95 μmol, 6.01% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.65 (s, 1H), 8.90 (br s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.01 (d, J = 7.2 Hz, 1H), 4.93 (s, 2H), 4.41-4.35 (m, 1H), 2.01-1.99 (m, 2H), 1.74-1.72 (m, 2H), 1.62-1.57 (m, 4H). MS (ESI): C 16 H 17 Calculated mass for BCl2N4O2: 378.08, measured m / z: 379.1 [M+H] + . HPLC: 94.64% (220 nm), 97.36% (254 nm).

[0499] 20. Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine

[0500] [ka]

[0501] 20.1 Preparation of 2-[2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol

[0502] [ka]

[0503] To a mixture of methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate (1 g, 2.17 mmol, 1 equiv.) was added MeMgBr (3 M, 10.9 mL, 15 equiv.) in small portions at 0° C., and the resulting mixture was stirred for 4 h at 0° C. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL), and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0-30% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 2-[2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol (0.6 g, 1.30 mmol, 59.99% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 8.33 (d, J = 2.8 Hz, 1H), 7.91 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.36 (s, 1H), 5.26 (d, J = 7.2 Hz, 1H), 4.42 (q, J = 6.8 Hz, 1H), 2.89 (s, 1H), 2.21-2.16 (m, 2H), 1.78 (s, 6H), 1.76-1.72 (m, 3H), 1.57-1.53 ​​(m, 2H).

[0504] 20.2 Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine

[0505] [ka]

[0506] To a mixture of 2-[2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol (0.5 g, 1.09 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (491 mg, 2.17 mmol, 2 equiv.) in dioxane (10 mL) was added KOAc (267 mg, 2.72 mmol, 2.5 equiv.) and Pd(PPh)Cl (76 mg, 108.65 μmol, 0.1 equiv.) in one portion at 20 °C, and the resulting mixture was stirred at 120 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and HCl (2 N, 1 mL) was added to the filtrate. The resulting mixture was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 30% to 50%, 10 min) to give 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidine-2,4-diamine (53 mg, 130.19 μmol, 11.98% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1H), 8.76 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.46-4.41 (m, 1H), 2.03-1.99 (m, 2H), 1.76-1.74 (m, 2H), 1.65-1.55 (m, 4H), 1.43 (s, 6H). MS (ESI): C 18 H 21 Calculated mass for BCl2N4O2: 406.11, measured m / z: 407.1 [M+H] + . HPLC: 98.76% (220 nm), 98.54% (254 nm).

[0507] 21. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

[0508] [ka]

[0509] 21.1 Preparation of 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanone

[0510] [ka]

[0511] To a solution of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 8.62 mmol, 1 equiv.) and 1-(5-amino-2-bromo-phenyl)ethanone (1.84 g, 8.62 mmol, 1 equiv.) in dioxane (60 mL) under a N atmosphere at 25 °C, TsOH.HO (2.46 g, 12.9 mmol, 1.5 equiv.) was added, and the resulting mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in HO (30 mL), the pH was adjusted to 9 with saturated aqueous NaHCO, and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-17% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanone (2.5 g, 6.10 mmol, 70.82% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.66 (dd, J = 9.2, 2.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 4.40-4.34 (m, 1H), 2.54 (s, 3H), 1.96-1.93 (m, 2H), 1.71-1.67 (m, 2H), 1.62-1.53 ​​(m, 4H).

[0512] 21.2 Preparation of [1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanol

[0513] [ka]

[0514] To a solution of 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanone (500 mg, 1.22 mmol, 1 equiv.) and MeOH (1.28 mmol, 51.7 μL, 1 equiv.) in THF (10 mL) was added NaBH (72.5 mg, 1.92 mmol, 1.5 equiv.) at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. The reaction was quenched by adding 2 N HCl, and HO (10 mL) was poured into the above mixture, the pH of which was adjusted to 5 with 2 N HCl, and then the aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by a short column to give 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanol (400 mg, 972 μmol, 76.05% yield) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz) δ 9.34 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.92 (s, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.28 (d, J = 3.2 Hz, 1H), 4.94-4.88 (m, 1H), 4.56-4.50 (m, 1H), 1.98-1.97 (m, 2H), 1.69-1.66 (m, 2H), 1.62-1.53 (m, 4H), 1.27 (d, J = 6.4 Hz, 3H).

[0515] 21.3 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0516] [ka]

[0517] To a solution of 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanol (300 mg, 729 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (411 mg, 1.82 mmol, 2.5 equiv.) in dioxane (10 mL) was added Pd(PPh3)2Cl2 (51 mg, 72.9 μmol, 0.1 equiv.) and KOAc (143 mg, 1.46 mmol, 2 equiv.) under a N2 atmosphere at 25 °C, and the resulting mixture was stirred at 80 °C for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in HO (10 mL), and the pH was adjusted to 5 with 2 N HCl. EtOAc (10 mL) was added to the above mixture, and the formed precipitate was collected by filtration and dried under vacuum to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 40%-60%, 12 min) to give 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (147 mg, 405 μmol, 55.60% yield, 98.84% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.74 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.46-7.41 (m, 2H), 5.15 (q, J = 6.4 Hz, 1H), 4.45-4.40 (m, 1H), 1.98-1.96 (m, 2H), 1.74-1.72 (m, 2H), 1.67-1.61 (m, 2H), 1.57-1.53 ​​(m, 2H), 1.38 (d, J = 6.4 Hz, 3H). MS (ESI): C 17 H 20 Calculated mass of BClN4O2: 358.14, measured m / z: 359.1 [M+H] +. HPLC: 98.84% (220 nm), 97.83% (254 nm).

[0518] 22. Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0519] [ka]

[0520] 22.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate

[0521] [ka]

[0522] To a solution of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 8.62 mmol, 1 equiv) and methyl 5-amino-2-bromo-benzoate (2.38 g, 10.3 mmol, 1.2 equiv) in dioxane (60 mL) under a N atmosphere at 25 °C was added TsOH.HO (2.46 g, 12.9 mmol, 1.5 equiv), and the reaction was heated to 80 °C and stirred for 12 h. The reaction mixture was concentrated in vacuo to give a residue, which was dissolved in HO (30 mL), the pH of which was adjusted to 9 with saturated aqueous NaHCO, and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-20% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate (3.30 g, 7.75 mmol, 89.96% yield) as a yellow solid.1 H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.66 (dd, J =8.8, 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 4.42-4.33 (m, 1H), 3.84 (s, 3H), 1.99-1.91 (m, 2H), 1.74-1.68 (m, 2H), 1.64-1.54 (m, 4H).

[0523] 22.2 Preparation of methyl 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol

[0524] [ka]

[0525] To a solution of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]benzoate (2.00 g, 4.70 mmol, 1 equiv.) in THF (20 mL) was added a solution of MeMgBr (3 M, 7.90 mL, 5 equiv.) dropwise over 30 min at 0 °C, and the resulting mixture was stirred at 25 °C for 1.5 h. The reaction mixture was then poured into a mixture of HO (15 mL) and saturated NH Cl (10 mL), and the aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0–55% ethyl acetate / petroleum ether gradient elution, 36 mL / min) to give 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol (1.3 g, 3.05 mmol, 64.99% yield) as a yellow oil. 1 H NMR (DMSO-d6, 6.78-6.75 (m, 1H), 5.10 (s, 1H), 4.52-4.45 (m 1H), 1.96-1.63 (m, 4H), 1.60 (s, 6H), 1.58-1.52 (m, 4H).

[0526] 22.3 Preparation of N2-[4-bromo-3-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]phenyl]-5-chloro-N4-cyclopentyl-pyrimidine-2,4-diamine

[0527] [ka]

[0528] To a solution of 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol (300 mg, 705 μmol, 1 equiv.) and 2,6-dimethylpyridine (2.11 mmol, 246 μL, 3 equiv.) in DCM (10 mL) was added [tert-butyl(dimethyl)silyl]trifluoromethanesulfonic acid (1.76 mmol, 405 μL, 2.5 equiv.) at 25 °C, and the resulting mixture was stirred at 40 °C for 6 h. Then, an additional portion of [tert-butyl(dimethyl)silyl]trifluoromethanesulfonic acid (352 μmol, 81.0 μL, 0.5 equiv.) was added to the above mixture in one portion at 25 °C, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was added to HO (15 mL), and the aqueous phase was extracted with DCM (3×8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 0-10% ethyl acetate / petroleum ether gradient elution, 36 mL / min) to give N2-[4-bromo-3-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]phenyl]-5-chloro-N4-cyclopentyl-pyrimidine-2,4-diamine (400 mg, 741 μmol, 52.56% yield) as a yellow oil. 1 H NMR (DMSO-d6, 6.82 (d, J = 8.0 Hz, 1H), 4.42-4.37(m, 1H), 1.96-1.93 (m, 2H), 1.74-1.71 (m, 8H), 1.58-1.52 (m, 4H), 0.89 (s, 9H), 0.10 (s, 6H).

[0529] 22.4 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine

[0530] [ka]

[0531] To a solution of N-[4-bromo-3-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]phenyl]-5-chloro-N-cyclopentyl-pyrimidine-2,4-diamine (400 mg, 741 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (418 mg, 1.85 mmol, 2.5 equiv.) in dioxane (10 mL) under a N atmosphere at 25° C., Pd(PPh)Cl (52.0 mg, 74.1 μmol, 0.1 equiv.) and KOAc (145 mg, 1.48 mmol, 2 equiv.) were added, and the resulting mixture was stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 × 30 mm 8 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25% to 45%, 10 min) to give 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (102 mg, 267 μmol, 36.04% yield, 97.54% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.74 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46-7.44 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), MS (ESI): C 18 H 22 Calculated mass of BClN4O2: 372.15, measured m / z: 373.1 [M+H] + . HPLC: 97.54% (220 nm), 96.29% (254 nm)

[0532] 23. Preparation of 3,3-dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0533] [ka]

[0534] 23.1 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate

[0535] [ka]

[0536] To a solution of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (1.50 g, 6.83 mmol, 1 equiv.) and methyl 5-amino-2-bromo-benzoate (1.73 g, 7.51 mmol, 1.1 equiv.) in dioxane (60 mL) under N atmosphere at 25 °C was added TsOH.HO (1.95 g, 10.2 mmol, 1.5 equiv.), and the resulting mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature, filtered, the filter cake was dissolved in HO (30 mL), the pH was adjusted to 9 with saturated NaHCO, and the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give a residue that was triturated with EtOAc (20 mL) to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate (1.70 g, 4.11 mmol, 60.24% yield) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.36 (s, 1H), 8.36 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.79 (dd, J = 8.8, 2.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 8.4 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 3.78 (s, 3H), 2.13 (s, 3H).

