Chemical compounds containing boron that inhibit Janus kinases (JAK), pharmaceutical compositions containing them, and their medical uses

Abstract

This disclosure describes innovative compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds in this disclosure have activity as dual modulators of Janus kinase (JAK), alone or in combination with one or more additional mechanisms, including a tyrosine kinase, such as TrkA or Syk, and PDE4, and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and indications where JAK modulation would be desirable. Methods for treating inflammation, autoimmune diseases, cancer, and other conditions amenable to JAK and PDE4 inhibition by administering a compound described herein are also described.

Description

CHEMICAL COMPOUNDS Cross reference to related requests The present application claims priority for each of the US Provisional Application Serial No. 62 / 870537 filed on July 3, 2019, US Provisional Application Serial No. 62 / 916697 filed on July 17, 2019. October 2019, US Provisional Application Serial No. 62 / 916700 filed on October 17, 2019, US Provisional Application Serial No. 62 / 949280 filed on December 17, 2019 and the Application US Provisional Serial No. 62 / 949301 filed December 17, 2019, each of which is incorporated herein by reference in its entirety. field of invention The present disclosure describes innovative compounds containing boron, or its pharmaceutically acceptable salts, pharmaceutical compositions containing them and their medical uses. In one embodiment, the compounds of the invention have activity as inhibitors of Janus kinases (JAK), either alone or in combination with at least one additional mechanism, such as inhibition of another tyrosine kinase, including JAK A kinase inhibitors. tropomyosin receptor (TrkA) or spleen tyrosine kinase (Syk) inhibitors, and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and indications where JAK modulation would be optionally desirable. together with one or more other mechanisms, such as inhibition of a tyrosine kinase, including TrkA and Syk. Also described herein are methods of treating inflammation, autoimmune diseases, cancer and other conditions susceptible to JAK inhibition, optionally in conjunction with one or more other mechanisms, such as inhibition of a tyrosine kinase, including TrkA and Syk by administration of a compound of the disclosure. In one embodiment, the compounds of the invention have activity as dual inhibitors of Janus kinases (JAK) and phosphodiesterase-4 (PDE4) and are useful in the treatment or control of inflammation, autoimmune diseases, cancer and other disorders and indications in the that modulation of JAK together with PDE4 would be desirable. Also described herein are methods of treating inflammation, autoimmune diseases, cancer and other conditions susceptible to inhibition of JAK together with PDE4 by administration of a compound of the disclosure. Likewise, where the compounds of the present disclosure have additional inhibitory mechanisms, the present disclosure includes methods for treating other conditions susceptible to such inhibition. Background 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 and imposing a significant economic and social burden due to medical costs. direct effects and decreased productivity of individuals with AD. The burden of AD appears to be mainly related to limited treatment methods. Additionally, according to AD treatment guidelines, there is no standard of care and treatment can be tailored to individual needs. QQ! ozn / zznz / q / ΥΙΛΙ needs of an individual. Topical interventions are the mainstay of AD therapy. Until now, topical corticosteroids have been the first-line treatment. However, its use may be limited by possible local and systemic adverse effects. Topical calcineurin inhibitors are classified as second-line anti-inflammatory therapy for AD, with advantages in long-term maintenance and special site application. Topical calcineurin inhibitors inhibit calcineurin-dependent T cell activation; However, a black box warning regarding the potential for development of malignancy with the use of topical calcineurin inhibitors reduces patient adherence to treatment. Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity, arising from mutation, overexpression or misregulation, dysregulation, as well as over or underproduction of growth factors or cytokines, has been implicated in many diseases, including but not limited to cancer. , cardiovascular diseases, 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 cellular biological responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell motility, which are implicated in the aforementioned diseases. and related. Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3 and Tyk-2) play 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 the cytokine receptor, thereby creating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family. which ultimately lead to gene expression, which stimulates biological responses such as an itch signal. Activation of the JAK-STAT pathway also results in several other ancillary biologic activities that contribute to the inflammation and pruritic processes that contribute to acute allergy in animals, but can also exacerbate clinical signs and contribute to chronic allergy. Selectivity between JAK subtypes may be useful in the treatment of certain diseases or disorders. The TrkA family are receptor tyrosine kinases (TrkA, TrkB, and TrkC) involved in a variety of intracellular signal transduction pathways involved in psoriasis and associated 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 is associated with the formation of psoriatic lesions. In addition, it is believed that NGF stimulates the expression and qq / Qzn / zznz / q / υιλι cation channel co-receptor of the transient potential receptor subfamily V member 1 (TRPV1) cation channel and that NGF-TrkA signaling -TRPV1 is implicated in these dermatological conditions. The phosphodiesterase (PDE) family of enzymes plays a role in the degradation of cyclic adenosine monophosphate, an important intracellular second messenger critical to multiple signaling pathways. PDE inhibitors have been developed and evaluated for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, erectile dysfunction, Alzheimer's disease, and chronic inflammatory skin diseases. A phosphodiesterase type 4 inhibitor, commonly called a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). Enzymes of the PDE4 family are the most common PDEs in immune cells and are primarily responsible for cAMP hydrolysis in both immune cells and those of the central nervous system. As noted above, phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells and brain cells, manifests as a non-receptor intracellular enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects through elevation of cyclic adenosine monophosphate (cAMP) level and subsequent regulation of a wide range of genes and proteins. As such, PDE4 may be a promising therapeutic target for the treatment of various serious pulmonary, dermatological, and neurological diseases. Numerous 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 spectacular effectiveness of a drug can be accompanied by adverse effects, such as nausea, vomiting, and gastrointestinal reactions. In addition to dermatological utilities, PDE4 inhibitors may have potential as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder, depression, anxiety disorders, 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. Inhibition of PDE4 is also known to attenuate ethanol seeking and consumption in rats, and may be useful in the treatment of alcohol dependence. Inflammation underlies the pathogenesis of various human diseases, including infections, immune-mediated disorders, metabolic disturbances, neurodegeneration, and cancer. Inflammatory diseases affect a certain population worldwide and have extremely complicated pathogenic mechanisms (Kazatchkine and Kaveri, 2001). To date, numerous therapeutic strategies have emerged in the treatment of inflammatory diseases (Tabas and Glass, 2013; Siebert et al, 2015). Although qq / Qzn / zznz / q / υιλι non-steroidal anti-inflammatory drugs (ΑΙΝΕ) and corticosteroids have contributed greatly to anti-inflammatory intervention, serious long-term adverse effects and multiple disease manifestations deter some patients from these therapeutic options (Hart and Huskisson, 1984). Therefore, there remains a great need to discover innovative therapeutic drugs to control inflammation with diverse anti-inflammatory spectrums (Uguccioni et al., 2017). Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) function as essential second messengers in the regulation of multiple cellular metabolisms. Phosphod i este rases (PDEs), consisting of 11 families (PDE1-PDE11), are available for cyclic nucleotide degradation (Kumar et al., 2013). The distributions of PDE subfamilies are diverse in different cells and tissues, which may provide substantial support for your pharmacological research in the field of inflammation, cognition, lipogenesis, proliferation, apoptosis, and differentiation. cAMP-specific PDE4 is widely expressed in the brain, cardiovascular tissues, smooth muscles, keratinocytes, and immunocytes (including T cells, monocytes, macrophages, neutrophils, dendritic cells, eosinophils) (Chiricozzi et al., 2016). PDE4 inhibition can raise the intracellular level of cAMP and subsequently modulate inflammatory responses and maintain immune balance (Maurice et al., 2014). Targeting PDE4 has been shown to be an effective therapeutic strategy for inflammatory conditions including asthma, COPD, psoriasis, atopic dermatitis (AD), inflammatory bowel disease (IBD), rheumatic arthritis (RA) , lupus and neuroinflammation. Several products such as roflumilast, apremilast, and crisaborole were successively approved for the treatment of inflammatory diseases of the airways or skin. In addition, a number of innovative PDE4 inhibitors have also been developed for the regulation of inflammation, and have shown satisfactory therapeutic efficacy. Growing evidence demonstrated that patients suffering from inflammatory diseases showed higher PDE4 expression than healthy individuals (Schafer et al., 2016). There are four subtypes of PDE4, namely PDE4A-PDE4D, which are highly specific for the degradation of cAMP, but not for cGMP. Inhibition of PDE4 results in the accumulation of intracellular cAMP and subsequently activates PKA, cyclic nucleotide-gated ion channels, and Epac1 / 2. These are involved in the regulation of proinflammatory and anti-inflammatory cytokine synthesis, T cell activation, neutrophil degranulation, antigen presentation performance, and epithelial integrity through the initiation of multiple downstream elements. Release of the catalytic subunit of the regulatory subunit upon PKA activation could subsequently increase phosphorylation of cAMP-sensitive element-binding protein (CREB), activating transcription factor-1 (ATF-1), and cAMP-sensitive element modulator. cAMP (CREM) and recruit CREB-binding protein (CBP) or p300 homologous protein, leading to reduced inflammatory cytokines and increased anti-inflammatory cytokines (Schafer, 2012). A previous study demonstrated that the transcriptional activity of the classical nuclear factor kappa light chain enhancer of activated B cells (NF-kB) can be stimulated by phosphorylation of p65 at Ser276 by PKA (Christian et al., 2016).CBP / p300 is closely associated with NF-kB p65, and qq / Qzn / zznz / q / υιλι PKA activation could regulate NF-kB transcriptional activity through modulation of its interaction with CBP / p300 without the degradation of IkBa or NF-kB DNA-binding activity, resulting in the downregulation of inflammatory responses (Zhong et al, 1998; Schafer, 2012). In addition, PKA activation could interfere with B-cell lymphoma protein-6 (Bcl-6)-mediated proinflammatory cytokine synthesis and immune cell proliferation (Page, 2014; Hernández-Flórez and Valor, 2016). Activation of Epac1 / 2 following cAMP elevation serves as a promising alternative mechanism to target inflammation and proliferation (Lehrke et al., 2015). The compartmentalization of intracellular cAMP in space and time contributes to the Epac signaling of transcription factors, small GTPases (Rap1), which function well in optimizing the treatment of inflammatory airway diseases, renal failure, alteration of vasculature and neuroinflammation (Schmidt et al., 2013). Given the role of cAMP in various physiological metabolisms in various cell types, elevation of cAMP after PDE4 inhibition is closely associated with suppression of overactive immune responses or intermediaries. Accumulating research indicates that PDE4 inhibition could modulate both innate and adaptive responses. PDE4 inhibition showed regulatory activities on macrophages, neutrophils, monocytes, and dendritic cells (Crilly et al., 2011; Schafer, 2012). In addition, PDE4 inhibition showed excellent effects on T cell receptor (TCR)-induced T cell activation, which was manifested in reduced release of cytokines and chemokines