[0537] 23.2 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]propan-2-ol

[0538] [ka]

[0539] To a solution of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate (500 mg, 1.21 mmol, 1 equiv.) in THF (10 mL) was added MeMgBr (3 M, 2.10 mL, 5 equiv.) dropwise over 30 min at 0 °C, and the resulting mixture was stirred at 25 °C for 1.5 h. The reaction was quenched by adding saturated NH Cl (15 mL), and the aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]propan-2-ol (350 mg, 847 μmol, 69.99% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 8.25 (s, 1H), 7.89 (d, J = 3.6 Hz, 2H), 7.79 (dd, J = 8.8, 2.8 Hz, 1H), 7.77-7.75 (m, 1H), 7.74-7.73 (m, 1H), 7.35-7.28 (m, 3H), 7.06 (t, J = 7.6 Hz, 1H), 5.09 (s, 1H), 2.11 (s, 3H), 1.58 (s, 6H).

[0540] 23.3 Preparation of N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0541] [ka]

[0542] To a solution of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]propan-2-ol (300 mg, 726 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (401 mg, 1.81 mmol, 2.5 equiv.) in dioxane (10 mL) under a N atmosphere at 25° C., Pd(PPh)Cl (51 mg, 72.6 μmol, 0.1 equiv.) and KOAc (143 mg, 1.45 mmol, 2 equiv.) were added, and the resulting mixture was stirred at 80° C. for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in HO (10 mL), the pH was adjusted to 5 with 2 N HCl, and the aqueous phase was extracted with EtOAc (3×8 mL). The combined organic layers were washed with brine (3×5 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%–30%, 12 min) to give N-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N-phenyl-pyrimidine-2,4-diamine (103 mg, 286 μmol, 39.39% yield, 100% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 9.64 (s, 1H), 8.91 (br s, 1H), 7.93 (s, 1H), 7.56-7.51 (m, 3H), 7.43-7.38 (m, 4H), 7.27 (t, J = 7.6 Hz, 1H), 2.18 (s, 3H), 1.29 (s, 6H). MS (ESI): C 20 H 21 Calculated mass of BN4O2: 360.18, measured m / z: 361.0 [M+H] + . HPLC: 100.00% (220 nm), 99.77% (254 nm).

[0543] 24. Preparation of 3-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0544] [ka]

[0545] 24.1 Preparation of 1-(5-amino-2-bromo-phenyl)ethanone

[0546] [ka]

[0547] To a solution of 1-(3-aminophenyl)ethanone (10.0 g, 74.0 mmol, 1 equiv.) in DMF (70 mL) was added a solution of NBS (13.2 g, 74.0 mmol, 1 equiv.) in DMF (70 mL) dropwise over 1 h at 25 °C, and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into HO (100 mL), and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with saturated aqueous NaHCO (3 x 20 mL), HO (3 x 15 mL), and brine (3 x 10 mL), dried over NaSO, filtered, and concentrated in vacuo to give 1-(5-amino-2-bromo-phenyl)ethanone (15.0 g, 70.1 mmol, 94.71% yield) as a brown oil. 1 H NMR (CDCl, 400 MHz) δ 7.34 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 6.62 (dd, J = 8.8, 2.8 Hz, 1H), 3.82 (br s, 2H).

[0548] 24.2 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate

[0549] [ka]

[0550] To a solution of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (2.00 g, 9.10 mmol, 1 equiv.) and methyl 5-amino-2-bromo-benzoate (2.30 g, 10.0 mmol, 1.1 equiv.) in dioxane (60 mL) at 25 °C under a N atmosphere was added TsOH.HO (2.60 g, 13.7 mmol, 1.5 equiv.), and the resulting mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered, the filter cake was dissolved in HO (30 mL), the pH was adjusted to 9 with saturated aqueous NaHCO, and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was triturated with EtOAc (20 mL) and the precipitate was collected by filtration and dried under vacuum to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate (2.00 g, 4.84 mmol, 53.15% yield) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.31 (s, 1H), 8.38 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.74-7.71 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 9.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H), 2.37 (s, 3H), 2.12 (s, 3H).

[0551] 24.3 Preparation of 1-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]ethanol

[0552] [ka]

[0553] To a solution of 1-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]ethanone (1.60 g, 4.03 mmol, 1 equiv.) and MeOH (4.03 mmol, 163 μL, 1 equiv.) in THF (25 mL) was added NaBH (229 mg, 6.04 mmol, 1.5 equiv.) at 0 °C, and the resulting mixture was stirred at 25 °C for 12 h. The reaction was quenched by adding 2 N HCl, and HO (25 mL) was added to the above mixture, the pH of which was adjusted to 5 with 2 N HCl, and the aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was triturated with MTBE (10 mL) at 25° C., and the precipitate was collected by filtration and dried under vacuum to give 1-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]ethanol (1.00 g, 2.50 mmol, 62.18% yield) as a brown solid. 1 H NMR (CDCl, 400 MHz) δ 10.09 (br s, 1H), 7.89 (s, 1H), 7.57-7.55 (m, 2H), 7.53-7.47 (m, 2H), 7.41 (t, J = 8.0 Hz, 3H), 7.36-7.32 (m, 1H), 7.30-7.24 (m, 2H) 4.88 (q, J = 6.4 Hz, 1H), 2.17 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H)

[0554] 24.4 Preparation of N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0555] [ka]

[0556] To a solution of 1-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]ethanol (600 mg, 1.50 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (849 mg, 3.76 mmol, 2.5 equiv) in dioxane (12 mL) under a N atmosphere at 25 °C, Pd(PPh)Cl (105 mg, 150 μmol, 0.1 equiv) and KOAc (295 mg, 3.01 mmol, 2 equiv) were added, and the resulting mixture was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in HO (15 mL), the pH was adjusted to 5 with 2 N HCl, and the aqueous phase was extracted with EtOAc (3×8 mL). The combined organic layers were washed with brine (3×5 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 35%–55%, 12 min) to give N-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N-phenyl-pyrimidine-2,4-diamine (140 mg, 384 μmol, 25.54% yield, 94.91% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.26 (s, 1H), 9.69 (s, 1H), 8.98 (br s, 1H), 7.93 (s, 1H), 7.56-7.53 (m, 4H), 7.43 (t, J = 8.4 Hz, 2H), 7.32-7.29 (m, MS (ESI): C 19 H 19 Calculated mass of BN4O2: 346.16, measured m / z: 347.1 [M+H] + . HPLC: 94.91% (220 nm), 93.77% (254 nm).

[0557] 25. Preparation of N4-(1-ethylpropyl)-N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol-5-yl]-5-methyl-pyrimidine-2,4-diamine

[0558] [ka]

[0559] 25.1 Preparation of methyl 2-amino-3-(trifluoromethyl)benzoate

[0560] [ka]

[0561] To a solution of 2-amino-3-(trifluoromethyl)benzoic acid (10.0 g, 48.75 mmol, 1 equiv.) in MeOH (150 mL) was slowly added H2SO4 (4.00 g, 41.15 mmol, 2.2 mL) at 0 °C. After the addition, the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into ice / water (300 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-amino-3-(trifluoromethyl)benzoate (8.00 g, 36.50 mmol, 74.88% yield) as a yellow oil. 1 H NMR (CDCl, 400 MHz) δ 8.07 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 8.0 Hz, 1H), 6.47 (br s, 2H), 3.89 (s, 3H).

[0562] 25.2 Preparation of methyl 2-bromo-3-(trifluoromethyl)benzoate

[0563] [ka]

[0564] To a solution of methyl 2-amino-3-(trifluoromethyl)benzoate (5.00 g, 22.81 mmol, 1 equiv.) and HBr (46.0 g, 228.14 mmol, 31 mL, 40% purity, 10 equiv.) in MeCN (50 mL) was added NaNO (1.90 g, 27.38 mmol, 1.2 equiv. in 10 mL of HO) dropwise at 0 °C over 15 min. Then, CuBr (3.93 g, 27.38 mmol, 833.81 μL, 1.2 equiv.) was added portionwise to the above mixture at 0 °C, and the resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was poured into ice / water (100 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL x 2), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-bromo-3-(trifluoromethyl)benzoate (5.20 g, 18.37 mmol, 80.53% yield) as a yellow oil. 1 H NMR (CDCl, 400 MHz) δ 7.80 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 3.98 (s, 3H).

[0565] 25.3 Preparation of methyl 2-bromo-5-nitro-3-(trifluoromethyl)benzoate

[0566] [ka]

[0567] To a solution of methyl 2-bromo-3-(trifluoromethyl)benzoate (5.00 g, 17.67 mmol, 1 equiv) in HSO (50 mL) was added fuming HNO (3.70 g, 53.05 mmol, 2.70 mL, 90% purity, 3.00 equiv) dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into ice / water (100 mL) at 0 °C, and the yellow solid that formed was collected by filtration and dried under vacuum to give methyl 2-bromo-5-nitro-3-(trifluoromethyl)benzoate (5.00 g, 15.24 mmol, 86.28% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.77 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H).

[0568] 25.4 Preparation of methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate

[0569] [ka]

[0570] To a solution of methyl 2-bromo-5-nitro-3-(trifluoromethyl)benzoate (5.00 g, 15.24 mmol, 1 equiv) in a mixture of HO (10 mL) and EtOH (100 mL) were added NHCl (2.50 g, 45.7 mmol, 1.60 mL, 3 equiv) and Fe (2.80 g, 45.7 mmol, 3 equiv) sequentially at 20 °C, and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was poured into ice / water (100 mL) at 0 °C and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (4.10 g, 13.76 mmol, 90.25% yield) as a white solid. 1 H NMR (CDCl, 400 MHz) δ 7.08 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 3.99 (br s, 2H), 3.94 (s, 3H).

[0571] 25.5 Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate

[0572] [ka]

[0573] To a solution of methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (1.50 g, 5.03 mmol, 1 equiv.) and 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.10 g, 5.0 mmol, 1 equiv.) in dioxane (30 mL) was added p-TsOH (1.30 g, 7.6 mmol, 1.5 equiv.) at 20° C., and the resulting mixture was stirred for 6 h at 100° C. The reaction mixture was poured into saturated NaHCO (60 mL) at 0° C., and the aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate (1.60 g, 3.37 mmol, 66.89% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.55 (s, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 6.29 (d, J = 8.8 Hz, 1H), 4.09-4.03 (m, 1H), 3.88 (s, 3H), 1.95 (s, 3H), 1.62-1.49 (m, 4H), 0.84 (t, J = 7.6 Hz, 6H).

[0574] 25.6 Preparation of [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]methanol

[0575] [ka]

[0576] To a mixture of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate (1.00 g, 2.10 mmol, 1 equiv.) in THF (20 mL) was added DIBAL-H (1 M, 10.5 mL, 5 equiv.) dropwise at 0 °C, and the mixture was then stirred at 20 °C under a N atmosphere for 2 h. The reaction was quenched by adding NaSO.10HO (20 g) at 0 °C. The resulting mixture was filtered, and the filtrate was concentrated in vacuo to give [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]methanol (600 mg, 1.34 mmol, 63.76% yield) as a yellow solid. 1 H NMR (DMSO-d6, 6.19 (d, J = 8.8 Hz, 1H), 5.52 (t, J = 5.2 Hz, 1H), 4.53 (d, J = 5.2 Hz, 2H), 4.23-4.13 (m, 1H), 1.95 (s, 3H), 1.60-1.42 (m, 4H), 0.84 (t, J = 7.2 Hz, 6H).

[0577] 25.7 Preparation of N4-(1-ethylpropyl)-N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol-5-yl]-5-methyl-pyrimidine-2,4-diamine

[0578] [ka]

[0579] A mixture of [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]methanol (200 mg, 447.14 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (152 mg, 670.70 μmol, 1.5 equiv), KOAc (132 mg, 1.34 mmol, 3 equiv), and Pd(PPh)Cl (32 mg, 44.71 μmol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N three times, after which the reaction mixture was stirred at 80 °C under N atmosphere for 6 h. The reaction mixture was poured into saturated NH4Cl (20 mL), and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue that was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) and preparative HPLC (column: Nano-micro Kromasil C18 100 x 30 mm 8 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-55%, 10 min) to give N4-(1-ethylpropyl)-N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol-5-yl]-5-methyl-pyrimidine-2,4-diamine (112 mg, 284.12 μmol, 21.18% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.51 (s, 1H), 9.13 (s, 1H), 8.23 ​​(s, 1H), 7.81 (br s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 5.06 (s, 2H), 4.11-4.06 (m, 1H), 2.04 (s, 3H), 1.65-1.55 (m, 4H), 0.83 (t, J = 7.2 Hz, 6H). MS (ESI): C 18 H 22 Calculated mass of BF3N4O2: 394.18, measured m / z: 395.1 [M+H] + . HPLC: 98.77% (220 nm), 99.23% (254 nm).

[0580] 26. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0581] [ka]

[0582] 26.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate

[0583] [ka]

[0584] The material was prepared by using the procedure used for the synthesis of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (1.40 g, 2.84 mmol, 56.35% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.89 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.01 (s, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.41-4.28 (m, 1H), 3.89 (s, 3H), 1.94-1.73 (m, 2H), 1.72-1.62 (m, 2H), 1.59-1.53 ​​(m, 4H).

[0585] 26.2 Preparation of [2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]methanol

[0586] [ka]

[0587] The material was prepared by using the procedure used to synthesize [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]methanol (600 mg, 1.29 mmol, 63.61% yield) as a yellow solid. 1 H NMR (DMSO-d6, 6.97 (d, J = 7.6 Hz, 1H), 5.57 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H), 4.50-4.45 (m, 1H), 1.99-1.95 (m, 2H), 1.71-1.66 (m, 2H), 1.59-1.54 (m, 4H).

[0588] 26.3 Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0589] [ka]

[0590] The material was prepared by using the procedure used to synthesize N-(1-ethylpropyl)-N-[1-hydroxy-7-(trifluoromethyl)-2,1-benzoxaborol-5-yl]-5-methyl-pyrimidine-2,4-diamine (60 mg, 145.42 μmol, 13.54% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.92 (s, 1H), 8.98 (br s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 5.01 (s, 2H), 4.44-4.37 (m, 1H), 2.00-1.90 (m, 2H), 1.78-1.70 (m, 2H), 1.67-1.46 (m, 4H). MS (ESI): C 17 H 17 Calculated mass for BClF3N4O2: 412.11, measured m / z: 413.0 [M+H] + . HPLC: 98.46% (220 nm), 98.87% (254 nm).

[0591] 27. Preparation of 7-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0592] [ka]

[0593] 27.1 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate

[0594] [ka]

[0595] To a mixture of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (0.9 g, 4.10 mmol, 1 equiv.) and methyl 5-amino-2-bromo-3-methyl-benzoate (1.00 g, 4.10 mmol, 1 equiv.) in dioxane (20 mL) was added TsOH.HO (1.17 g, 6.15 mmol, 1.5 equiv.), and the resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, and cold NaCO solution (10 mL) was added. The aqueous phase was extracted twice with EtOAc (50 mL). The combined organic layers were washed with cold water, dried over NaSO, and concentrated in vacuo to give the crude product. The crude product was purified by recrystallization from EtOAc / petroleum ether (1:2) to give pure methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate (1.71 g, 4.00 mmol, 97.68% yield) as a grey solid. 1H NMR (DMSO, 400 MHz) δ 9.26 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.80 (dd, J = 8.0, 2.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.30 (t, J =8.0 Hz, 2H), 7.06 (t, J =7.2 Hz, 2H) 3.78 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H).

[0596] 27.2 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate

[0597] [ka]

[0598] To a mixture of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate (380 mg, 889 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (803 mg, 3.56 mmol, 4 equiv.) in anhydrous dioxane (20 mL) was added KOAc (175 mg, 1.78 mmol, 2 equiv.) and Pd(PPh3)2Cl2 (31.2 mg, 44.4 μmol, 0.05 equiv.), and the resulting mixture was bubbled with nitrogen for 10 minutes, then sealed and stirred at 80 °C for 8 hours. The reaction mixture was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 20% to 100% ethyl acetate / petroleum ether gradient elution, 50 mL / min) to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate (290 mg, 630 μmol, 70.84% ​​yield) as a light brown solid. 1H NMR (DMSO, 400 MHz) δ 9.12 (s, 1H), 8.27 (s, 1H), 7.95-7.91 (m, 2H), 7.80 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.29 (t, J =8.4 Hz, 2H), 7.05 (t, J =7.2 Hz, 1H), 3.78 (s, 3H), 3.67 (s, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.06 (s, 6H).

[0599] 27.3 Preparation of N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0600] [ka]

[0601] To a mixture of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate (240 mg, 521.3 μmol, 1 equiv.) and MeOH (33 μL, 1.6 equiv.) in THF (6 mL) was added NaBH (59 mg, 1.56 mmol, 3 equiv.) in portions at 0 °C, and the resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into ice-water (w / w = 1 / 1) (8 mL), and the pH of the aqueous phase was adjusted to 3–4 with HCl (2 N) and extracted with (3 x 5 mL). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by preparative HPLC (column: Nano-micro Kromasil C 18 100 x 30 mm 8 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-35%, 10 min) to give N-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N-phenyl-pyrimidine-2,4-diamine (84 mg, 219 μmol, 42.0% yield, 90.25% purity) as a gray solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.78 (br s, 1H), 9.01 (br s, 1H), 8.70 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.40 (t, J = 7.6 Hz, MS (ESI): C 19 H 19 Calculated mass of BN4O2: 346.16, measured m / z: 347.1 [M+H] + . HPLC: 90.25% (220 nm), 88.74% (254 nm).

[0602] 28. Preparation of 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0603] [ka]

[0604] 28.1 Preparation of methyl 2-bromo-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-3-(trifluoromethyl)benzoate

[0605] [ka]

[0606] A mixture of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (500 mg, 2.28 mmol, 1 equiv.) and methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (712 mg, 2.39 mmol, 1.05 equiv.) in dioxane (10 mL) / HCl (0.5 mL, 12 N) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The pH of the aqueous phase was adjusted to 9 with saturated NaHCO (20 mL), and the organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was then triturated with MTBE (10 mL) and the precipitate was collected by filtration and dried under vacuum to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)benzoate (670 mg, 1.39 mmol, 61.16% yield) as a gray solid. 1 H NMR (DMSO-d 6,400 MHz) δ 9.65 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.23 ​​(s, 1H), 7.96 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.81 (s, 3H), 2.12 (s, 3H).

[0607] 28.2 Preparation of [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)phenyl]methanol

[0608] [ka]

[0609] To a solution of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)benzoate (500 mg, 1.04 mmol, 1 equiv.) in THF (10 mL) was added DIBAL (1 M, 4.20 mL, 4 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 0–25 °C for 1 h. The reaction was quenched by the portionwise addition of NaSO.10HO (5 g) at 0 °C, and the resulting suspension was passed through a Celite pad. The filter cake was washed with EtOAc (10 mL), and the filtrate was concentrated in vacuo to give [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)phenyl]methanol (420 mg, 926.63 μmol, 89.19% yield) as a yellow oil.

[0610] 28.3 Preparation of 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol

[0611] [ka]

[0612] A mixture of [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)phenyl]methanol (400 mg, 882.51 μmol, 1 equiv.), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (997 mg, 4.41 mmol, 5 equiv.), Pd(PPh)Cl (124 mg, 176.50 μmol, 0.2 equiv.) and KOAc (433 mg, 4.41 mmol, 5 equiv.) in dioxane (20 mL) was stirred at 80 °C for 10 h. The suspension was passed through a Celite pad, and the filtrate was concentrated under vacuum to give a residue that was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15% to 30%, 12 min) to give 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (54 mg, 134.95 μmol, 15.29% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.70 (s, 1H), 8.91 (s, 1H), 8.65 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.37 (t, MS (ESI): C 19 H 16 Calculated mass of BF3N4O2: 400.13, measured m / z: 401.1 [M+H] + . HPLC: 99.28% (220 nm), 99.80% (254 nm).

[0613] 29. Preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0614] [ka]

[0615] 29.1 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol

[0616] [ka]

[0617] Methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate (500 mg, 1.17 mmol, 1 equiv.) was added to MeMgBr (3 M, 7.80 mL, 20 equiv.) over 30 min at 0 °C, and the resulting mixture was stirred at 25 °C for 6.5 h. The reaction mixture was then poured into saturated aqueous NH Cl (15 mL), and the aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 0-100% ethyl acetate / petroleum ether gradient elution, 36 mL / min) to give 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol (250 mg, 585 μmol, 49.99% yield) as a yellow solid.

[0618] 29.2 Preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0619] [ka]

[0620] To a solution of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol (50 mg, 117 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (66.1 mg, 293 μmol, 2.5 equiv.) in dioxane (3 mL) was added KOAc (23.0 mg, 234 μmol, 2 equiv.) and Pd(PPh)Cl (8.21 mg, 11.7 μmol, 0.1 equiv.) under a N atmosphere at 25° C., and the resulting mixture was stirred at 120° C. for 5 h. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 15% to 35%, 12 min) to give N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine (8.4 mg, 19.18% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 9.49 (s, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.58-7.56 (m, 2H), 7.42-7.38 (m, 2H), 7.26-7.25 (m, 2H), 7.23-7.16 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 3.83 (s, 6H). MS (ESI): C 21 H 23 Calculated mass of BN4O2: 374.19, measured m / z: 375.1 [M+H] + . HPLC: 100.00% (220 nm), 100.00% (254 nm).