from T helper-1 (Th1) cells. , Th2 and Th17 (Sakkas et al., 2017), while PDE4 inhibition might have little effect on B cell phenotype and function (Schafer et al., 2014). Furthermore, elevated cAMP in keratinocytes and epithelial cells could also inhibit inflammatory responses and regulate cell growth and barrier functions (Page, 2014). See, Li H, et al., Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 9:1048 (2018), within which sub-references are cited, and all of which are incorporated herein by reference with respect to the referenced biological teachings. Therefore, PDE4 represents a more upstream anti-inflammatory target than JAK that regulates cytokines through the JAK-STATS pathway. Thus, PDE4 inhibitors have complementary biological effects to JAK inhibitors. A combination of JAK and PDE4 inhibition activities in one molecule results in drugs with a unique and attractive anti-inflammatory profile and spectrum for the treatment of inflammatory diseases with extremely complicated pathogenic mechanisms. Until now, no such drugs have been reported in the literature. The central role that Syk (spleen tyrosine kinase) plays in the immune system in mediating inflammatory responses, together with its more recently identified association with malignancy, 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 couple immune cell receptors to intracellular signaling pathways that regulate cellular responses to extracellular antigens and antigen-immunoglobulin complexes of particular importance for the initiation of inflammatory responses. Thus, Syk is an attractive target for therapeutic kinase inhibitors designed to ameliorate the symptoms and consequences of acute and chronic inflammation. Given the central role of SYK in the transmission of activation signals within B cells, a deletion of this tyrosine kinase could help in the treatment of B cell neoplasms and autoimmune diseases. Syk Inhibition has been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia. Syk inhibitors are in clinical development, including cerdulatinib and entospletinib. Other inhibitors of B cell receptor (BCR) signaling, including ibrutinib (PCI-32765), which inhibits BTK, and idelalisib (PI3K inhibitor - CAL-101 / GS-1101) also showed activity in the diseases. The orally active SYK inhibitor fostamatinib (R788) is being developed for the treatment of rheumatoid arthritis. The Syk inhibitor nilvadipine has been shown to regulate β-amyloid production and Tau phosphorylation, which is why it has been proposed as a treatment for Alzheimer's disease. Therefore, JAK inhibitors, with or without additional tyrosine kinase activity, and with or without PDE4, a dual inhibitory mechanism may provide an innovative therapeutic strategy for various immune and inflammatory diseases, including rheumatoid arthritis (RA), arthritis, colitis ulcerative disease, 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, lupus erythematosus systemic (SLE), dermatomyositis, Sjógren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis and cancer. Reference is made to Schwartz et al., JAK inhibition as a therapeutic strategy for immune and inflammatory diseases, Nat Rev Drug Discov., December 28, 2017, 17(1):78, incorporated herein by reference with respect to justification for the focus on JAK. Psoriasis and psoriatic arthritis are associated with aberrant inflammation and the production of proinflammatory mediators. Psoriasis and psoriatic arthritis are inflammatory diseases with overlapping features and shared immunological mechanisms. Psoriasis is a systemic disease that primarily affects the skin, but up to 40% of people with psoriasis can develop psoriatic arthritis. Psoriatic arthritis usually affects the peripheral joints and can occasionally affect the spine and sacroiliac area. Enthesitis, dactylitis, and nail changes such as pitting and discoloration are also common manifestations of psoriatic disease in patients with joint involvement. Therefore, there is a need for therapies targeting and modulating JAK alone or JAK and one or more of an additional mechanism, such as inhibition of a tyrosine kinase, including TrkA and Syk, and further optionally in combination with PDE4, for the treatment or control of inflammation, autoimmune diseases, cancer and other disorders and indications where modulation would be desirable. In addition, compounds with additional activity to modulate one or more tyrosines would also be desirable. QQ / 070 / 7707 / 31 / ΥΙΛΙ additional kinases, including inhibition of tropomyosin receptor kinase A (TrkA) or spleen tyrosine kinase (Syk). Brief description of the invention An embodiment of the present disclosure includes a compound of formula (I): qq / Qzn / zznz / q / υιλι where: A is selected from the group consisting of: and X is selected from the group consisting of: NH, O, and S; when present, R1 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, haloalkynyl C2-C3, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl) and O(C1-C3 haloalkyl); when present, each R1t>is independently selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-haloalkenyl C3, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl) and O(C1-C3 haloalkyl); when present, each of R2 and R3 is independently selected from the group consisting of: C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and, when present, R2 and R3 taken together form a 3-membered cycloalkyl ring ; and when present, each of R2a and R3a, is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and R2a and R3 taken together form a 3-cycloalkyl ring. members, RB is selected from the group consisting of: substituted phenyl, unsubstituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Ci-Ce alkenyl, substituted Ci-Ce alkenyl, Ci-Cb alkynyl unsubstituted, substituted Ci-Ce alkynyl, unsubstituted Ca-Ce cycloalkyl, substituted Cs-Ce cycloalkyl and unsubstituted arylalkyl, substituted arylalkyl; and Rc 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 haloalkynyl -C3 and partially or completely halogenated cyclopropyl, or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. In one aspect, when present, R1 is selected from the group consisting of: hydrogen and fluorine; or selected from the group consisting of: chloro, bromine, iodine, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-haloalkynyl C3, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl) and O(C1-C3 haloalkyl). One embodiment of the present disclosure includes a compound of formula (IA): H qq / Qzn / zznz / q / υιλιM(IA), where: X is selected from the group consisting of: NH, O and S; R1 is selected from the group consisting of: hydrogen and fluorine; RB is selected from the group consisting of: substituted phenyl, unsubstituted phenyl, unsubstituted O-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Ci-Ce alkenyl, substituted Ci-Ce alkenyl, C1-C5 alkynyl unsubstituted, substituted Ci-Ce alkynyl, unsubstituted Cs-Ce cycloalkyl, substituted Cs-Cs cycloalkyl, unsubstituted arylalkyl and substituted arylalkyl; and Rc 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 haloalkynyl -C3 and partially or completely halogenated cyclopropyl, or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. In one aspect, Rc is selected from the group consisting of: halogen, C1-C3 alkyl and C1-C3 haloalkyl. In one aspect, Rc is selected from the group consisting of: CHs, CF3, F and Cl. In one aspect, X is NH. In one aspect, RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Cs-Cs cycloalkyl, substituted Cs-Ce cycloalkyl, arylalkyl unsubstituted and substituted arylalkyl. In one aspect, RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Cs-Ce cycloalkyl, substituted Cs-Ce cycloalkyl, benzyl unsubstituted and substituted benzyl. In one aspect, each of the substituted phenyl, substituted Ci-Ce alkyl, substituted Cs-Ce cycloalkyl or substituted benzyl are independently substituted with one or more substituents selected from the group consisting of: -C(O)O (Ci-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, RB is selected from the group consisting of: unsubstituted Ci-Ce alkyl and unsubstituted C3-Ce cycloalkyl. In one aspect, R1 is hydrogen. In one aspect, R1 is fluorine. One embodiment of the present disclosure includes a compound selected from the group consisting of: qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι ΗΟ qq / ozn / zznz / q / υιλι or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. One embodiment of the present disclosure includes a compound selected from the group consisting of: qq / Qzn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. One embodiment of the present disclosure includes a compound of formula (IB): h (IB), where: A is selected from the group consisting of: qq / Qzn / zznz / q / υιλι X is selected from the group consisting of: NH, O and S; RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Cb alkyl, substituted Ci-Ce alkyl, unsubstituted Cz-Ce alkenyl, substituted Cz-Ce alkenyl, Cz-Cb alkynyl unsubstituted, substituted Cz-Ce alkynyl, unsubstituted Cs-Cb cycloalkyl, substituted Cs-Cb cycloalkyl and unsubstituted arylalkyl, substituted arylalkyl; Rc 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, C2C3 haloalkynyl, and cyclopropyl partially or fully halogenated; each R1, when present, is selected from the group consisting of: chloro, bromine, iodine, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2 haloalkenyl -C3, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl) and □(C1-C3 haloalkyl); each R1b, when 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-haloalkenyl C3, C2-C3 haloalkynyl, partially or fully halogenated cyclopropyl, □(C1-C3 alkyl) and O(C1-C3 haloalkyl); each of R2 and R3, when present, is independently selected from the group consisting of: C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and, when present, R2 and R3 taken together form a cycloalkyl ring of 3 members; and each of R2a and R3a, when present, is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and R2a and R3 taken together form a 3-cycloalkyl ring members, or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. In one aspect, A is selected from the group consisting of: qq / Qzn / zznz / q / υιλι In one aspect, when present, R1 is selected from the group consisting of: chloro, bromine, iodine, C1-C3 alkyl and C1-C3 haloalkyl. In one aspect, when present, R1b is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl. In one aspect, when present, R,b is selected from the group consisting of: halogen, C1-C3 alkyl and C1-C3 haloalkyl. In one aspect, when present, each of R2 and R3 is methyl. In aspect A, it is: In one aspect X is NH. In one aspect, RB is unsubstituted phenyl, substituted phenyl, unsubstituted C1Ce alkyl, substituted Ci-Ce alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl. In one aspect, RB is unsubstituted phenyl, unsubstituted Ci-Cs alkyl, or unsubstituted C3-C6 cycloalkyl. In one aspect, RB is unsubstituted O-Ce alkyl or unsubstituted C3-C6 cycloalkyl. In one aspect, RB is unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted C2-C6 alkenyl, substituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, substituted C2-C6 alkynyl, unsubstituted Cs-Ce cycloalkyl or substituted Cs-Ce cycloalkyl. In one aspect, the substituted is selected from one or more of CH2OH, C1-C3 alkyl, C1-C3 haloalkyl and SO2(C1-C3 alkyl). In one aspect, Rc is selected from the group consisting of: halogen, C1-C3 alkyl and partially or fully halogenated C1-C3 alkyl. In one aspect, Rc is selected from the group consisting of: CH3, CF3, F and Cl. In one embodiment of the present disclosure it includes a compound selected from the group consisting of: Yo qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι qq / Qzn / zznz / q / υιλι or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. One embodiment of the present disclosure includes a compound selected from the group consisting of: qq / ozn / zznz / q / υιλι qq / ozn / zznz / q / υιλι An embodiment of the present disclosure includes a method of treating a patient having a disease or disorder susceptible to modulation of one or more of (i) JAK and (i) JAK and an additional enzyme, comprising administering a therapeutically administered amount effective 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. One embodiment of the present invention includes a method of treating a patient who has a disease or disorder susceptible to JAK modulation, either alone or with dual or multiple modulation with one or more of an additional enzyme inhibitor, 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 aspect, the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet'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, Sjógren's syndrome, dry eye, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis and cancer. In one aspect, the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis. In one aspect, the compound is administered in an amount that perturbs an immune regulatory pathway in a cell. In one aspect, the perturbation results in an effect on the JAK-STAT pathway. One embodiment of the present invention includes a method of inhibiting JAK alone or in combination with the inhibition of one or more additional mechanisms in a mammalian cell comprising contacting the mammalian cell with a compound of the present disclosure. In one aspect, a further mechanism is also the inhibition of a tyrosine kinase. In one aspect, the tyrosine kinase is one or more TrkA and Syk. In one aspect, the additional mechanism is inhibition of PDE4. One embodiment of the present invention includes a method of treating a patient having a disease or disorder susceptible to JAK modulation, either alone or in dual modulation with PDE4, comprising administering a therapeutically effective amount of a compound of the present invention. divulgation. In one aspect, the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet'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, Sjógren's syndrome, dry eye, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis and cancer. In one aspect, the disease or disorder is one or more of atopic dermatitis, psoriasis and rheumatoid arthritis. In one aspect, the compound is administered in an amount that disrupts an immune regulatory pathway in a cell. In one aspect, the perturbation results in an effect on the JAK-STAT pathway. 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, 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 suffering from an inflammatory condition. In one aspect, the method further comprises modulating one or more of TrkA and Syk. One embodiment of the present invention includes a method of 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 humans, livestock mammals, domestic mammals, or companion mammals. In one aspect, the mammal is a human being. In one aspect, the mammal is one or more of cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs and cats. One embodiment of the present invention includes a composition comprising a compound of the present disclosure and a veterinary or pharmaceutically acceptable carrier. One embodiment of the present invention includes a combination comprising a compound of the present disclosure and one or more other pharmaceutical or veterinary active substances. One embodiment of the present invention includes a compound of the present disclosure, for use in medicine. 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. 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. Surprisingly, when structural modifications are made to the depicted pyrimidine core, including the number and placement of one or more nitrogen atoms in that ring, but when the variables are otherwise consistent with the compounds of the present disclosure, the core modified is characterized by a substantially different biological activity. Such compounds appear to have no JAK activity or significantly decrease JAK activity compared to the compounds of the present disclosure. However, it is interesting that such compounds maintain a level of PDE4 activity. Furthermore, unexpectedly, when the compound is a compound of formula (IA) and when the NH linker represented is alkylated, for example, N-CH3, the compound has no JAK activity or a significantly decreased JAK activity. Furthermore, the NH alkylated linker causes the compounds to also decrease PDE4 activity. A non-limiting hypothesis is that alkylation of the NH group eliminates the hydrogen bond and decreases its binding affinity to JAK1. Examples include Comparative Compounds A and B described herein. Furthermore, unexpectedly, when the compound is a compound of formula (I) and X is Nalkyl, for example, N-CH3, the compound has greatly decreased JAK activity. A non-limiting hypothesis is that NH is a key pharmacophore that provides an important hydrogen bond donor to the hinge domain of the kinase. Furthermore, unexpectedly, when the regiochemistry of (IA) is modified as shown in a compound of formula (III) as shown below, the activity of JAK and PDE4 decreases. This is exemplified in the data shown below: qq / Qzn / zznz / q / υιλι (III) JAK2: 60.2ηΜ PDE4: 85ηΜ JAK1: 77ηΜ JAK2: 914 ηΜ PDE4>1000 ηΜ qq / Qzn / zznz / q / υιλι One or more aspects and modalities may be incorporated into a different modality, even if not specifically described. That is, all aspects and modalities can be combined in any way or combination. Brief description of the drawings Figure 1 is a table providing the results of biological tests for the compounds of the present disclosure, as described herein in more detail. Figure 2 illustrates the results of a docking model with compounds of the present disclosure at the active site of JAK1 showing NH(X) forming hydrogen bonds with Gly1020 and Asp1021 through a water crystal. Alkylation of the NH group abrogates the hydrogen bond and decreases its binding affinity to JAK1. Detailed description of the invention Definitions Any reference in the specification to one modality or another modality or a similar phrase means that the particular features, structures, characteristics, operation or function described is included in at least one modality. Therefore, any occurrence of the phrase in a modality in the specification does not necessarily refer to the same modality. Furthermore, particular features, structures, characteristics, operations or functions may be combined in any suitable manner in one or more embodiments, and it is intended that the embodiments of the described subject matter can and do cover modifications and variations of the described embodiments. Particular aspects, as used herein, should be treated similarly. The phrases at least one, one or more, and / or are open expressions that are conjunctive and disjunctive in operation. For example, each of 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” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. The term an entity refers to one or more of that entity. As such, the terms one, one or more, and at least one may be used interchangeably herein. It should also be noted that the terms comprises, includes and has can be used interchangeably. A compound of this disclosure includes those described generally, and are further illustrated by the classes, subclasses and species described herein. As used herein, the following definitions shall apply unless otherwise noted. For the purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, “Handbook of Chemistry and Physics”, 75th Ed., CRC Press, New York, NY (1995). In addition, the 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, M.B. and March, J., John Wiley & Sons, New York, NY (2001), the entire contents of which are incorporated herein by reference. When referring to the compounds described herein, the following terms have the following meanings unless otherwise indicated. The following definitions are qq / Qzn / zznz / q / υιλι intended to clarify, but not limit, the defined terms. If a particular term used herein is not specifically defined, such term should not be considered undefined. Rather, the terms are used within their accepted meanings. As used herein, alkyl refers to substituted or unsubstituted monovalent saturated aliphatic hydrocarbyl groups having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The hydrocarbon chain can be linear or branched. Illustrative alkyl groups include methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl and tert-butyl. Similarly, an alkenyl group refers to an alkyl group that has one or more double bonds present in the chain, and an alkynyl group refers to an alkyl group that has one or more triple bonds present in the chain. The alkyl groups may be substituted or unsubstituted. The alkenyl groups may be substituted or unsubstituted. The alkynyl groups may be substituted or unsubstituted. As used herein, aryl refers to a substituted or unsubstituted, pendant or fused carbocyclic aromatic ring system, such as phenyl, naphthyl, anthracenyl, phenanthril, tetrahydronaphthyl, indane or biphenyl. A preferred aryl is phenyl. As used herein, cycloalkyl refers to an unsaturated or partially saturated hydrocarbon ring, substituted or unsubstituted, containing 3 to 15 ring atoms. Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, as well as partially saturated versions thereof, such as cyclohexenyl and cyclohexadienyl. The cycloalkyl groups may be substituted or unsubstituted. As used herein, halogen or halo refers to a halogen. In some embodiments, the halogen is preferably Cl (chlorine) or F (fluorine). As used herein, haloalkyl refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, wherein at least one atom of hydrogen is replaced by a halogen, including, but not limited to, perhalo groups where all hydrogen atoms are replaced with halogen atoms. A preferred perhalo group is a perfluoro group. The haloalkyl chain may be linear or branched. Illustrative haloalkyl groups include trifluoromethyl, trichloromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl and pentafluoroethyl. Similarly, a haloalkenyl group refers to a haloalkyl group that has one or more double bonds present in the chain and a haloalkynyl refers to a haloalkyl group that has one or more triple bonds present in the chain. As used herein, the term heterocyclyl refers to a substituted or unsubstituted, unsaturated or partially saturated hydrocarbon ring, containing 3 to 15 ring atoms, wherein one or more carbon atoms are replaced with a heteroatom selected from O, N, S or Si, where each N, S or Si can be oxidized and where each N can be quaternized. A heterocyclyl group can be attached to the rest of the molecule through a heteroatom. As used herein, the term heteroaryl or heteroaromatic refers to groups of qq / Qzn / zznz / q / υιλι substituted or unsubstituted aromatic rings having 5 to 14 ring atoms selected from carbon and at least one heteroatom ( typically 1-4, more typically 1 or 2) (e.g. oxygen, nitrogen, sulfur or silicon). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused with one or more other carbocyclic aromatic 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, 5oxadiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g. 3-pyrazolyl, 4-pyrazolyl ), 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 tend (for example, 2-thienyl, 3thienyl. Examples of nitrogen-containing six-membered monocyclic 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 may be attached to the rest of the molecule through a heteroatom. The terms arylalkyl refer to those radicals in which an aryl group, such as a phenyl (Ph), is attached through an alkyl group. Examples include benzyl, phenethyl and the like. The term benzyl, as used herein, is a radical in which a phenyl group is attached to a CH2 group, hence a ChhPh group. The term substituted benzyl refers to radicals in which the benzyl group contains one or more substituents. In a preferred embodiment, the phenyl group has a substituent. In another preferred embodiment, the phenyl group has zero substituents (is unsubstituted). In one embodiment, the phenyl group may have 1 to 5 substituents, or in another embodiment, 2 to 3 substituents. Furthermore, the alkylene linking group may also carry at least one substituent. As used herein, substituted or 'optionally substituted' refers to a substitution of a hydrogen atom, which would otherwise be present for the substituent. When talking about ring systems, optional substitution is typically with 1, 2, or 3 substituents replacing the normally present hydrogen. However, when referring to linear and branched portions, the number of substitutions may be greater, occurring whenever hydrogen is present. Substitutions can be the same or different. As used herein, with reference to the activity of a compound of the present invention, selectivity refers to a greater than 10-fold differential in activity. In one embodiment, the compounds of the present disclosure can be characterized as selective for JAK1 over other JAK subtypes. In one embodiment, the compounds of the present disclosure can be characterized by having a JAK2:JAK1 ratio of about 10 to about 1000. In one embodiment, the compounds of the present disclosure can be characterized by having a JAK2:JAK1 ratio of about 10 to about 1000. JAK3:JAK1 from about 0.5 to about 800. In one embodiment, upon administration to a subject in need thereof, the compounds of the present disclosure preferentially inhibit the activity of Jak1 over the activity of Jak2, the activity of Jak3 and the activity of Tyk2, and inhibit less than 50%, 40%, 30%, 25%, 20%, 15%, 10% or 5% of one or more of the activities of Jak2, Jak3 or Tyk2 in the subject. In certain embodiments, Jak1 activity is preferentially inhibited over Jak2 activity, Jak3 activity, and Tyk2 activity. In certain embodiments, more than 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% of Jak1 activity is inhibited in the mammalian subject. In certain embodiments, the activity of Jak1 is preferentially inhibited over the activity of Jak2. For example, preferential inhibition can be measured by the Jak1 / Jak2 potency ratio, defined as the inverse ratio of ICso of Jak1 inhibition over ICso of Jak2 inhibition. In certain embodiments, the Jak1 / Jak2 power 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 ICso of Jak1 