[0621] 30. Preparation of 7-chloro-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0622] [ka]

[0623] 30.1 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-benzoate

[0624] [ka]

[0625] To a mixture of methyl 5-amino-2-bromo-3-chlorobenzoate (3.97 g, 15.0 mmol, 1.1 equiv.) and 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (3 g, 13.7 mmol, 1 equiv.) in dioxane (30 mL) was added TsOH.HO (3.90 g, 20.49 mmol, 1.5 equiv.) in one portion at 25 °C, and the resulting mixture was stirred at 80 °C for 6 h. The reaction mixture was cooled to room temperature, and the organic solvent was removed in vacuo to give the crude product, which was neutralized by adding saturated aqueous NaHCO. The precipitate from the mixture was collected by filtration and dried in vacuo to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chlorobenzoate (2.5 g, 5.58 mmol, 40.89% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 8.15 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.42-7.36 (m, 3H), 7.15 (t, J=7.4 Hz, 1H), 6.38 (s, 1H), 3.88 (s, 3H), 2.15 (s, 3H).

[0626] 30.2 Preparation of [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]methanol

[0627] [ka]

[0628] To a mixture of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-benzoate (1.2 g, 2.68 mmol, 1 equiv.) in THF (20 mL) was added DIBAL-H (1 M, 13.40 mL, 5 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into HO (150 mL), NaSO.10HO (5 g) was added to the above mixture, and the resulting mixture was stirred at 25 °C for 10 min. The insoluble material was removed by filtration, and the filtrate was concentrated under vacuum to give [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]methanol (0.7 g, 1.67 mmol, 62.23% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.36 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.34 (t, J = 7.2 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 5.47 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 5.6 Hz, 2H), 2.13 (s, 3H).

[0629] 30.3 Preparation of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0630] [ka]

[0631] To a mixture of [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]methanol (0.6 g, 1.43 mmol, 1 equiv) in THF (10 mL) was added TBSOTf (567 mg, 2.14 mmol, 500 μL, 1.5 equiv) and 2,6-dimethylpyridine (260 mg, 2.43 mmol, 280 μL, 1.7 equiv) in one portion at 25° C., and the resulting mixture was stirred for 3 h at 25° C. The reaction mixture was poured into HO (10 mL), and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0-30% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-methyl-N-phenyl-pyrimidine-2,4-diamine (450 mg, 842.76 μmol, 58.95% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.44 (s, 1H), 8.34 (s, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.92 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 4.63 (s, 2H), 2.13 (s, 3H), 0.93 (s, 9H), 0.11 (s, 6H).

[0632] 30.4 Preparation of N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0633] [ka]

[0634] To a mixture of N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-methyl-N-phenyl-pyrimidine-2,4-diamine (0.35 g, 655.48 μmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (296 mg, 1.31 mmol, 2 equiv.) in dioxane (8 mL) at 25 °C, KOAc (193 mg, 1.97 mmol, 3 equiv.) and Pd(PPh)Cl (46 mg, 65.55 μmol, 0.1 equiv.) were added in one portion, and the resulting mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was cooled to room temperature, and the precipitate was removed by filtration. HCl (2N, 1 mL) was then added to the filtrate, and the mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 150 × 30 mm × 5 μm column; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%–35%, 12 min) to give N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine (78 mg, 212.76 μmol, 32.46% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.98 (br s, 1H), 9.31 (br s, 1H), 8.98 (br s, 1H), 7.94 (s, 1H), 7.55 (d, J = 8.0 Hz, 3H), 7.45-7.41 (m, 3H), 7.27-7.25 (m, 1H), 4.80 (s, 2H), 2.17 (s, 3H). MS (ESI): C 18 H 16 Calculated mass of BClN4O2: 366.11, measured m / z: 367.1 [M+H] + . HPLC: 96% (220 nm), 98.16% (254 nm).

[0635] 31. Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0636] [ka]

[0637] 31.1 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]propan-2-ol

[0638] [ka]

[0639] To a solution of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-benzoate (1 g, 2.23 mmol, 1 equiv) in THF (10 mL) was added MeMgBr (3 M, 11.2 mL, 15 equiv) at 0° C. and the resulting mixture was stirred for 1 h at 25° C. Then the reaction mixture was poured into saturated aqueous NH4Cl (20 mL) and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, 0-60% ethyl acetate / petroleum ether gradient elution, 75 mL / min) to give 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]propan-2-ol (0.8 g, 1.79 mmol, 79.99% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.34 (s, 1H), 8.29 (d, J = 2.8 Hz, 2H), 7.94-7.93 (m, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.07-7.04 (m, 1H), 5.23 (s, 1H), 2.13 (s, 3H), 1.61 (s, 6H).

[0640] 31.2 Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine

[0641] [ka]

[0642] To a mixture of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-phenyl]propan-2-ol (0.7 g, 1.56 mmol, 1 equiv.) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (706 mg, 3.13 mmol, 2 equiv.) in dioxane (10 mL), KOAc (460 mg, 4.69 mmol, 3 equiv.) and Pd(PPh3)2Cl2 (110 mg, 156 μmol, 0.1 equiv.) were added in one portion at 25 °C, and the resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. The reaction mixture was cooled to room temperature and filtered. To the filtrate was added HCl (2 N, 1 mL), and the resulting mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%-40%, 12 min) to give N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine (220 mg, 557.44 μmol, 35.66% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.03 (br s, 1H), 9.30 (br s, 1H), 8.84 (br s, 1H), 7.95 (s, 1H), 7.58 (d, J = 8.0 Hz, 3H), 7.41 (t, J = 8.0 Hz, 2H), 7.35 (s, 1H), 7.23-7.19 (m, 1H), 2.17 (s, 3H), 1.32 (s, 6H). MS (ESI): C 20 H 20 Calculated mass of BClN4O2: 394.14, measured m / z: 395.1 [M+H] + . HPLC: 96.13% (220 nm), 98.95% (254 nm).

[0643] 32. Preparation of N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine and N-(4-anilino)-5-methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-1,1,1-trifluoro-methanesulfonamide

[0644] [ka]

[0645] 32.1 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-3-ethyl-2-hydroxy-benzoate

[0646] [ka]

[0647] To a solution of methyl 5-amino-3-ethyl-2-hydroxy-benzoate (600 mg, 3.07 mmol, 1 equiv) and 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (675 mg, 3.07 mmol, 1 equiv) in dioxane (20 mL) was added p-TsOH (793 mg, 4.60 mmol, 1.5 equiv) at 20° C., and the resulting mixture was stirred at 100° C. for 8 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give a residue that was poured into saturated NaHCO (30 mL) at 0° C. The aqueous phase was extracted with EtOAc (30 mL x 3) and the combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-3-ethyl-2-hydroxy-benzoate (750 mg, 1.98 mmol, 64.56% yield) as a yellow solid. 1 H NMR (CDCl, 400 MHz) δ 10.82 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.31 (s, 1H), 3.85 (s, 3H), 2.67 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H).

[0648] 32.2 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate

[0649] [ka]

[0650] To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (213 mg, 594.57 μmol, 1.5 equiv) and methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-3-ethyl-2-hydroxy-benzoate (150 mg, 396.38 μmol, 1 equiv) in DCM (10 mL) were added DMAP (24 mg, 198.19 μmol, 0.5 equiv) and TEA (120.33 mg, 1.19 mmol, 165.52 μL, 3 equiv) at 0° C., and the resulting mixture was stirred at 25° C. for 8 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate (440 mg, 684.77 μmol, 34.55% yield) as a yellow oil.

[0651] 32.3 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-benzoate

[0652] [ka]

[0653] A mixture of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate (100 mg, 157.09 μmol, 1 equiv., 4 batches), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (107 mg, 471.27 μmol, 3 equiv.), KOAc (46.25 mg, 471.27 μmol, 3 equiv.), and Pd(PPh)Cl (11.03 mg, 15.71 μmol, 0.1 equiv.) in dioxane (10 mL) was degassed and purged with N three times, then stirred at 80 °C for 2 h under a N atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-benzoate (600 mg, 494.71 μmol, 78.73% yield, 50% purity) as a black oil.

[0654] 32.4 Preparation of N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine and N-(4-anilino-5-methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-1,1,1-trifluoro-methanesulfonamide

[0655] [ka]

[0656] To a mixture of [4-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2-ethyl-6-methoxycarbonyl-phenyl]borinic acid (200 mg, 191.46 μmol, 1 equiv.) in MeOH (1 mL) and THF (10 mL) was added NaBH (72.43 mg, 1.91 mmol, 10 equiv.) in portions at 0 °C, and the resulting mixture was stirred at 25 °C under N atmosphere for 2 h. The reaction was quenched by adding HCl (1M, 5 mL) at 0 °C, and the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Nano-micro Kromasil C18 100*30 mm 8 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%~70%, 10 min and column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50%~80%, 10.5 min) to give N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenyl-pyrimidine-2,4-diamine (10 mg, 27.76 μmol, 4.83% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.13 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, MS (ESI): C 20 H 21 Calculated mass of BN4O2 360.18, measured m / z 361.1 [M+H] +. HPLC: 92.87% (220 nm), 94.53% (254 nm); and N-(4-anilino-5-methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-1,1,1-trifluoro-methanesulfonamide (60 mg, 121.88 μmol, 21.22% yield, 20 mg delivered) was obtained as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.15 (s, 1H), 8.71 (s, 1H), 8.10 (s, 1H), 7.30-7.28 (m, 3H), 7.15 (s, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.2 MS (ESI): C 21 H 20 Calculated mass of BF3N4O4S: 492.13, measured m / z: 493.1 [M+H] + . HPLC: 99.84% (220 nm), 99.87% (254 nm).

[0657] Part 2-1: General synthetic instructions for compounds of formula (IA)

[0658] General synthetic scheme A:

[0659] [ka]

[0660] Detailed procedures are as shown in the preparation of 5-((5-fluoro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol. See also Example 7 below.

[0661] General synthetic scheme B:

[0662] [ka]

[0663] Detailed procedures are as shown in the preparation of 5-((5-chloro-4-(cyclohexylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol.

[0664] [ka]

[0665] To a mixture of 5-chloro-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-4-methylsulfonyl-pyrimidin-2-amine (200 mg, 588.99 μmol, 1 equiv.) and cyclohexanamine (64 mg, 647.89 μmol, 74.15 μL, 1.1 equiv.) in dioxane (3 mL), TEA (149 mg, 1.47 mmol, 204.95 μL, 2.5 equiv.) was added in one portion at 25 °C under a N atmosphere, and the resulting reaction mixture was stirred at 25 °C for 2 h. HO (10 mL) was then added to the reaction mixture, the pH was adjusted to 5 with 2 N HCl, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%-45%, 10 min) to give 5-chloro-N4-cyclohexyl-N2-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidine-2,4-diamine (47 mg, 131.05 μmol, 22.25% yield) as a white solid.

[0666] Part 2-2: Example of synthesis of compounds of formula (IA)

[0667] [Example 1] 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0668] [ka]

[0669] To a mixture of 5-chloro-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-4-methylsulfanyl-pyrimidin-2-amine (250 mg, 812.84 μmol, 1 equiv.) in THF (8 mL) and HO (2 mL), NaIO (522 mg, 2.44 mmol, 135.12 μL, 3 equiv.) and RuCl (17 mg, 81.28 μmol, 5.42 μL, 0.1 equiv.) were added at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered, and water (20 mL) was added to the filtrate. The resulting mixture was extracted with EtOAc (3 x 20 mL), and the combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%~60%, 12 min to give 5-chloro-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-4-methylsulfonyl-pyrimidin-2-amine (0.041 g, 120.74 umol, 14.85% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.56 (s, 1H), 9.07 (br s, 1H), 8.88 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 3.48 (s, 3H). MS (ESI): m / z actual value 338.0 [MH] -Purity by HPLC: 89.32% (220 nm), 88.4% (254 nm).

[0670] [Example 2] 5-((5-chloro-4-(cyclohexylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0671] [ka]

[0672] This material was prepared according to General Synthetic Scheme B by reacting 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol with cyclohexanamine in the presence of TEA in THF. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.61 (s, 1H), 8.99 (br, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.63-7.58 (m, 2H), 7.13 (br, 1H), 4.95 (s, 2H), 3.98-3.96 (m, 1H), 1.93-1.90 (m, 2H), 1.82-1.79 (m, 2H), 1.70-1.66 (m, 1H), 1.46-1.40 (m, 2H), 1.34-1.31 (m, 2H), 1.20-1.15 (m, 1H) ppm. MS (ESI): m / z Measured value: 359.1 [M+H] + Purity by HPLC: 94.33% (220 nm), 96.85% (254 nm).

[0673] [Example 3] 5-((5-chloro-4-(propylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0674] [ka]

[0675] This material was prepared according to General Synthetic Scheme B starting with 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol using propylamine in the presence of TEA in THF. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.75 (s, 1H), 9.23 (br, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.82 (br, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H), 3.42-3.36 (m, 2H), 1.67-1.58 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). MS (ESI): m / z actual value 319.1 [M+H] + Purity by HPLC: 98.74% (220 nm), 99% (254 nm).

[0676] [Example 4] 5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-ol

[0677] [ka]

[0678] This material was prepared according to general synthetic scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.98 (s, 1H), 7.79 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H). MS (ESI): m / z Actual value 278.0 [M+H] +Purity by HPLC: 95.22% (220 nm), 93.22% (254 nm).

[0679] [Example 5] 5-((4-(benzylamino)-5-chloropyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0680] [ka]

[0681] This material was prepared according to general synthetic scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and benzylamine using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.52 (s, 1H), 8.09 (br, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.34-7.33 (m, 4H), 7.25 (br, 1H), 4.79 (s, 2H), 4.66 (d, J = 6.0 Hz, 1H). MS (ESI): m / z actual value 367.0 [M+H] + Purity by HPLC: 99.08% (220 nm), 98.63% (254 nm).

[0682] [Example 6] 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0683] [ka]

[0684] This material was prepared according to general synthetic scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and cyclopentylamine using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.58 (s, 1H), 8.0 (s, 1H), 7.93 (s, 1H), 7.61-7.54 (m, 2H), 7.17 (br, 1H), 4.94 (s, 2H), 4.40-4.38 (m, 1H), 2.0-1.97 (m, 2H), 1.74-1.65 (m, 2H), 1.59-1.56 (m, 4H). MS (ESI): m / z actual value 345.1 [M+H] + Purity by HPLC: 84.75% (220 nm), 86.81% (254 nm).

[0685] [Example 7] 5-((5-fluoro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0686] [ka]

[0687] To a solution of 2,4-dichloro-5-fluoropyrimidine (1.6 g, 10.0 mmol) and hexane-3-amine (0.73 g, 10 mmol) in EtOH (15 mL) was added EtN (2.8 mL, 20.0 mmol) at room temperature. The reaction was heated to 50° C. for 2 hours, and then the reaction mixture was concentrated in vacuo to give a residue that was purified by column chromatography (PE / EtOAc=10 / 1) to give 2-chloro-5-fluoro-N-(hexane-3-yl)pyrimidin-4-amine (1.1 g, 88% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.77 (s, 1H), 4.85 (br, 1H), 4.18-4.08 (m, 1H), 1.64-1.51 (m, 2H), 1.49-1.39 (m, 2H), 1.35-1.25 (m, 2H), 0.86 (t, J = 7.5 Hz, 6H).

[0688] To a solution of 2-chloro-5-fluoro-N-(hexane-3-yl)pyrimidin-4-amine (1.1 g, 5 mmol) in EtOH (20 mL) was added methyl 5-amino-2-bromobenzoate (1.15 g, 5 mmol) and HCl (1.5 N, 4 mL). The resulting reaction mixture was heated to reflux for 3 hours. The reaction was then cooled to room temperature, diluted with water, extracted with EtOAc, and the combined organic phase was washed with water, brine, and concentrated under reduced pressure to give a residue that was triturated with 1:5 EtOAc:PE to give methyl 2-bromo-5-((5-fluoro-4-(hexane-3-ylamino)pyrimidin-2-yl)amino)benzoate (1.4 g, 80% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 9.40 (s, 1H), 8.44 (d, J = 2.7 Hz, 1H), 7.88 (d, J = 3.9 Hz, 1H), 7.65 (dd, J = 8.8, 2.7 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.26 (dd, J = 23.8, 8.7 Hz, 1H), 4.16-4.04 (m, 1H), 3.85 (s, 3H), 1.65-1.45 (m, 4H), 1.35-1.23 (m, 2H), 0.91-0.79 (m, 6H).

[0689] To a solution of methyl 2-bromo-5-((5-fluoro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)benzoate (1.2 g, 3 mmol) in THF (20 mL) were added KOAc (412 mg, 9 mol), (BPin) (1.1 g, 4.2 mmol), and (dppf)PdCl (937 mg, 1.2 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 100° C. overnight, then the solid was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography with PE / EtOAc (100 / 1 to 20 / 1) to give crude methyl 5-((5-fluoro-4-(hexane-3-ylamino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, 52% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 9.35 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 3.9 Hz, 1H), 7.77 (dd, J = 8.2, 2.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.22-7.18 (m, 1H), 4.24-4.11 (m, 1H), 3.81 (s, 3H), 1.61 - 1.49 (m, 4H), 1.38-1.31 (m, 2H), 1.30 (s, 12H), 0.87 (d, J = 7.0 Hz, 6H).

[0690] To a solution of crude methyl 5-((5-fluoro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, 1.7 mmol) in MeOH (15 mL) was added NaBH (532 mg, 14.0 mmol) in portions at 30° C. The reaction was stirred at 30° C. for 30 min, 6 N HCl (3 mL) was added, and stirred for an additional 20 min. It was then neutralized with saturated aqueous NaHCO3, filtered, and the filter cake was purified by trituration with MeOH and water (v / v=5:1) to give 5-((5-fluoro-4-(hexane-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (117 mg, 20% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.22 (s, 1H), 8.89 (s, 1H), 7.96-7.82 (m, 2H), 7.64-7.51 (m, 2H), 7.19 (d, J = 8.6 Hz, 1H), 4.91 (s, Purity by HPLC: 97.79% / 210 nm and 97.96% / 254 nm. MS: m / z = 345.2, (M+H)+.

[0691] [Example 8] 5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0692] [ka]

[0693] To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added 3-methylcyclohexane-1-amine (1.7 g, 15 mmol, cis-trans mixture) and EtN (2.0 g, 20.0 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed in vacuo to give a residue that was purified by silica chromatography using PE / EtOAc (20 / 1 to 5 / 1) to give 2-chloro-5-methyl-N-(3-methylcyclohexyl)pyrimidin-4-amine (1.6 g, 67% yield, cis:trans = 3:1) as a yellow solid, which was used directly in the next step.

[0694] To a solution of 2-chloro-5-methyl-N-(3-methylcyclohexyl)pyrimidin-4-amine (1.0 g, 4.2 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.0 g, 4.2 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90 °C, 30 min), then cooled to room temperature, poured into water, extracted with DCM, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 10 / 1) to give methyl 2-bromo-5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 56% yield) as a yellow solid.

[0695] To a solution of methyl 2-bromo-5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 2.3 mmol) in THF (15 mL) were added KOAc (676 mg, 6.9 mmol), (BPin) (864 mg, 3.4 mmol), and (dppf)PdCl (734 mg, 0.9 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux overnight, then the formed solid was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give crude methyl 5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, LCMS contained 40% de-Br product) as a black solid which was used directly in the next step. MS: m / z =481.3, (M+H) + .

[0696] To a solution of crude methyl 5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, crude) in MeOH (20 mL) was added NaBH (437 mg, 11.5 mmol) in portions at 25° C. The reaction was stirred at 25° C. for 30 min, 6 N HCl (3 mL) was added, and stirred for an additional 20 min. It was then neutralized by adding saturated aqueous NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine and concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product which was triturated with CH3CN and water to give 5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (57 mg, 7% yield, cis:trans=1:1) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 9.05 (s, 1H), 8.87 (s, 1H), 7.95 (d, J = 10.7 Hz, 1H), 7.74-7.45 (m, 3H), 6.27 (d, J = 7.4 Hz, 0.5H), 5.95 (d, J = 7.4 Hz, 0.5H), 4.90 (s, 2H), 4.38-4.24 (m, 0.5H), 4.07-3.90 (m, 0.5H), 2.05-1.83 (m, 3H), 1.83-1.62 (m, 2H), 1.62-1.39 (m, 3H), 1.39-1.14 (m, 2H), 1.14-0.76 (m, 4H). HPLC purity: 98.33% at 210 nm and 99.03% at 254 nm. MS: m / z = 353.2, (M+H) + .

[0697] [Example 9] 5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0698] [ka]

[0699] To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added (4-fluorophenyl)methanamine (1.9 g, 15 mmol) and EtN (2.0 g, 20.0 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed in vacuo to give a residue that was purified by silica chromatography using PE / EtOAc (20 / 1 to 5 / 1) to give 2-chloro-N-(4-fluorobenzyl)-5-methylpyrimidin-4-amine (1.6 g, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.88 (t, J = 5.9 Hz, 1H), 7.84 (s, 1H), 7.40-7.31 (m, 2H), 7.18-7.10 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 2.01 (s, 3H) ppm.