inhibition is measured by inhibiting 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 ICso of Jak2 inhibition is measured by the inhibition of EPO-stimulated STAT5 phosphorylation ex vivo, for example, using a sample (for example, a blood sample) from a subject to whom it is administered a compound of the present disclosure. In certain embodiments, Jak1 activity is preferentially inhibited over Jak3 activity. For example, preferential inhibition can be measured by the Jak1 / Jak3 potency ratio, defined as the inverse ratio of ICso of Jak1 inhibition over ICso of Jak3 inhibition. In certain embodiments, the Jak1 / Jak3 power 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 ICso of Jak1 inhibition is measured by inhibiting 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. Illustrative substitutions, which with multiple substituents can be the same or different, include halogen, such as fluorine, chlorine, bromine or iodine, haloalkyl, such as -CF3, -CF2CF3, -CHF2, -CH2F, and the like, R', OR' , OH, SH, SR', NO2, CN, C(O)R', C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2 , NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S) NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S( O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', and Si( R')3, where each of the above can be linked through an alkylene linker, that is (CH2)X, where x is 1,2 or 3. In embodiments where a saturated carbon atom is optionally substituted with one or more substituent groups, the substituents may be the same or different and may also include =0, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH , =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =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 bonded to a nitrogen atom, they can qq / Qzn / zznz / q / υιλι form a saturated or unsaturated heterocyclic ring containing 4 to 6 ring atoms. In some embodiments of the present disclosure, particularly preferred embodiments of substituents include -C(O)O(Ci-C3), OH, CH2OH, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, halogen , O(C1-C3 alkyl) and O(C1-C3 haloalkyl). As used herein, the phrase veterinary or veterinary, or pharmaceutical or pharmaceutically acceptable salt refers to any salt of a compound described herein that retains its biological properties and that is not toxic or otherwise undesirable for veterinary or veterinary use. pharmacist. Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3(4-hydroxybenzo¡l)benzoic, picric, cinnamic, mandelic, italic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2naphthalenesulfonic, 4-toluenesulfonic, camphor, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic acid, muconic acid and similar acids. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as halides, such as chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate ), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphor, camphosulfonate, 4methylbicyclo[2.2.2]-oct-2-ene- 1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tere-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like. 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. 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, ethoxide lithium, 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, qq 7 Qzn / zznz / q / υιλι alkenylamines, alkynylamines and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars and polyamines. According to embodiments of the present disclosure, the base may be a quaternary ammonium hydroxide, wherein 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 in accordance with the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide and preferably choline hydroxide. According to embodiments of the present disclosure, an alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that may be used in accordance with the present disclosure include methylamine, ethylamine, diethylamine and triethylamine. A substituted alkylamine base is preferably substituted with one or more hydroxyl groups, and preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that may be used in accordance with the present disclosure include 2-(diethylamino)ethanol, N,Ndimethylethanolamine (deanol), tromethamine, ethanolamine and diolamine. In certain cases, the substituents represented may contribute to optical isomers and / or stereoisomerism. Compounds that have the same molecular formula but differ in the nature or bonding sequence of their atoms or in the arrangement of their atoms in space are called isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereomers and those that are non-superimposable mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, when it is attached to four different groups, a pair of enantiomers is possible. A molecule with at least one stereocenter can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog. (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (erratum: 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: 657-668) or it may be characterized by the way the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers, respectively). A chiral compound can exist as an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a racemic mixture. In certain embodiments, the compounds described herein may possess one or more asymmetric centers and, therefore, said compounds may be produced as a racemic mixture, an enantiomerically enriched mixture, or as an individual enantiomer. Unless otherwise indicated, for example, by the designation of stereochemistry at any position in a formula, the description or designation of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise. , thereof. qq / Qzn / zznz / q / υιλι Methods for determining stereochemistry and separating stereoisomers are well known in the art. In certain embodiments, the compounds described herein are stereochemically pure. A stereochemically pure compound has a level of stereochemical purity that those skilled in the art would recognize as pure. Of course, this purity level can be less than 100%. In certain embodiments, stereochemically pure designates a compound that is substantially free, that is, at least about 85% or more, of alternative isomers. In particular 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 of other isomers. As used herein, the terms subject and patient may be used interchangeably herein. In one embodiment, the subject is a human being. In one embodiment, the subject is a companion animal, such as a dog or cat. In a further embodiment, the subject is an animal such as a sheep, cow, horse, goat, fish, pig, or domestic bird (e.g., chicken, turkey, duck, or goose). In another embodiment, the subject is a primate, such as a monkey, such as a cynomolgous monkey or a chimpanzee. Furthermore, a pharmaceutically acceptable prodrug of the compound represented by formula (I) is also included in the present disclosure. The 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 the prodrug 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 the specification to describe any pharmaceutically acceptable form of a compound that, upon administration to a patient, provides the active compound. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form the compound of the present disclosure. Typical examples of prodrugs include compounds having biologically labile protecting groups on a functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the disclosure wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number being normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123L and 125L, nitrogen, such as 13N and 15N, oxygen, such as 15O. ,17O and 18O, phosphorus, as 32P, and sulfur, as 35S. Certain isotopically labeled qq / Qzn / zznz / q / υιλι compounds of the disclosure, such as those incorporating a radioactive isotope, may be useful in drug or substrate distribution studies in tissues. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements, and may therefore be preferable in some circumstances. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in positron emission topography (PET) studies to examine receptor occupancy of the substrate. The isotopically labeled compounds of the 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 using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed. Compositions and methods of administration The compounds of the present disclosure used in the methods described herein can be administered in certain embodiments using veterinary or pharmaceutical compositions that include at least one compound of the present disclosure, if appropriate in salt form, either used alone or in the form of a combination with one or more compatible and veterinary or pharmaceutically acceptable vehicles, such as diluents or adjuvants, or with another agent. Compositions are provided comprising a derivative of the present disclosure or a salt thereof, and an acceptable excipient, vehicle or diluent. The composition may also be in a variety of forms including, but not limited to, oral formulations, injectable formulations and topical, dermal or subdermal formulations. The composition may be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups or elixirs. 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 said compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents to provide elegant and appetizing preparations. Lozenges are solid compositions containing one or more active ingredients intended to dissolve or disintegrate slowly in the oral cavity by passive incubation in the oral cavity, or actively by suction or chewing. They can be used for a systemic effect if the drug is absorbed through the oral or esophageal lining or ingested. In particular, soft lozenges can be chewed or allowed to dissolve slowly in the mouth. These dosage forms have the advantage of being flavored and therefore easy to administer to both human and animal patients; They have formulas that are easy to change and can be specific for each patient; qq j αζη / ζζηζα / υιλι can deliver precise amounts of the active ingredient to the oral cavity and digestive system; and allow the drug to remain in contact with the oral or esophageal cavity for a prolonged period of time. The tablets may contain the active ingredient mixed with non-toxic and pharmaceutically acceptable excipients that are 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, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or gum arabic and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and therefore provide sustained action over a longer period. Formulations for oral use may be hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. The capsules may also be soft gelatin capsules, where the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEG and ethanol, or an oil medium, for example, peanut oil, liquid paraffin or olive oil. The compositions may also be in the form of oil-in-water or water-in-oil emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be phosphatides of natural origin, for example, soy, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of said partial esters with ethylene oxide. , for example, polyoxyethylenesorbitan monooleate. Emulsions may also contain sweetening agents, bittering agents, flavoring agents and preservatives. In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are very suitable as liquid carrier vehicles. Microemulsions are quaternary systems that comprise an aqueous phase, an oil phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids. Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oil phase or, conversely, of microdroplets of the oil phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surfactant (Co-SA) molecules that, by reducing the interfacial tension, allow the microemulsion to form spontaneously. In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oil phase, the oil phase comprises triglycerides; In another embodiment of the oil phase, the triglycerides are medium chain triglycerides, for example, Ce-Cío caprylic / capric triglyceride. In another embodiment, the oil phase QQ / 070 / 7707 / 31 / ΥΙΛΙ shall represent a % v / v range selected from the group consisting of about 2 to about 15%; from about 7 to about 10%; and from about 8 to about 9% v / v of the microemulsion. The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion of about 1 to about 4% v / v in the microemulsion. Surfactants for microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolized Cs-Cw glycerides, or polyglyceryl-6 dioleate. In addition to these surfactants, cosurfactants include short chain alcohols, such as ethanol and propanol. Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, different compounds can be substituted for each component of the same formulation. In one embodiment for the amount of surfactant / cosurfactant, the ratio of cosurfactant to surfactant may be from about 1 / 7 to about 1 / 2. In another embodiment for the amount of cosurfactant, it should be about 25 to about 75% v / v surfactant and about 10 to about 55% v / v cosurfactant in the microemulsion. Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents 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 adding an antioxidant, such as ascorbic acid or other known preservatives. The aqueous suspensions may contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; Dispersing or wetting agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylenesorbitan 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 agents and / or bittering agents, such as described herein. qq / Qzn / zznz / q / υιλι Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed 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 may also be present, for example sweetening, bittering, flavoring and coloring agents. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring agent(s), and a coloring agent(s). The compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3butanediol. 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 glycols can also be used. Preservatives, such as phenol or benzyl alcohol, may be used. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used including synthetic mono- or diglycerides. Additionally, fatty acids like oleic acid find use in the preparation of injectables. Topical, dermal and subdermal formulations may include emulsions, creams, ointments, gels or pastes. Organic solvents that may be used in the disclosure include, but are not limited to: acetyltributyl citrate, fatty acid esters such as dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyldiglycol, 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. As a carrier or diluent, the compositions of the present disclosure may include vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, seed oil. grape, sunflower oil, etc.; mineral oils such as, but not limited to, petroleum jelly, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium chain triglycerides (such as C8-C12). The dosage forms may contain from about 0.5 mg to about 5 g of an active agent. qq / Qzn / zznz / q / υιλι In one embodiment of the disclosure, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight / volume. A compound of the present disclosure may be employed as such or in the form of its preparations or formulations as combinations. A compound of the present disclosure according to the disclosure can be combined with one or more agents having the same sphere of activity, for example, to increase activity, or with substances having another sphere of activity, for example, to expand the activity interval. As an example, a combination of a compound of the present disclosure with one or more of an additional JAK inhibitor or a JAK modulator / signal transducer and activator of transcription (JAK / STAT) may offer a therapeutic advantage. 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. The compounds of the present disclosure according to the disclosure can be combined with one or more additional active agents. Other additional active agents that may be used in the methods provided herein in combination with a compound of the present disclosure include, but are not limited to, disease-modifying antirheumatic drugs (DMARDs such as cyclosporine A and methotrexate), anti-inflammatory agents such as such as nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, mycophenolate mofetil, biologic agents, TNF-α inhibitors (such as etanercept), Cox-2 inhibitors, and analgesics. These agents may include, but are not limited to, cyclosporine A, e.g., Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualine, mycophenolate, e.g., Cellcept®, azathioprine, e.g., Imuran® , daclizumab, for example, Zenapax®, OKT3, for example, Orthocolone®, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids, for example, prednisolone or dexamethasone. In some embodiments, the second active agents may include, but are not limited to, anti-inflammatories such as NSAIDs including, but not limited to, diclofenac (e.g., ARTHROTEC®), diflunisal (e.g., DOLOBID®), etodolac ( for example, LODINE®), fenoprofen (for example, NALFON®), ibuprofen (for example, ADVIL®, CHILDREN'S ADVIUMOTRIN®, MEDIPREN®, MOTRIN®, NUPRIN®, or PEDIACARE FEVER®), indomethacin (for example, ARTHREXIN® ), ketoprofen (e.g., ORUVAIL®), ketorolac (e.g., TORADOL®), fosfomycin tromethamine (e.g., MONURAL®), meclofenamate (e.g., MECLOMEN®), nabumetone (e.g., RELAFEN®), naproxen (e.g. for example, ANAPROX®, ANAPROX® DS, ECNAPROSYN®, NAPRELAN® or NAPROSYN®), oxaprozin (for example, DAY PRO®), piroxicam (for example, FELDENE®), sulindac (for example, CLINORIL®), and tolmetin (for example, TOLECTIN® DS or TOLECTIN®). In other embodiments, the second active agents may include, but are not limited to, disease-modifying antirheumatic drugs (e.g., DMARD) or immunosuppressants such as, but not limited to, methotrexate (e.g., RHEUMATREX®), sulfasalazine ( For example, AZULFIDINE®), and cyclosporine (for example, SANDIMMUNE® or NEROAL®; and including cyclosporine A). In other embodiments, second active agents may include, but are not limited to, mycophenolate mofetil (e.g., CelICept®), an immunosuppressive agent widely used in organ transplantation and gaining favor in the treatment of inflammatory skin disorders and autoimmune. In additional embodiments, the second active agents may include, but are not limited to, biological agents such as etanercept (ENBREL®), infliximab (REMICADE®) and adalimumab (HUMIRA®). In other embodiments of interest, second active agents may include, but are not limited to, Cox-2 inhibitors such as celecoxib (CELEBREX®), valdecoxib (BEXTRA®) and meloxicam (MOBIC®). These one or more additional active agents may be administered as part of the same dosage form or separately, through the same or different routes of administration, and in the same or different administration schedules in accordance with standard pharmaceutical practice. The pharmaceutical preparation comprising the compounds of the present disclosure, for administration to a human or other mammal, is preferably in unit dosage form, wherein the preparation is subdivided into unit doses containing an appropriate amount of the active component. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet or lozenge itself, or may be an appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component. If desired, the composition may also contain other compatible therapeutic agents. In therapeutic use for the treatment or relief of inflammation, autoimmune diseases and cancer in a human or other mammal, the compounds used in the treatment method are administered in an initial dose of about 0.1 mg / kg to about 100 mg / kg per interval, approximately 0.1 mg / kg to approximately 50.0 mg / kg per interval, approximately 0.1 mg / kg to approximately 10.0 mg / kg per interval, approximately 0.1 mg / kg to approximately 5.0 mg / kg per interval, approximately 0.1 mg / kg at approximately 2.5 mg / kg per interval, approximately 0.1 mg / kg to approximately 2.0 mg / kg per interval, approximately 0.1 mg / kg to approximately 1.0 mg / kg per interval, approximately 0.4 mg / kg to approximately 1.0 mg / kg per interval , or from about 0.4 mg / kg to about 0.6 mg / kg per interval. Preferred intervals can be daily, weekly, monthly, quarterly, semi-annual or yearly. Doses can be varied depending on the patient's requirements, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound(s) being treated. it is in use. Determining the appropriate dose and route of qq / Qzn / zznz / q / υιλι administration for a particular situation is within the skill of the physician. Generally, treatment will be started with smaller doses, which are less than the optimal dose of the compound, which can be increased in small increments until the optimal effect is achieved in the particular circumstances of the condition. For convenience, the total daily dose can be divided and administered in portions throughout the day if desired. In therapeutic use, embodiments of the compounds of the present disclosure are useful in the manufacture of a medicament for a method of treating any indication where inhibition of JAK, optionally in dual PDE4 modulation, and, optionally, with one or more of TykA and Syk would be desirable, including, but not limited to, cancer, neuroinflammation, inflammatory airway diseases, ankylosing spondylitis, inflammatory bowel diseases, rheumatoid arthritis, psoriasis and atopic dermatitis. In one or more embodiments, a compound of the present disclosure is useful in the treatment of one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet'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, Sjógren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis and cancer. In therapeutic use, the compounds of the present disclosure are useful in the manufacture of a medicament for a method of treatment of any indication including, but not limited to, cancer, neuroinflammation, inflammatory airway diseases, ankylosing spondylitis, diseases inflammatory bowel diseases, rheumatoid arthritis, psoriasis or atopic dermatitis. In one or more embodiments, a compound of the present disclosure is useful in the treatment of one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet'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, Sjógren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, arteriosclerosis and cancer. The present disclosure explicitly covers the compounds presented below in the Compound Lists, including salt forms thereof. A composition comprising a therapeutically acceptable amount of any of these compounds is also within the scope of the disclosure. The composition may further comprise a veterinary or pharmaceutically acceptable excipient, diluent, vehicle or mixture thereof. Such a composition may be administered 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, alone or in combination with inhibition of tropomyosin receptor kinase A (TrkA). o Spleen tyrosine kinase (Syk) and, optionally, with PDE4 inhibition. The composition may further comprise an additional active agent, as described herein. List of compounds It should be understood that when found in an aqueous medium, some contemplated compounds of the present disclosure may be present in a reversible equilibrium with water due to the Lewis acidic nature of the planar trigonal boron center. This dynamic equilibrium may be important for the biological activity of the compounds of the present disclosure. The compounds of the present disclosure in this dynamic equilibrium are another aspect of the present disclosure. Embodiments of the present disclosure are provided in the following list, where an aspect of the activity of the compound is indicated. For each listing, this disclosure includes a stereoisomer, enantiomer or tautomer of each compound, as well as a veterinary or pharmaceutically acceptable salt thereof. Symbols (+) identify a compound of the present disclosure with the indicated target activity. Symbols (*) indicate preferential activity, where the largest number identifies the most preferred compounds. qq / Qzn / zznz / q / υιλι Activity note IUPAC structure JAK+ “* 5-((5-chloro-4(clclopentllamino)plr¡m¡d¡n-2ll)amino)-7etllbenzo[c][1,2]oxaborol-1 (3H)-ol JAK+ 7-etll-5-((5-metll-4-(pentan-3ylamino)p¡rim¡d¡n-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ *** 3,3,7-trimethyl-5-((5-methyl¡l-4(phen¡lano)p¡rim¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H )-ol JAK+ ** JAK+ *** 7-chloro-5-((5-chloro-4(cyclopentylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 3,3,7-trimethyl-5-((5-methyl-4-(pentan3-ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol JAK+ *** 3,7-dimethyl-5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol JAK+ *** 7-chloro-5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 7-methyl-5-((5-methyl-4-(pentan-3¡lamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ *** 3,3-dimethyl-5-((5-methyl-4(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ JAK+ 3,3-dimethyl-5-((5-methyl-4-(pentan3-ilamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 7-chloro-5-((5-methyl-4(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 6-((4-(cyclopentylamino)-5methylpyrimidin-2-yl)amino)-3,4dihydro-1 Hbenzo[c][1,2]oxaborynin-1 -ol JAK+ JAK+ *** JAK+ *** 7-chloro-3,3-dimethyl-5-((5-methyl-4(pentan-3-ylamino)pyr¡m¡d¡n-2yl)amino)benzo[c][1,2]oxaborol1 (3H )-ol 7-methyl-5-((5-methyl-4(phenylamino)pinmin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 7-ethyl-5-((5-methyl-4(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ ** JAK+ ** JAK+ JAK+ *“ JAK+ *“ JAK+ *“ 5-((5-chloro-4(cyclopentylamino)pyrimidin-2yl)amino)-7methylbenzo[c][1,2]oxaborol-1 (3H)-ol 5-((5-chloro-4(cyclopentylamino)p¡r¡m¡din-2yl)amino)-3methylbenzo[c][1,2]oxaborol-1 (3H)-ol 5-((4-(cyclopentylamino)-5methylpyrimidin-2-yl)amino)-7methylbenzo[c][1,2]oxaborol-1 (3H)-ol 5-((4-(cyclopentylarnino)-5methylpyrimidin-2-yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)ol 5-((5-methyl-4-(phenylamino)pyrimidin-2yl)amino)-7(trifluoromethyl)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4(cyclopent¡lamino)pyr¡m¡din-2yl)amino)-3,3,7trimethylbenzo[c][1,2]oxaborol-1 (3H)ol JAK+ *** JAK+ JAK+ JAK+ *** JAK+ *** JAK+ *** OH 7-chloro-3,3-dimethyl-5-((5-methyl-4(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 5-((4-(cyclopentylamino)-5methylpyrimidin-2-yl)amino)-3methylbenzo[c][1,2]oxaborol-1 (3H)-ol 7-chloro-5-((5-chloro-4(cyclopentylamino)pyrimidin-2yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)ol 5-((5-chloro-4(cyclopentylamino)pyrimidín-2yl)amino)-7(trifluoromethyl)benzo[c][1,2]oxaborol1 (3H)-ol 3-methyl-5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 3-methyl-5-((5-methyl-4(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol JAK+ 5-((5-chloro-4(cyclopentylamino)pyrimidin-2yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)ol 5-((5-methyl-4-(pentan-3ylam¡no)pyrimidin-2-¡l)amino)-7(trifluoromethyl)benzo[c][1,2]oxaborol1(3H)-ol JAK+ JAK+ “ JAK+ JAK+ “ 5-((4-(cyclopentylam¡no)p¡r¡m¡din-2yl)amino)-7ethylbenzo[c][1,2]oxaborol-1 (3H)-ol 6-((5-methyl-4-((4met¡lc¡clohexyl)amino)pyrám¡din-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 3,3-dimethyl-6-((5-methyl-4-((3(methylsulfon¡l)phen¡l)amino)pyrámidín2-¡l)amino)benzo[c ][1,2]oxaborol1 (3H)-ol 7-methoxy-5-((5-methyl-4(methylthio)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ JAK+ 6-((5-iodo-4(propylam¡no)pyr¡mid¡n-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 6-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 6-((4-(((1 r,4r)-4(hydroxylmethyl)cyclohexyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol JAK+ JAK+ 6-((4-(cyclohexylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 6-((5-methyl-4-((3(methylsulfonyl)phenyl)amino)pyrimiden2-l)amino)benzo[c][1,2]oxaborol1 (3H) -ol JAK+ JAK+ 6-((5-methyl-4-((1 -methylpiperidin-4¡l)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 7-fluoro-6-((5-methyl-4-((3(methylsulfonyl)phenyl)amino)pyrimiden2-l)amino)benzo[c][1,2]oxaborol1(3H) -ol JAK+ * JAK+ JAK+ PDE4+JAK+ PDE4+JAK+ 7-methyl-6-((5-methyl-4-((3(methylsulfonyl)phenyl)amino)pyrimidin2-¡l)amino)benzo[c][1,2]oxaborol1 (3H)-ol Tf N-(7-ethyl-1-hydroxy-1,3dihydrobenzo[c][1,2]oxaborol-5-yl)1,1,1-trifluoro-N-(5-methyl-4(pentan-3-ylamino )pyrámíd¡n-2¡l)methanesulfonamide Neither Tf OH / B or N-(4-anilino-5-methyl-pyrimidin-2-yl)N-(7-ethyl-1-hydroxy-3H-2,1benzoxaborol-5-yl)-1,1 ,1-trifluoromethanesulfonamide 6-((4-(cyclopentylamino)-5methylpyrimidin-2-yl)amino)-8-methyl3,4-dihydro-1 Hbenzo[c][1,2]oxaborynin-1 -ol 5-((5-methyl-4-((4methylcyclohexyl)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 7-fluoro-5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol qq / Qzn / zznz / q / υιλι PDE4+JAK+ *** PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ ** PDE4+JAK+ PDE4+JAK+ 5-((4-((2-methoxyphenyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 5-((4-((2-chlorophenyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((2-ethylphenyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4(cyclopentylamino)pyrám¡din-2yl)amino)-7fluorobenzo[c][1,2]oxaborol1(3H)-ol 5-((5-chloro-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-methyl-4-(otolilamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+*** || ] H Ί i H F OH / 0 7-fluoro-5-((5-methyl-4- (phenylamino)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol- 1 (3H) -ol OH / ^-B PDE4+JAK+ *** I l II í 5-((4-((2-fluorophenyl)amino)-5- A Λ Λ''· methylpyrimidin-2- H V XNX H yl)amino )benzo[c][1,2]oxaborol- F 1 (3H)-ol OH Ck / 5-((4-(sec-butylamino)-5- PDE4+JAK+ JI i 0 chloropyrimidin-2- yl)amino) benzo[c][1,2]oxaborol- H H 1 (3H)-ol OH / xn A Α\χΧ ^B 5-((5-methyl-4-(pentan-3- PDE4+JAK+ *** | A A 0 ylamino)pyrimidin-2- Λ'' yl)amino)benzo[c][1,2]oxaborol- H H 1 (3H)-ol OH / / ^B. 5-((5-methyl-4-((3- PDE4+JAK+ *** N II I x o met¡lc¡clohex¡l)amino)p¡r¡m¡d¡n- L 1 J ^1 J 2- H H yl)amino)benzo[c][1,2]oxaborol- 1 (3H)-ol OH Ck / A A Άκ 5-((5-chloro-4-(hexan-3- PDE4+JAK+ A 0 ¡ lamino)pyrimidín-2- yl)amino)benzo[c][1,2]oxaborol- H H 1 (3H)-ol qq / ozn / zznz / q / υιλι 5-((4-((3-fluorobenzyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ ** 5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ ** PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ ** 5-((5-methyl-4-((2(trifluoromethoxy)phen¡l)amino)p¡r¡m¡d¡n -2-¡l)amino)benzo[c][1,2] oxaborol1 (3H)-ol 5-((5-methyl-4-(phenylamino)pyrimidin2-¡l)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclohexylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4(cyclopent¡lamino)pyrimid¡n-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+“ 5-((4-((3-chlorobenzyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ 5-((5-methyl-4-((2(trifluoromethyl)phenyl)amino)pyrimidi n-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ *** PDE4+JAK+ *** 5-((4-(benzylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 7-fluoro-5-((4-(pentan-3-ylamino)5-(trifluoromethyl)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ *** 5-((5-chloro-4(cyclohex¡lano)pyrim¡din-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol PDE4+JAK+ *** 5-((4-(cyclopentylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol PDE4+JAK+ *** PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ *** 5-((4-(cyclopentylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(benzylamino)-5chloropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4(propylamino)p¡rim¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(benzylamino)-5fluoropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(propylamino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclohexylamine)-5fluoropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ *** PDE4+JAK+ PDE4+JAK+ *** PDE4+JAK+ *** PDE4+JAK+ *** PDE4+JAK+ ** 5-((4-((3(hydroxymethyl)phenyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4-((1-hydroxybutan-2¡l)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 5-((4-(pentan-3-ylamino)-5(trifluoromethyl)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(sec-butylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-fluoro-4-(hexan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 2-((1-hydroxy-1,3dihydrobenzo[c][1,2]oxaborol-5yl)amino)-4-(pentan-3-ylamino)pyrimidine-5-carbonitrile PDE4+JAK+ PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ 5-((5-methyl-4-(pentan-3yloxy)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-methyl-4-((1 phenylpropyl)amino)p¡r¡m¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 2-((1-hydroxy-1,3dihydrobenzo[c][1,2]oxaborol-5yl)amino)-4(prop¡lamino)pinm¡dine-5carbaldehyde 5-((4-(cyclohexyloxy¡)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 5-((4-((4-fluorobenzyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4(methylsulfonyl)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ ** PDE4+JAK+ ** PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ ** PDE4+JAK+ ** 5-((4-((2-hydroxytetrahydro-2Hpyran-4-yl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(sec-butylamino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-methyl-4-(pentan-3ylthio)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclopentylox¡)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 3-((2-((1 -hydroxy¡-1,3dihydrobenzo[c][1,2]oxaborol-5¡l)amino)-5-methylp¡r¡m¡d¡n-4yl)amino)benzoate ethyl 5-((5-fluoro-4-(pentan-3ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ ** PDE4+JAK+ ** PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ “ 5-((4-(hexan-3-ylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(benzylamino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclobutylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((1,5-difluoropentan-3yl)am¡no)-5-met¡lp¡r¡midín-2yl)amino)benzo[c][1,2]oxaborol1 (3H) -ol 5-((4-(sec-butylamino)-5fluoropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclopentylamino)-5(trifluoromethyl)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol PDE4+JAK+ ** PDE4+JAK+ ** PDE4+JAK+ ** PDE4+JAK+ ** PDE4+JAK+ ** 5-((4-(cyclopentylamino)-5fluoropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((2-cycloprop¡leth¡l)amino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-methyl-4-((1phenylethyl)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 2-(2-fluoroethyl)-7-((2-((1 -hdroxy1,3dihydrobenzo[c][1,2]oxaborol-5yl)amino)-5-methylpyri¡m¡d¡n-4¡ l) am i no)isoindol in-1 -one 5-((4-((1 -methoxypentan-3yl)amino)-5(trifl uoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol qq / Qzn / zznz / q / υιλι PDE4+JAK+ ** PDE4+JAK+ “ PDE4+JAK+ “ PDE4+JAK+ PDE4+JAK+ “ PDE4+JAK+ * 5-((4-(cyclohexylamino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-methyl-4(propylamino)pyrim¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclohexylamino)p¡r¡m¡din2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((1 -hydroxybutan-2yl)amino)-5-methylpyrim¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((2-cyclopropylethyl)amino)-5fluoropyrimidin-2yl)amino)benzo[c][1,2]oxaborol1(3H)-ol 5-((5-chloro-4-((2cyclopropylethyl)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ PDE4+JAK+ 5-((5-chloro-4-(methylthio)pyrám¡din2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol OH 5-((4-(cyclopentyl(methyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-fluoro-4(propylamino)p¡rim¡din-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-((4-chlorobenzyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclopent¡lamino)pyr¡mid¡n2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(hexan-3-ylamino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ PDE4+JAK+ * PDE4+JAK+ PDE4+JAK+ 5-((4-(cyclopropylamino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclohexylthio)-5-methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 3-((2-((1 -hydroxy-1,3dihydrobenzo[c][1,2]oxaborol-5yl)amino)-5-methylp¡r¡m¡din-4yl)amino)pentane-1, 5-diol 5-((4-(cyclohexyloxy)-5-methylpyrimidin2¡l)(methyl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-chloro-5-(trifluoromet¡l)p¡r¡m¡d¡n2-¡l)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((5-chloro-4-(2-ethylazir¡din-1-yl)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol1 (3H)-ol PDE4+JAK+ PDE4+JAK+ * 5-((4-(cyclopentylamino)-5methylpyrimidin-2yl)(methyl)amino)benzo[c][1,2]oxaborol1 (3H)-ol 5-((4-(cyclohexyloxy)pyrimidín-2yl)amino)benzo[c][1,2]oxaborol-1 (3H)ol 5-chloro-2-((1 -hydroxy-1,3dihydrobenzo[c][1,2]oxaborol-5yl)amino)pyrimidin-4-ol 5-((4-((2-cyclopropylethyl)amino)-5methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol-1 (3H)ol 5-((4-(pentan-3-ylam¡no)p¡rim¡d¡n-2yl)amino)benzo[c][1,2]oxaborol-1 (3H)ol List of Additional Compounds A1: Additional embodiments of the present disclosure include a compound selected from the group consisting of: qq / Qzn / zznz / q / υιλι List of Additional Compounds B1: Additional embodiments of the present disclosure include a compound selected from the group consisting of: OH OH HO. careo gold EXAMPLES The numbering of examples is coordinated within each designated section and is not continuous between sections. Additionally, different naming conventions may be used throughout the present disclosure. Therefore, a compound can be referred to by different chemical names, depending on the convention used. Those skilled in the art will appreciate the differences and the chemical names, although different, are nevertheless clear. Variables provided in the following example schemes may not match variables elsewhere in this disclosure. However, in context, the description is still clear. PART 1-1: General Synthesis Teachings for Formula Compounds (IB) General synthesis scheme A: The detailed procedure is as shown in the preparation of 7-methyl-5-((5-methyl-4(pentan-3-¡lamino)pyrimidin-2-¡l)am¡no)benzo[c][1, 2]oxaborol-1(3H)-ol. DIPEA. dloxane TA. overnight TeOH. H;O dloxane 25'C-80eC. 1Gh KOAC. PdfPPhO'CI: dloxane. 25s-80'C. 4 p.m. C C 25 *C 0 £h Α.1 Preparation of 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine;N ... ....... - á ------ Ί Γ ΪNDIPEA. dioxane --- Ν' Ν' Cl ΤΑ. during the night qq / Qzn / zznz / q / υιλι 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)pyrimidín-4-amine (1.45 g, 45% yield) as white powder. MS: m / z = 214.0 (M+H)+. A.2 Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3-methylbenzoate I B, IsOII II -O dioxane Η H 25nC-80rC. 16h0 To a mixture of 2-chloro-5-methyl-N-(pentan-3-yl)pyrimidin-4-amine (1 g, 4.68 mmol, 1 eq) and 5-amino-2-bromo-3-methyl-benzoate of methyl (1.14 g, 4.68 mmol, 1 eq) in dioxane (30 mL) TsOH.HzO (1.34 g, 7.02 mmol, 1.5 eq) was added in one portion at room temperature under N2 atmosphere. The resulting mixture was heated to 80°C and stirred for 16 h. Next, the reaction mixture was poured into saturated NaHCOs 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 NasSO4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO?, petroleum ether / petroleum acetate). ethyl=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). A.3 Preparation of 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1-ethylpropylamino)-5-methylpyrimidin-2-yl]amino]- methyl 3-methyl-benzoate 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 eq) in dioxane (10 mL) KOAc (291 mg, 2.97 mmol, 2.5 eq), Pd(PPh3)2Cl2 (83.30 mg, 118.67 pmol, 0.1 eq) and 2-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2dioxaborinane (600 mg, 2.66 mmol, 2.24 eq) in one portion at 25°C under N2 atmosphere, the reaction mixture The resulting mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was filtered, concentrated in vacuo to give a residue, which was purified by column chromatography (SIÜ2, petroleum ether / ethyl acetate=3 / 1 to 1 / 1) to give 2-(5.5 Methyl-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1ethylpropylamino)-5-methyl pyrimidin-2-yl]amino]-3-methyl-benzoate (700 mg, crude ) as brown oil, which was directly used in the next step without further purification. MS (ESI): calculated mass. For C24H25BN4O4, 454.28, m / z found 455.2 [M+H]+. A.4 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methylpyrimidin-2,4-diamine QQ / Q7n / 77n7 / q / ΥΙΛΙ To a mixture of 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-[[4-(1 -ethylpropylamino)-5-methyl-pyrimidin-2yl]amino] Methyl-3-methyl-benzoate (700 mg, crude, 1 eq) and MeOH (0.1 mL) in THF (8 mL) NaBH4 (174 mg, 4.62 mmol, 3 eq) was added in portions at 0°C, the 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), the pH of the aqueous phase was adjusted to 3-4 using aqueous HCl (2N), and extracted with ethyl acetate. (5 mL x 3). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Welch Xtimate C18 150*25mm*5pm ; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-45%,10.5min). 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 using aqueous NaHCOs (2N), and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na2SÜ4, filtered and concentrated in vacuo to give N4-(1-ethylpropyl)-N2-(1 hydroxy-7-methyl-3H- 2,1-benzoxaborol-5-yl)-5-methyl-pyrimidin-2,4-diamine (46 mg, 116.46 pmol, 7.56% yield, 86.14% purity) as a yellow solid. 1H NMR (DMSO-de, 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, 2H), 4.10-4.04 (m, 1H), 2.36 (s, 3H), 1.94 (s, 3H), 1.61 -1.55 (m, 4H), 0.88 (t , J = 7.2 Hz, 6H). MS (ESI): calculated mass. For C18H25BN4O2, 340.21, m / z found 341.1 [M+H]+. HPLC: 86.14% (220nm), 93.84% (254nm). General synthesis scheme B: The detailed procedure is as shown in the preparation of 5-((4-(cyclopentylam¡no)-5methylpyr¡mid¡n-2-¡l)amino)-7-methylbenzo[c ][1,2]oxaborol-1(3H)-ol qq / ozn / zznz / q / υιλι 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-cyclopent! l-5-methyl!rim¡din-4-amine (591 mg, 2.8 mmol) and two drops of concentrated HCl at room temperature, the resulting reaction mixture was kept stirring at room temperature during the evening. It was then neutralized by adding aqueous NaHCOs, extracted with EtOAc. The combined organic phase was washed with brine and concentrated in vacuo to give a residue, which was purified by silica chromatography eluting with DCM / MeOH (100 / 1 to 10 / 1) to give the crude product, which was triturated with MeCN. and water to give 5-((4-(cyclopentylam¡no)-5-met¡lp¡r¡m¡d¡n-2yl)amino)-7-methylbenzo[c][1,2]oxaborol- 1(3H)-ol (69 mg, 7% yield) as 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, 2H), 4.41-4.39 (m, 1H), 2.36 (s, 3H), 2.01-1.99 (m, 2H), 1.73 (s, 3H), 1.60-1.53 ​​(m, 2H), 1.24-1.22 (m, 4H) ppm. Purity by HPLC: 98.51% at 210 nm and 98.35% at 254 nm. MS: (M+H)+: m / z = 339.2. Purity by HPLC: 98.51% at 210 nm and 98.35% at 254 nm. MS: (M+H)+: m / z = 339.2. General synthesis scheme C: The detailed procedure is as shown in the preparation of N2-(1-hydroxy-3,3,7-trimethyl2,1-benzoxaborol-5-¡l)-5-methyl-N4-phenyl-p¡ r¡m¡din-2,4-d¡amine C.1 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methylphenyl]propan-2-ol Methyl 5-[(4-anílino-5-methyl-pyrimidín-2-íl)amino]-2-bromo-3-methyl-benzoate (500 mg, 1.17) was added mmol, 1 eq) to MeMgBr (3 M, 7.80 mL, 20 eq) at 0°C for 30 min, the resulting mixture was stirred at 25°C for 6.5 h. The reaction mixture was then poured into aq. NH4CI. sat. (15 mL), and the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0~100% ethyl acetate / petroleum ether gradient @ 36 mL / min) to give 2-[ 5[(4-an¡l¡no-5-methyl-pyr¡midín-2-yl)amino]-2-bromo-3-methyl-phenyl]propan-2-ol ( 250 mg, 585 pmol, yield 49.99%) as yellow solid. C.2 Preparation of N2-(1-hydroxy¡-3,3,7-trimethyl-2,1-benzoxaborol-5-¡l)-5-methyl-N4-phenylpyrimidin-2,4 -diamine To a solution of 2-[5-[(4-anílino-5-methyl-pyrimídin-24l)amino]-2-bromo-3-methyl-pheníl]propan-2-ol qq / Qzn / zznz / q / υιλι (50 mg, 117 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl -1,3,2-dioxaboñnane (66.1 mg, 293 pmol, 2.5 eq) in dioxane (3 mL) was added KOAc (23.0 mg, 234 pmol, 2 eq), Pd(PPh3)2Cl2 (8.21 mg, 11.7 pmol, 0.1 eq) at 25°C under a N2 atmosphere, the resulting mixture was stirred at 120°C for 5 h. Then, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Welch hydrox¡-3,3,7-trimet¡l-2,1-benzoxaborol-5-¡l)-5-methyl-N4-phen¡lp¡rímidín-2,4-d amine (8.4 mg, yield 19.18%) as a white solid.1H NMR (DMSO-de,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): calculated mass. For C21H23BN4O2 374.19, m / z found 375.1 [M+H]+. HPLC: 100.00% (220nm), 100.00% (254nm). General synthesis scheme D: The detailed procedure is that shown in the preparation of 3-methyl-5-((5-methyl-4-(pentan-3ylamino)pyrimidin-2-!l)amino)benzo[ c][1,2]oxaborol-1 (3H)-ol II l< Ndi'H, m~:;h ih- 011 D.1 Preparation il]amino]phenyl]ethanone 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2- TsOH.HiO, dioxane 25-80’C, 12 h To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.5 g, 7.02 mmol, 1 eq) and 1 -(5amino-2-bromo -phenyl)ethanone (1.50 g, 7.02 mmol, 1 eq) in dioxane (50 mL) TsOH.HzO (2.00 g, 10.5 mmol, 1.5 eq) was added at 25°C, the resulting mixture was heated to 80°C and It was stirred for 12 h. H2O (30 mL) was poured into the above mixture, and its pH was adjusted to 9 with aq. NaHCOs. sat., extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over NazSCU, filtered and concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 75 mL / min) to give 1-[ 2-bromo-5-[[4-(1-ethylpropylamino)-5methyl-pyrimidin-2-yl]amino]phenyl]ethanone (1.3 g, 3.32 mmol, 47.33% yield) as 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), 1.621.49 (m, 4H ), 0.85 (t, J = 7.6 Hz, 6H). D.2 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino] phenyl]ethanol 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 eq) and MeOH (1.79 mmol, 72.4 pL, 1 eq) in THF (5 mL) NaBH4 (102 mg, 2.69 mmol, 1.5 eq) was added at 0°C, the resulting mixture was stirred at 25°C for 3 h. The reaction mixture was poured into H2O (10 mL), its pH was adjusted to 5 with 2N HCl, and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SÜ4, filtered and concentrated in vacuo to give a residue. The residue was purified by short column to give 1-[2-bromo5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (400 mg, 1.02 mmol, yield56.98%) as a white solid.1H NMR (DMSO-de, 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) D.3 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methylpyrimidin-2,4-diamine To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamine)-5-methyl-pyrimidin-2-l]amino]phen l]ethanol (300 mg, 763 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-¡l)-5,5-dimethyl-1,3 ,2-dioxaborinane (431 mg, 1.91 mmol, 2.5 eq) in dioxane (10 mL) Pd(PPh3)2CÍ2 (53.5 mg, 76.3 pmol, 0.1 eq), KOAc (150 mg, 1.53 mmol, 2 eq) was added to 25°C under N2 atmosphere, 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, which was dissolved in H2O (10 mL), and its pH was adjusted to 5 with 2N HCl, extracted with EtOAc (8 mL x 3). . The combined organic layers were washed with brine (5 mL x 3), dried over Na2SÜ4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Welch -ethylpropyl)-N2(1-hydrox¡-3-methyl-3H-2,1-benzoxaborole-5-¡l)-5-methyl-pymmidina-2,4-diam 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, 1H), 5.20 (q, J = 6.8 Hz, 1H), 4.12-4.03 (m, 1H), 2.03 (s, 3H), 1.64-1.59 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 0.880.82 (m, 6H ). MS (ESI): calculated mass. For C20H26BF3N4O4 454.20, m / z found 341.0 [M+H]+. HPLC: 99.80% (220nm), 99.74% (254nm). PART 1-2: Examples of syntheses for compounds of Formula (IB) Example 1: 7-methoxy-5-((5-methyl-4-(methylthio)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)ol This substance was prepared following General Synthesis Scheme A.1H NMR (DMSO-d6, 400 ΜΗζ) δ (ppm) 9.60 (s, 1 Η), 8.58 (br, 1 Η), 8.05 (s, 1 Η), 7.50 (s, 1 Η), 7.22 (s, 1 Η), 4.87 (s, 2Η), 3.78 (s, 3H), 2.59 (s, 3H), 2.06 (s, 3H). MS (ESI): m / z found 318.0 [M+H]+. Purity by HPLC: 98.8% (220 nm), 98.93% (254 nm). Example 2: 5-((4-(cyclopentylamino)-5-methylpyrimidine-2-yl)amino)-3methylbenzo[c][1,2]oxaborol-1 (3H)-ol OH This substance was prepared following the General Synthesis Scheme D.1H NMR (DMSO-d6, 400 ΜΗζ) 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), 1.601.57 (m, 4H), 1.37 (d, J = 6.4 Hz, 1H). MS (ESI): m / z found 339.2 [M+H]+. Purity by HPLC: 97.16% (220 nm), 97.78% (254 nm). Example 3: 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)-ol OH This substance was prepared following the General Synthesis Scheme C.1H NMR (DMSO-d6, 400 ΜΗζ) 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, 1 H), 6.44 (d, J = 7.2 Hz, 1H), 4.53-4.47 (m, 1 H), 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 found 353.2 [M+H]+. Purity by HPLC: 95.93% (220 nm), 94.50% (254 nm). Example 4: 6-((4-(cyclopentylamino)-5-methylpyrimidine-2-yl)amino)-3,4-dihydro-1 Hbenzo[c][1,2] oxaborin-1-ol ΗH This substance was prepared following General Synthesis Scheme B.1H NMR (DMSO-d6, 400 ΜΗζ) δ (ppm) 8.95 (s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.66 ( s, 1 H), 7.51 (s, 2H), 6.35 (d, J = 7.2 Hz, 1 H), 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), 1.751.73 (m, 2H), 1.59-1.57 (m, 4H). MS (ESI): m / z found 339.2 [M+H]+. Purity by HPLC: 96.64% (220 nm), 98.79% (254 nm). Example 5: 7-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-¡l)amino) benzo[c][1,2]oxaborol-1 (3H)-ol OH / Βχb This substance was prepared following General Synthesis Scheme A.1H 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, 2H), 4.10-4.04 (m, 1H), 2.36 (s, 3H), 1.94 (s, 3H), 1.61-1.55 (m, 4H), 0.88 (t, J = 7.2 Hz, 6H) ppm. Purity by HPLC: 86.14% at 210 nm and 93.84% at 254 nm. MS: (M+H)+: m / z = 341.1. Example 3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme B.1H 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% at 210 nm and 99.99% at 254 nm. MS: (M+H)+: m / z = 355.2. Example 7: 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7methylbenzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme B.1H 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, 2H), 4.41 -4.39 (m, 1H), 2.36 (s, 3H), 2.01 -1.99 (m, 2H), 1.73 (s, 3H), 1.60-1.53 ​​(m, 2H), 1.24-1.22 (m, 4H) ppm. HPLC purity: 98.51% at 210 nm and 98.35% at 254 nm. MS: (M+H)+: m / z = 339.2. Example 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7 methylbenzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis 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,1 H), 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 found 359.1 [M+H]+. Purity by HPLC: 93.73% (220 nm), 94.52% (254 nm). Example 9: 6-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-8-methyl-3,4-dihydro-1 H79 benzo[c][1,2]oxaborynin-1 -ol h H qq / ozn / zznz / q / υιλι This substance was prepared following General Synthesis Scheme B. TFA.1H NMR (DMSO-d6, 400 ΜΗζ) δ 11.78 (br s, 1H), 9.40 (br s, 1H), 8.36 (s, 1H) salt was obtained as a salt. 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% at 210 nm and 95.12% at 254 nm. MS: (M+H)+: m / z = 353.2. Example 10: 7-chloro-3,3-dimethyl·5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2] oxaborole-1 (3H)-ol CL This substance was prepared following the General Synthesis Scheme C.1H NMR (DMSO-d6, 400 ΜΗζ) 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, 1 H), 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 found 389.2 [M+H]+. Purity by HPLC: 99.84% (220 nm), 99.83% (254 nm). Example eleven: 5-((5-chloro-4-(cyclopentalamino)pyrimidín-2-yl)amino)-3,3,7trimethylbenzo[c][1,2]oxaborol-1(3H)-ol This substance was prepared following the General Synthesis Scheme C.1H NMR (DMSO-d6, 400 ΜΗζ) 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 found 387.1 [M+H]+. Purity by HPLC: 97.21% (220 nm), 88.55% (254 nm). Example 12: 7-chloro-5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following the General Synthesis Scheme C.1H NMR (DMSO-d6, 400 ΜΗζ) 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 found 407.1 [M+H]+. Purity by HPLC: 98.76% (220 nm), 98.54% (254 nm). Example 13: 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3methylbenzo[c][1,2]oxaborol-1 (3H)-ol qq / azn / zznz / q / υιλι This substance was prepared following General Synthesis Scheme D.1H 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 found 359.1 [M+H]+. Purity by HPLC: 98.84% (220 nm), 97.83% (254 nm). Example 14: 3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme D.