[0700] To a solution of 2-chloro-N-(4-fluorobenzyl)-5-methylpyrimidin-4-amine (1.6 g, 6.4 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.5 g, 6.4 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90° C., 30 min), then cooled to room temperature and poured into water. The solid formed was filtered and dried under vacuum to give methyl 2-bromo-5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (1.6 g, 57% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6):δ 10.92 (s, 1H), 9.13 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.85 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.8, 2.7 Hz, 1H), 7.39-7.27 (m, 2H), 7.18-7.05 (m, 2H), 4.68 (d, J = 5.9 Hz, 2H), 3.76 (s, 3H), 2.06 (s, 3H) ppm.

[0701] To a solution of methyl 2-bromo-5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (1.6 g, 3.6 mmol) in THF (15 mL) were added KOAc (1.1 g, 10.8 mmol), (BPin) (1.4 g, 5.4 mmol), and (dppf)PdCl (1.1 g, 1.4 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to reflux overnight, then the formed solid was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give methyl 5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.3 g, LCMS contained 30% de-Br product) as a black solid which was used directly in the next step. MS: m / z =493.3, (M+H) + .

[0702] To a solution of crude methyl 5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.3 g, crude) in MeOH (20 mL) was added NaBH4 (722 mg, 19.0 mmol) in portions at 30° C. The reaction was stirred at 30° C. for 30 min, then 6 N HCl (3 mL) was added and the resulting mixture was continued to stir for an additional 20 min. The reaction mixture was neutralized with saturated aqueous NaHCO3, extracted with EtOAc, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was triturated with CH3CN and water to give 5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (186 mg, 14% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.86 (s, 1H), 7.77 (d, J = 26.9 Hz, 2H), 7.59-7.30 (m, 5H), 7.16 (t, J = 8.8 Hz, 2H), 4.81 (s, 2H), 4.64 (d, J = 5.4 Hz, 2H), 2.00 (s, 3H) ppm. Purity by HPLC: 99.55% / 210 nm and 98.97% / 254 nm. MS: (M+H) + : m / z = 365.1.

[0703] [Example 10] 5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0704] [ka]

[0705] To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added 3-methylcyclohexane-1-amine (1.7 g, 15 mmol, cis-trans mixture) and EtN (2.0 g, 20.0 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed under vacuum to give a residue that was purified by silica chromatography using PE / EtOAc (20 / 1 to 5 / 1) to give 2-chloro-5-methyl-N-(4-methylcyclohexyl)pyrimidin-4-amine (1.6 g, 67% yield, cis:trans = 1:1) as a yellow solid.

[0706] To a solution of 2-chloro-5-methyl-N-(4-methylcyclohexyl)pyrimidin-4-amine (1.0 g, 4.2 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.0 g, 4.2 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90 °C, 30 min), then cooled to room temperature, poured into water, the aqueous phase extracted with DCM, and the combined organic phases washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 10 / 1) to give methyl 2-bromo-5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 56% yield) as a yellow solid.

[0707] To a solution of methyl 2-bromo-5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 2.3 mmol) in THF (15 mL) were added KOAc (676 mg, 6.9 mmol), (BPin) (864 mg, 3.4 mmol), and (dppf)PdCl (734 mg, 0.9 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux overnight, then the solids were removed by filtration and the filtrate was concentrated in vacuo to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give crude methyl 5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, LCMS contained 40% de-Br product) as a black solid which was used directly in the next step. MS: (M+H) + : m / z =481.3.

[0708] To a solution of crude methyl 5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, crude) in MeOH (20 mL) was added NaBH (437 mg, 11.5 mmol) in portions at 25° C. The reaction was stirred at 25° C. for 30 min, then 6 N HCl (3 mL) was added and the resulting mixture was continued stirring for an additional 20 min. The reaction mixture was neutralized by adding saturated aqueous NaHCO3, extracted with DCM, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was triturated with CH3CN and water to give 5-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (99 mg, 7% yield, cis:trans=2:1) ​​as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.89 (d, J = 7.1 Hz, 1H), 8.00 (s, 1H), 7.69 (d, J = 6.1 Hz, 1H), 7.64-7.58 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 7.8 Hz, 0.35H), 6.11 (d, J = 7.4 Hz, 0.67H), 4.93 (s, 2H), 4.14-3.89 (m, 1H), 2.06-1.89 (m, 3H), 1.86-1.33 (m, 8H), 1.14-0.90 (m, 4H) ppm. Purity by HPLC: 98.65% at 210 nm and 96.91% at 254 nm. MS: (M+H) + : m / z = 353.3.

[0709] [Example 11] 5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0710] [ka]

[0711] To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added cyclobutanamine (1.1 g, 15 mmol) and EtN (2.0 g, 20.0 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed in vacuo to give a residue that was triturated with CHCN and HO to give 2-chloro-N-cyclobutyl-5-methylpyrimidin-4-amine (1.6 g, 80% yield) as a pale yellow solid. 1 H NMR (300 MHz, CDCl3): δ 7.80 (s, 1H), 4.84 (s, 1H), 4.76-4.52 (m, 1H), 2.58-2.30 (m, 3H), 2.06-1.50 (m, 6H) ppm.

[0712] To a solution of 2-chloro-N-cyclobutyl-5-methylpyrimidin-4-amine (1.6 g, 8.1 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.9 g, 8.1 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90° C., 30 min), then cooled to room temperature and poured into water. The solid formed was collected by filtration and dried under vacuum to give methyl 2-bromo-5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)benzoate (2.1 g, 68% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 8.27 (d, J = 2.7 Hz, 1H), 7.59-7.50 (m, 1H), 7.50-7.29 (m, 2H), 6.23 (d, J = 6.3 Hz, 1H), 4.66-4.44 (m, 1H), 3.86 (s, 3H), 2.47-2.32 (m, 2H), 2.32-1.58 (m, 7H) ppm.

[0713] To a solution of methyl 2-bromo-5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)benzoate (1.6 g, 4.1 mmol) in THF (15 mL) were added KOAc (1.2 g, 12.3 mmol), (BPin) (1.5 g, 6.1 mmol), and (dppf)PdCl (1.3 g, 1.6 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to reflux overnight, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give crude methyl 5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.1 g, 70% purity by LCMS) as a black solid which was used directly in the next step. MS: (M+H) + : m / z =439.3.

[0714] To a solution of crude methyl 5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.1 g, crude) in MeOH (20 mL) was added NaBH (760 mg, 20.0 mmol) portionwise at 30 °C. The reaction was stirred at 30 °C for 30 min, then 6 N HCl (3 mL) was added and the resulting mixture was continued stirring for an additional 20 min. The reaction mixture was neutralized by adding saturated aqueous NaHCO, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, brine and concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product which was triturated with CHCN and water to give 5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (260 mg, 20% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.85 (s, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 7.55 (q, J = 8.0 Hz, 2H), 6.73 (d, J = 7.0 Hz, 1H), 4.92 (s, 2H), 4.65-4.45 (m, 1H), 2.33-2.18 (m, 2H), 2.18-2.01 (m, 2H), 1.93 (s, 3H), 1.81-1.57 (m, 2H) ppm. HPLC purity: 98.57% / 210 nm and 98.69% / 254 nm.MS: (M+H) + : m / z = 311.1.

[0715] [Example 12] 5-((4-(sec-butylamino)-5-chloropyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0716] [ka]

[0717] This material was prepared according to General Synthetic Scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and butan-2-amine, using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.61 (s, 1H), 8.20 (br, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.62-7.55 (m, 2H), 4.94 (s, 2H), 4.16-4.11 (m, 2H), 1.70-1.65 (m, 1H), 1.56-1.52 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 3.4 Hz, 3H). MS (ESI): m / z actual value 333.1 [M+H] +Purity by HPLC: 97.93% (220 nm), 95.61% (254 nm).

[0718] [Example 13] 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0719] [ka]

[0720] To a solution of 2,4-dichloro-5-methylpyrimidine (1.1 g, 7.0 mmol) in EtOAc (10 mL) was added 1-phenylpropan-1-amine (945 mg, 7.0 mmol) and EtN (1.4 g, 14.0 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed in vacuo to give a residue that was triturated with CHCN and HO to give 2-chloro-5-methyl-N-(1-phenylpropyl)pyrimidin-4-amine (1.2 g, 67% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.37-7.20 (m, 5H), 5.16-5.10 (m, 1H), 4.84-4.82 (m, 1H), 2.02-1.75 (m, 5H), 0.86 (t, J = 7.4 Hz, 3H) ppm.

[0721] To a solution of 2-chloro-5-methyl-N-(1-phenylpropyl)pyrimidin-4-amine (1.2 g, 4.6 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.1 g, 4.6 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90 °C, 30 min), then cooled to room temperature and poured into water. The aqueous phase was extracted with DCM, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give methyl 2-bromo-5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 48% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.45-7.41 (m, 2H), 7.33-7.20 (m, 5H), 5.10-5.05 (m, 1H), 4.93-4.91 (m, 1H), 3.83 (s, 3H), 2.02-1.73 (m, 5H), 0.89 (t, J = 7.4 Hz, 3H) ppm.

[0722] To a solution of methyl 2-bromo-5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)benzoate (1.0 g, 2.1 mmol) in THF (15 mL) were added KOAc (617 mg, 6.3 mmol), (BPin) (787 mg, 3.1 mmol), and (dppf)PdCl (653 mg, 0.8 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to reflux overnight, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give crude methyl 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (800 mg, 30% de-Br product in LCMS) as a black solid which was used directly in the next step. MS: (M+H) + : m / z =503.3.

[0723] To a solution of crude methyl 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (800 mg, crude) in MeOH (10 mL) was added NaBH (380 mg, 10.0 mmol) in portions at 30° C. The reaction was stirred at 30° C. for 30 min, then 6 N HCl (3 mL) was added and the resulting mixture was continued stirring for an additional 20 min. The reaction mixture was neutralized by adding saturated aqueous NaHCO3, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product which was triturated with CH3CN and water to give 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (77 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.86 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.55-7.41 (m, 4H), 7.32 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.14 (dd, J = 14.6, 8.6 Hz, 1H), 5.10-4.80 (m, 2H), 2.04 (s, 3H), 1.99-1.75 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 96.48% / 210 nm and 98.14% / 254 nm. MS: (M+H) + : m / z = 375.2.

[0724] [Example 14] 5-((5-chloro-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0725] [ka]

[0726] This material was prepared according to general synthetic scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and pentan-3-amine using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.39 (s, 1H), 8.93 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.61-7.56 (m, 2H), 6.70 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H), 4.05-4.0 (m,1H), 1.64-1.57 (m, 4H), 0.90-0.86 (m, 6H). MS (ESI): m / z actual value 347.0 [M+H]+ Purity by HPLC: 95.31% (220 nm), 99.07% (254 nm).

[0727] [Example 15] 5-((5-chloro-4-((1-hydroxybutan-2-yl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H))-ol

[0728] [ka]

[0729] This material was prepared according to general synthetic scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and 2-aminobutan-1-ol, using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.47 (s, 1H), 8.95 (br, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.59-7.57 (m, 2H), 6.64-6.63 (m, 1H), 4.93 MS (ESI): m / z actual value 349.0 [M+H] + Purity by HPLC: 91.87% (220 nm), 95.66% (254 nm).

[0730] [Example 16] 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0731] [ka]

[0732] To a solution of methyl 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.4 g, crude), prepared using the general experimental procedure, in MeOH (50 mL) was added NaBH (4.6 g, 0.12 mol) in portions at room temperature. The reaction was stirred at room temperature for 1 h, then 6 N HCl (10 mL) was added and stirred for an additional 20 min. The reaction mixture was neutralized by adding saturated NaHCO3, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography with MeOH / DCM (100 / 1 to 50 / 1) to give the crude product, which was triturated with MeCN / HO (10 / 1) to give 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (1.43 g, 29% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.87 (s, 1H), 8.04 (s, 1H), 7.68 (s, 1H), 7.56 (dd, J = 19.7, 8.1 Hz, 2H), 6.36 (d, J = 6.9 Hz, HPLC purity: 98.40% / 210 nm and 97.77% / 254 nm. MS: (M+H) + : m / z = 325.1.

[0733] [Example 17] 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0734] [ka]

[0735] To a solution of 2,4-dichloro-5-methylpyrimidine (2.0 g, 12.3 mmol) in EtOAc (20 mL) was added 2-aminobutan-1-ol (2.2 g, 24.6 mmol) and EtN (2.5 g, 24.6 mmol) at room temperature. The reaction was heated to reflux overnight, and then the solvent was removed in vacuo to give a residue that was triturated with water and MeOH to give 2-((2-chloro-5-methylpyrimidin-4-yl)amino)butan-1-ol (2.1 g, 81% yield) as a pale yellow solid. 1 H NMR (300 MHz, CDCl3): δ 7.81 (s, 1H), 4.91 (d, J = 6.5 Hz, 1H), 4.29-4.06 (m, 1H), 3.88-3.65 (m, 2H), 2.03 (s, 3H), 1.80-1.56 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H) ppm.

[0736] To a solution of 2-((2-chloro-5-methylpyrimidin-4-yl)amino)butan-1-ol (1.3 g, 6.0 mmol) in EtOH (6 mL) was added methyl 5-amino-2-bromobenzoate (1.4 g, 6.0 mmol) and HCl (1.5 N, 4 mL). The reaction was subjected to microwave irradiation (90° C., 30 min), then cooled to room temperature and extracted with EtOAc. The organics were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography with DCM / MeOH (100 / 1 to 10 / 1) to give methyl 2-bromo-5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (1.4 g, 58% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.76 (s, 1H), 8.27 (s, 1H), 7.60-7.33 (m, 3H), 6.01 (d, J = 8.4 Hz, 1H), 4.47-4.24 (m, 1H), 4.03-3.73 (m, 5H), 2.05 (s, 3H), 1.87-1.56 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H) ppm.

[0737] To a solution of methyl 2-bromo-5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (1.4 g, 3.4 mmol) in THF (15 mL) were added KOAc (1.0 g, 10.2 mmol), (BPin) (1.3 g, 5.1 mmol), and (dppf)PdCl (1.1 g, 1.3 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to reflux overnight, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give crude methyl 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, LCMS contained 45% de-Br product) as a black solid. MS: (M+H) + : m / z =457.2.

[0738] To a solution of methyl 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, crude) in MeOH (20 mL) was added NaBH (570 mg, 15.0 mmol) in portions at 30° C. The reaction was stirred at 30° C. for 30 min, then 6 N HCl (3 mL) was added and stirred for an additional 20 min. The reaction mixture was neutralized by addition of saturated NaHCO3, extracted with EtOAc, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue that was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was further purified by preparative HPLC (0.1% TFA in MeCN and HO) to give 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin)-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (90 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.68 (s, 1H), 7.55 (dd, J = 21.2, 8.1 Hz, 2H), 6.02 (d, J = 8.1 Hz, 1H), 4.91 (s, 2H), 4.67 (s, 1H), 4.21-4.04 (m, 1H), 3.63-3.41 (m, 2H), 1.94 (s, 3H), 1.78-1.66 (m, 1H), 1.63-1.49 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 98.18% / 210 nm and 99.94% / 254 nm. MS: (M+H) + : m / z = 329.2.

[0739] [Example 18] 5-((4-((3-(hydroxymethyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0740] [ka]

[0741] To a solution of ethyl 3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)benzoate (500 mg, 1.2 mmol) in THF (10 mL), prepared as in Example 61, at 0° C. under a N atmosphere was added DIBAL-H (1.5 N, 4 mL), and the reaction was stirred at 0° C. for 2 h, then it was quenched by adding 6 N HCl, poured into water, neutralized by adding saturated aqueous NaHCO, and extracted with EtOAc. The combined organic phases were washed with water, brine and concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 10 / 1) to give the crude product which was further purified by preparative HPLC (0.1% TFA in MeCN) to give 5-((4-((3-(hydroxymethyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (62 mg, 14% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.85 (s, 1H), 8.38 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.49 (s, HPLC purity: 98.72% / 210 nm and 98.83% / 254 nm. MS: (M+H) + : m / z = 363.1.

[0742] [Example 19] 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0743] [ka]

[0744] To a solution of cyclopentanone (5.0 g, 59.5 mmol) in MeOH (50 mL) was added NaBH (4.5 g, 0.12 mol). The reaction was stirred at room temperature overnight, then it was poured into water, extracted with DCM, and the combined organic phases were washed with water, brine, and concentrated in vacuo to give crude cyclopentanol (3.0 g, 51% yield) as a light oil. 1 H NMR (400 MHz, CDCl3): δ 4.56 (s, 1H), 3.27-3.01 (m, 1H), 2.53 (d, J = 3.4 Hz, 3H), 2.09-1.88 (m, 2H), 1.88-1.68 (m, 2H), 1.68-1.37 (m, 4H) ppm.

[0745] To a solution of 2,4-dichloro-5-methylpyrimidine (3.7 g, 23.0 mmol) in DMF (20 mL) at room temperature was added cyclopentanol (2.0 g, 23 mmol) and NaH (1.8 g, 46 mmol). The reaction was heated at 60° C. overnight, then the mixture was quenched by adding water, extracted with EA, and the combined organic phases were washed with brine (3×50 mL) and concentrated in vacuo to give a residue that was purified by silica chromatography using PE / EtOAc (20 / 1 to 10 / 1) to give 2-chloro-4-(cyclopentyloxy)-5-methylpyrimidine (2.2 g, 45% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 5.61-5.47 (m, 1H), 2.08 (s, 3H), 2.03-1.93 (m, 2H), 1.86-1.78 (m, 4H), 1.70-1.62 (m, 2H) ppm.

[0746] To a solution of 2-chloro-4-(cyclopentyloxy)-5-methylpyrimidine (1.1 g, 5 mmol) in EtOH (10 mL) was added methyl 5-amino-2-bromobenzoate (1.15 g, 5 mmol) and HCl (1.5 N, 4 mL). The resulting mixture was heated to 80° C. for 5 hours, then cooled to room temperature and poured into water. The solid was collected by filtration and dried under vacuum to give methyl 2-bromo-5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)benzoate (1.0 g, 61% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 11.09 (s, 1H), 8.32 (d, J = 2.6 Hz, 1H), 7.83 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.6 Hz, 1H), 5.66-5.50 (m, 1H), 3.92 (s, 3H), 2.09 (s, 3H), 2.04-2.03 (m, 2H), 1.98-1.66 (m, 6H) ppm.

[0747] To a solution of methyl 2-bromo-5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)benzoate (1.0 g, 2.4 mmol) in dioxane (15 mL) were added KOAc (706 mg, 7.2 mmol), (BPin) (914 mg, 3.6 mmol), and (dppf)PdCl (800 mg, 1.0 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to reflux overnight, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica chromatography with PE / EA (10 / 1 to 3 / 1) to give crude methyl 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (650 mg, purity 70%) as a colorless oil. 1H NMR(400 MHz, DMSO): δ 9.62 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 0.6 Hz, 1H), 7.93 (s, 1H), 7.83 (dd, J = 8.2, 2.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 5.57 - 5.41 (m, 1H), 3.82 (s, 3H), 2.08 - 1.94 (m, 5H), 1.82 - 1.69 (m, 4H), 1.63 (t, J = 6.7 Hz, 2H), 1.30 (s, 12H) ppm.

[0748] To a solution of methyl 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (650 mg, 1.3 mmol) in MeOH (10 mL) was added NaBH (380 mg, 10.0 mmol) portionwise at room temperature. The reaction was continued to stir at room temperature for 30 min, then 6 N HCl (3 mL) was added and stirred for an additional 20 min. The reaction mixture was neutralized by adding saturated NaHCO3, extracted with EtOAc, and the combined organic phases were washed with water, brine, and concentrated under reduced pressure to give a residue which was purified by silica chromatography using DCM / MeOH (100 / 1 to 20 / 1) to give the crude product which was triturated with CH3CN and water to give 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (236 mg, 56% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.91 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.68 - 7.48 (m, 2H), 5.56 - 5.37 (m, 1H), 4.94 (s, 2H), 2.08 - 1.87 (m, 5H), 1.84 - 1.67 (m, 4H), 1.67 - 1.52 (m, 2H). ppm. HPLC purity: 96.53% / 210 nm and 95.01% / 254 nm. MS: (M+H) + : m / z = 326.2.

[0749] [Example 20] 5-((4-(cyclopentyl(methyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0750] [ka]

[0751] This material was prepared using the general procedures described in the schemes above and in general synthesis Scheme A. 1 H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.88 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.66-7.43 (m, 2H), 4.91 (s, 2H), 4.68-4.48 (m, HPLC purity: 98.74% / 210 nm and 98.51% / 254 nm. MS: (M+H) + : m / z = 339.2.

[0752] [Example 21] 5-((5-chloro-4-((2-cyclopropylethyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0753] [ka]

[0754] This material was prepared according to general synthetic scheme B, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and pentan-3-amine using the procedure of Example 2. 1 H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.47 (s, 1H), 8.88 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.57-7.52 (m, 2H), 7.41-7.39 (m, 1H), 4.87 (s, 2H), 3.47-3.41 (m, 2H), 1.47-1.41 (m, 2H), 0.65-0.64 (m, 1H), 0.37-0.35 (m, 2H), 0.02-0.01 (m, 2H). MS (ESI): m / z actual value 345.1 [M+H] + Purity by HPLC: 97.31% (220 nm), 98.41% (254 nm).

[0755] [Example 22] 5-((5-chloro-4-(2-ethylaziridin-1-yl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0756] [ka]

[0757] This material was prepared from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (prepared using the procedure in Example 2) and 2-ethylaziridine according to General Synthetic Scheme B. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.55 (s, 1H), 9.95 (s, 1H), 9.22 (s, 1H), 8.31 (s, 1H), 7.76 (d, J= 7.6 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 4.69-4.64 (m, 1H), 4.41-4.40 (m, 1H), 4.28-4.26 (m, 1H),1.81-1.72 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS (ESI): m / z actual value 331.0 [M+H] + Purity by HPLC: 99.26% (220 nm), 99% (254 nm).

[0758] [Example 23] 5-((4-(cyclopentylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0759] [ka]

[0760] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1 H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.87 (s, 1H), 8.02 (s, 1H), 7.79 (br, 1H), 7.61-7.53 (m, 2H), 7.24 (br, 1H), 5.95 (d, J = 6.0 HPLC purity: 98.05% / 210 nm and 98.18% / 254 nm. MS: (M+H) + : m / z = 311.1.

[0761] [Example 24] 5-((4-(cyclohexylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0762] [ka]

[0763] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1 H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.89 (s, 1H), 8.01 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55-7.53 (m, 2H), 7.12 (br, 1H), 5.94 (d, J = 5.6 Hz, 1H), 4.92 (s, 2H), 3.82-3.81 (m, 1H), 1.98-1.95 (m, 2H), 1.78-1.75 (m, 2H), 1.66-1.63 (m, 1H), 1.36-1.17 (m, 5 H) ppm. HPLC purity: 99.34% / 210 nm and 98.18% / 254 nm.MS: (M+H) + : m / z = 325.2.

[0764] [Example 25] 5-((5-methyl-4-((2-(trifluoromethyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0765] [ka]

[0766] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 7.89-7.78 (m, 3H), 7.63-7.58 (m, 2H), 7.49 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.8, 1.6 Hz, 1H), 4.61 (s, 2H), 2.11 (s, 3H) ppm. HPLC purity: 99.85% / 210 nm and 99.84% / 254 nm. MS: (M+H) + : m / z = 401.1.

[0767] [Example 26] 5-((4-((2-ethylphenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0768] [ka]

[0769] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A below. 1 H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.79 (s, 1H), 8.23 ​​(s, 1H), 7.83 (s, 1H), 7.56 (s, 1H), 7.39-7.19 (m, 6H), 4.62 (s, 2H), 2.59-2.49 (m, 2H), 2.11 (s, 3H), 1.08 (t, J = 7.8 Hz, 3H) ppm. HPLC purity: 98.66% / 210 nm and 98.32% / 254 nm. MS: (M+H) + : m / z = 361.2.

[0770] [Example 27] 5-((4-((2-fluorophenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0771] [ka]

[0772] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1 H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.82 (s, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.51-7.47 (m, 1H), 7.40-7.34 (m, HPLC purity: 97.19% / 210 nm and 97.7% / 254 nm. MS: (M+H) + : m / z = 351.1.

[0773] [Example 28] 5-((4-((2-methoxyphenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0774] [ka]

[0775] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.86 (s, 1H), 7.89 (s, 1H), 7.82-7.77 (m, 3H), 7.46 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, HPLC purity: 99.72% / 210 nm and 99.74% / 254 nm. MS: (M+H) + : m / z = 363.1.

[0776] [Example 29] 5-((4-(cyclohexyloxy)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0777] [ka]

[0778] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 6.25 (d, J = 5.6 Hz, 1H), 5.04-5.03 (m, 1H), 4.95 (s, 2H), 2.05-2.03 (m, 2H), 1.79-1.76 (m, 2H), 1.59-1.57 (m, 1H), 1.49-1.38 (m, 4H), 1.27-1.24 (m, 1H) ppm. HPLC purity: 98.35% / 210 nm and 98.69% / 254 nm.MS: (M+H) + : m / z = 326.1.

[0779] [Example 30] 5-((4-((2-chlorophenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0780] [ka]

[0781] This material was prepared using the general experimental procedure as shown in General Synthetic Scheme A. 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.87 (s, 1H), 8.71 (br, 1H), 7.93 (s, 1H), 7.65-7.57 (m, 3H), 7.48-7.38 (m, 3H), 7.23 (d, J = 8.0 Hz, 1H), 4.68 (s, 2H), 2.14 (s, 3H) ppm. HPLC purity: 97.04% / 210 nm and 96.10% / 254 nm. MS: (M+H) + : m / z = 367.1.

[0782] [Example 31] 5-((5-methyl-4-((2-(trifluoromethoxy)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0783] [ka]

[0784] This material was prepared using the general experimental procedure shown in General Synthetic Scheme A. 1H NMR (DMSO-d6, 400 MHz) δ 9.18 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 7.92 (s, 1H), 7.64-7.62 (m, 2H), 7.51-7.38 (m, 4H), 7.28-7.26 (m, 1H), 4.67 (s, 2H), 2.11 (s, 3H) ppm. HPLC purity: 99.7% / 210 nm and 99.81% / 254 nm. MS: (M+H) + : m / z = 417.1.

[0785] [Example 32] 5-((5-chloro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol

[0786] [ka]

[0787] This material was prepared according to the general synthetic scheme, starting from 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol and hexan-3-amine using the procedure in Example 2. 1 H NMR (DMSO-d6, 400 MHz)...

Claims

1. Compounds of formula (IB): [Formula 1] [In the formula, A is, [chemical 2] is selected from the group consisting of X is selected from the group consisting of NH and S; R B is unsubstituted phenyl, substituted phenyl, unsubstituted C 1 ~C 6 Alkyl, substituted C 1 ~C 6 Alkyl, unsubstituted C 3 ~C 6 Cycloalkyl and substituted C 3 ~C 6 cycloalkyl, where the substituents are selected from one or more of CH 2 OH, C 1 -C 3 alkyl, and SO 2 (C 1 -C 3 alkyl); R C is hydrogen, halogen, C 1 ~C 3 Alkyl, and C 1 ~C 3 haloalkyl; Each R 1 If present, chlorine, bromine, iodine, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, O(C 1 ~C 3 alkyl), and O(C 1 ~C 3 haloalkyl); Each R 1b When present, each independently represents hydrogen, halogen, or C. 1 ~C 3 Alkyl, and C 1 ~C 3 haloalkyl; R 2 and R 3 Each of, when present, independently, 1 ~C 3 Alkyl, C 2 ~C 3 Alkenyl, C 2 ~C 3 alkynyl, and when present, R 2 and R 3 taken together form a three-membered cycloalkyl ring, R 2a and R 3a Each of, when present, independently, 1 ~C 3 is alkyl] or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutically acceptable salt thereof.

2. A, [C3] 13. The compound of claim 1, selected from the group consisting of:

3. 2. The compound of claim 1, wherein X is NH, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutically acceptable salt thereof.

4.

4. [ka] [ka] [ka] [ka] or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutically acceptable salt thereof.

5.

5. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutically acceptable salt thereof.

6. 10. A medicament comprising a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof, for the treatment of a disease or disorder susceptible to modulation of one or more of: (i) JAK, and (ii) JAK and an additional enzyme.

7. The pharmaceutical of claim 6, wherein the additional enzyme is a tyrosine kinase.

8. The pharmaceutical of claim 7, wherein the additional tyrosine kinase is one or more of TrkA and Syk.

9. The pharmaceutical composition of claim 6, wherein the additional enzyme is PDE4.

10. 10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behcet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, dry eye disease, secondary eosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, artherosclerosis, and cancer.

11. The pharmaceutical composition according to claim 10, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis.

12. A medicament according to any one of claims 6 to 11 for perturbing an immunoregulatory pathway in a cell.

13. The pharmaceutical of claim 12, wherein the perturbation produces an effect on the JAK-STAT pathway.

14. A method for inhibiting JAK in a mammalian cell in vitro, either alone or in combination with inhibition of one or more additional mechanisms, comprising contacting the mammalian cell with a compound of any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof.

15. 15. The method of claim 14, wherein the additional mechanism is inhibition of tyrosine kinase.

16. 16. The method of claim 15, wherein the tyrosine kinase is one or more of TrkA and Syk.

17. The method of claim 14, wherein the additional mechanism is inhibition of PDE4.

18. A medicament comprising a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof, for the treatment of a disease or disorder susceptible to modulation of JAK, either alone or with dual modulation by PDE4.

19. 19. The pharmaceutical composition of claim 18, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behcet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, dry eye disease, secondary eosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer.

20. The pharmaceutical composition according to claim 19, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis.

21. A medicament according to any one of claims 18 to 20 for perturbing an immunoregulatory pathway in a cell.

22. The pharmaceutical of claim 21 , wherein the perturbation produces an effect on the JAK-STAT pathway.

23. A method for inhibiting JAK in combination with PDE4 in a mammalian cell in vitro, comprising contacting the mammalian cell with a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof.

24. The pharmaceutical agent according to any one of claims 6 to 13 and 18 to 22, wherein the JAK is JAK-1.

25. The pharmaceutical agent of claim 24, wherein the inhibition is selective for JAK-1.

26. 24. The method of claim 23, wherein the mammalian cell is a cell from a subject having an inflammatory condition.

27. A method for inhibiting JAK in a mammalian cell in vitro, either alone or together with one or more of TrkA and Syk, comprising contacting the mammalian cell with a compound of any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof.

28. 30. The method of any one of claims 14 to 17, 23 and 27, wherein the JAK is JAK-1.

29. 29. The method of claim 28, wherein the inhibition is selective for JAK-1.

30. 30. The method of any one of claims 27 to 29, wherein the mammalian cell is a cell from a subject having an inflammatory condition.

31. 6. A pharmaceutical agent for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer comprising a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof.

32. The pharmaceutical composition according to claim 31, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

33. 33. A medicament according to any one of claims 6 to 13, 18 to 22, 24, 25, 31 and 32 for administration to a mammal.

34. 34. The method of claim 33, wherein the mammal is selected from a human, a domestic mammal, a captive mammal, or a companion mammal.

35. The pharmaceutical according to claim 33 or 34, wherein the mammal is a human.

36. 35. The method of claim 33 or 34, wherein the mammal is one or more of a cow, a sheep, a goat, a llama, an alpaca, a pig, a horse, a donkey, a dog, and a cat.

37. The method of any one of claims 14 to 17, 23 and 26 to 30, wherein the mammal is selected from a human, a domestic mammal, a captive mammal, or a companion mammal.

38. The method of claim 37, wherein the mammal is a human.

39. The method of claim 37, wherein the mammal is one or more of a cow, sheep, goat, llama, alpaca, pig, horse, donkey, dog, and cat.

40. 6. A composition comprising a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, or tautomer thereof, or a veterinarily or pharma- ceutically acceptable salt thereof, and a pharma-ceutically or veterinarily acceptable carrier.

41. 10. A pharmaceutical combination comprising a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof, and one or more other pharma- ceutical or veterinarily active substances.

42. 13. Use of a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer or tautomer thereof, or a veterinarily or pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment of one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer.

43. 43. The use according to claim 42, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

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