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 found 341.1 [M+H]+. Purity by HPLC: 99.8% (220 nm), 99.74% (254 nm). Example 15: 3,3-dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol OH This substance was prepared following the General Synthesis Scheme C.1H 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, 1 H), 2.18 (s, 3H), 1.29 (s, 6H). MS (ESI): m / z found 361.0 [M+H]+. Purity by HPLC: 100% (220 nm), 99.77% (254 nm). Example 16: 5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-¡l)amino)-7(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)- ol QQ! ozn / zznz / q / ΥΙΛΙ This substance was prepared following General Synthesis Scheme A.1H 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 found 395.1 [M+H]+. Purity by HPLC: 98.77% (220 nm), 99.23% (254 nm). Example 17: 7-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared following General Synthesis 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 found 347.1 [M+H]+. Purity by HPLC: 90.25% (220 nm), 88.74% (254 nm). Example 18: 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2] oxaborol-1(3H)-ol This substance was prepared following General Synthesis Scheme A.1H 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 found 401.1 [M+H]+. Purity by HPLC: 99.28% (220 nm), 99.8% (254 nm). Example 19: 3-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared following General Synthesis Scheme D.1H 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 found 347.1 [M+H]+. Purity by HPLC: 94.91% (220 nm), 93.77% (254 nm). Example 20: 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3dimethylbenzo[c][1,2]oxaborol-1 (3H)-ol OH This substance was prepared following the General Synthesis 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, 1H), 4.50-4.44 (m, 1H), 1.98-1.97 (m, 2H), 1.75-1.73 ( m, 2H), 1.65-1.64 (m, 2H), 1.53-1.51 (m, 2H), 1.43 (s, 6H). MS (ESI): m / z found 373.1 [M+H]+. Purity by HPLC: 96.66% (220 nm), 95.82% (254 nm). Example 21: 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol ΗH This substance was prepared following General Synthesis Scheme A.1H 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 found 413.0 [M+H]+. Purity by HPLC: 98.46% (220 nm), 98.87% (254 nm). Example 22: 7-chloro-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) This substance was prepared following General Synthesis Scheme A.1H 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 found 361.1 [M+H]+. Purity by HPLC: 99.83% (220 nm), 99.82% (254 nm). Example 23: 7-ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol qq / ozn / zznz / q / υιλι This substance was prepared following General Synthesis 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 found 355.1 [M+H]+. Purity by HPLC: 93.05% (220 nm), 95.97% (254 nm). Example 24: 3,3,7-trimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborole-1 (3H)-ol This substance was prepared following the General Synthesis Scheme C.1H 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 found 369.2 [M+H]+. Purity by HPLC: 98.87% (220 nm), 99.07% (254 nm). Example 25: 7-chloro-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared following General Synthesis Scheme A.1H 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 found 367.1 [M+H]+. Purity by HPLC: 96% (220 nm), 98.16% (254 nm). Example 26: 7-chloro-3,3-dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following the General Synthesis 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 found 395.1 [M+H]+. Purity by HPLC: 96.13% (220 nm), 98.95% (254 nm). Example 27: 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7ethylbenzo[c][1,2]oxaborol-1(3H)-ol qq / ozn / zznz / q / υιλι This substance was prepared following General Synthesis Scheme A.1H 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 found 373.1 [M+H]+. Purity by HPLC: 98.74% (220 nm), 98.68% (254 nm). Example 28: 7-chloro-5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol ΗH This substance was prepared following General Synthesis Scheme A.1H 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 found 379.1 [M+H]+. Purity by HPLC: 94.64% (220 nm), 97.36% (254 nm). Example 29: 3,7-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)- ol This substance was prepared following General Synthesis Scheme D.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 found 355.2 [M+H]+. Purity by HPLC: 97.41% (220 nm), 96.99% (254 nm). Example 30: 3,3,7-trimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following the General Synthesis Scheme C.1H 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 found 375.1 [M+H]+. Purity by HPLC: 99.84% (220 nm), 99.82% (254 nm). Example 31: 5-((4-(cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborol-1(3H)- This substance was prepared following General Synthesis Scheme A.1H 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, 1 H), 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 found 339.2 [M+H]+. Purity by HPLC: 98.52% (220 nm), 98.84% (254 nm). Example 32: 7-ethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)- H H This substance was prepared following General Synthesis 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 (t, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.13-7.11 (m, 1H) , 4.78 (s, 2H), 2.64 (q, J = 7.4 Hz, 2H), 2.12 (s, 3H), 1.10 (t, J =7.4 Hz, 3H). MS (ESI): m / z found 361.1 [M+H]+. Purity by HPLC: 92.87% (220 nm), 94.53% (254 nm). Example 34: 6-((5-methyl-4-((4-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme B. The analytical data for this compound are as follows.1H NMR (400 MHz, DMSO-de): δ 9.01 (s, 1H), 8.83 (s, 1H), 8.03 & 8.00 (two 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)+. Example 51: 6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι This substance was prepared following General Synthesis Scheme B. The analytical data of this compound are as follows.1H NMR (400 MHz, DMSO-de):ó 10.18 (br s, 1H), 9.67 (br s, 1H), 9.24 (s, 1H), 8.15 (d, J = 8.4 Ηζ, 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 Ηζ, 1H), 4.98 (s, 2H), 3.18 (s, 3H), 2.19 (s, 3H) ppm. HPLC purity: 98.73% at 210 nm and 99.38% at 254 nm. MS: (M+H)+: m / z = 411.1. Example 52: 3,3-dimethyl-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborole-1 (3H)-ol This substance was prepared following General Synthesis Scheme B. The analytical data for this compound are as follows.1H NMR (400 MHz, DMSO-ds): 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, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 - 7.46 (m, 3H), 7.40 (d, J = 8.4 Hz, 1H), 3.19 (s, 3H), 2.19 (s, 3H), 1.45 (s, 6H) ppm. HPLC purity: 98.30% at 210 nm and 99.14% at 254 nm. MS: m / z =438.9 (M+H)+. Example 55: 7-methyl-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H )-ol This substance was prepared following General Synthesis Scheme B. The analytical data for this compound are as follows.1H NMR (400 MHz, DMSO-ds): δ 9.74 (brs, 1H), 9.66 (brs, 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% at 210 nm and 99.63% at 254 nm. MS: m / z =425.1 (M+H)+. Example 59: 6-((4-((1 r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-5-methylpyrimidin-2yl)amino)benzo[c][1,2]oxaborol-1 (3H) -ol This substance was prepared following General Synthesis Scheme A. The analytical data for this compound are as follows.1H NMR (400 MHz, DMSO-de): δ 12.11 (br s, 1H), 10.20 (s, 1H), 9.20 (s, 1H), 7.96 (d, J = 12 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, J = 11.1 Hz, 2H), 1.54 - 1.25 (m, 4H), 1.04 - 0.88 (m, 2H) ppm. HPLC purity: 94.70% at 210 nm and 94.29% at 254 nm. MS: m / z = 369.2 (M+H)+. Example 62: 7-fluoro-6-((5-methyl-4-((3-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H )-ol This substance was prepared following General Synthesis Scheme B. The analytical data for this compound are as follows.1H NMR (300 MHz, DMSO-ds): 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% at 210 nm and 98.04% at 254 nm; MS: m / z = 429.1 [M+H]+. Example 63: 6-((5-methyl-4-((1-methylp¡peridin-4-yl)amino)pyrimidin-2-¡l)amino) benzo[c][1,2]oxaborole-1 (3H)-ol This substance was prepared following General Synthesis Scheme B. The analytical data for this compound are as follows.1H NMR (400 MHz, DMSO-de): 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, 1 H), 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% at 210 nm and 97.13% at 254 nm. MS: m / z = 354.2 (M+H)+. Example 64: 6-((5-methyl-4-(piperidin-4-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared following General Synthesis Scheme B. It was obtained as 2«HCI salt. The analytical data of this compound are as follows.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 99.18% at 254 nm. MS: m / z = 340.2 (M+H)+. Example 65: 6-((4-(cyclohexylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)88 ol The title compound was prepared using the scheme and procedures shown below: DIPEA, dicxane TA, ’2 h min. MW A mixture of cyclohexanamine (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-cyclohex¡l-5-met¡lp¡rimídina-4-am¡ na (1.4 g, yield 41%) as 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 at 145°C under microwave for 20 min. The reaction mixture was concentrated and purified by prep HPLC to obtain 6-((4-(cyclohexylam¡no)-5-methylpyrim¡din-2-¡l)amino)benzo[c ][1,2]oxaborol-1(3H)-ol (40 mg) as white powder.1H 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), 4.024.00 (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% at 214 nm and 95.4% at 254 nm. MS: m / z = 339.1 [M + H]+. Example 66: 6-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol The title compound was prepared using the scheme and procedures shown below: TA. last:- night 20 min MW 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-am. na (1.45 g, yield 45%) as white powder. MS: m / z = 214.0 (M+H)+. A mixture of 2-chloro-5-methyl-N-(pentan-3-¡l)pyrm¡din-4-am¡ne (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 at 145 °C under microwave for 20 min. The reaction mixture was concentrated and purified by prep TLC and prep HPLC to provide 6-((5-methyl-4-(pentan-3-lam¡no)pyrimidin-2-¡l)am¡ no)benzo[c][1,2]oxaborol-1(3H)-ol (8 mg) as 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% at 214 nm and 95.3% at 254 nm. MS: m / z = 327.1 [M+H]+. PART 1-3: Synthesis examples for compounds of Formula (IB) 3. 5-amino-3-methylbenzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι 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, the mixture The resulting mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction was quenched by pouring into ice water (500 mL), the aqueous phase was extracted with dichloromethane (2 χ 150 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (eluting with 10% EA in PE) to give 1-(2-bromo -5nitrophenyl)ethan-1-one (13.9 g, 54%) as white powder.1H NMR (400 MHz, DMSO-ds): 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. 3.2 Preparation of 1-(2-bromo-5-nitrophenyl)ethane-1-ol To a solution of 1-(2-bromo-5-nitrophenyl)ethan-1-one (4.8 g, 20 mmol) in MeOH (30 mL) was added NaBH4 (1.15 g, 30 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature for 2h. The reaction was then quenched with water, extracted with EA and the combined organic phase was washed with water, brine and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EA (100 / 1 to 10 / 1)) to give 1-(2-bromo-5-nitrophenyl)ethan-1ol (3.7 g, 77% yield) as a white solid.1H NMR (300 MHz, DMSO-de): 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, 1 H), 5.09-4.84 (m, 1H), 1.35 ( d, J = 6.4 Hz, 3H) ppm. 3.3 Preparation of 1-bromo-2-(1-(methoxymethoxy)ethyl)-4-n¡trobenzene qq / ozn / zznz / q / υιλι MoMCI. DIEA DCM.TA a40:C To a solution of 1-(2-bromo-5-nitrophenyl)ethanol-1-ol (3.7 g, 15 mmol) in DMC (30 mL) was added DEA (5.2 mL, 30 mmol). MOMCI (2.4 g, 30 mmol) was then added dropwise to the mixture. The resulting mixture was heated at 40°C for 2h, then cooled to room temperature, washed with sat. NaHCOs, brine, and concentrated in vacuo to give a residue, which 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. MHz, CDCh): δ 8.34 (d, J = 2.6 Hz, 1H), 7.91 (dd, J = 8.7, 2.1 Hz, 1 H), 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. 3.4. Preparation of 2-(2-(1-(methoxymethoxy)ethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane To a solution of the compound 1-bromo-2-(1-(methoxymethoxy)ethyl)-4-nitrobenzene (3.1 g, 10 mmol) in dioxane (30 mL) was added KOAc (1.96 g, 20 mol), BzPinz (3.0 g, 12 mmol) and (dppf)PdCl2-DCM (816 mg, 1 mmol) at room temperature under a nitrogen atmosphere. The mixture was heated to 100°C overnight. Then, the precipitate of the reaction mixture was removed by filtration, the filtrate was concentrated in vacuo to give a residue, which was purified by chromatography on silica (PE / EA (20 / 1 to 5 / 1)) to give 2 -(2-(1-(methoxyethoxy)ethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g, crude) as white solid. Ή NMR (400 MHz, CDCh): 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. 3.5 Preparation of 3-methyl-5-nitrobenzo[c][1,2]oxaborol-1(3H)-ol 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) 6N HCl (3 mL) was added. 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 layer was washed with water, brine, and concentrated in vacuo to give a residue, which was purified by prep HPLC (eluting with 0.1% TFA in water and ACN) to give 3-methyl-5-nitrobenzo[c][1 ,2]oxaborol-1(3H)-ol (1.0 g, 81% yield) as white solid.1H NMR (400 MHz, DMSO-de): 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, 1 H), 1.48 (d, J = 6.6 Hz, 3H) ppm. 3.6 Preparation of 5-amino-3-methylbenzo[c][1,2]oxaborol-1 (3H)-ol HO HO QQ! ozn / zznz / q / ΥΙΛΙ 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 washed three times with Ha, then stirred at room temperature overnight. The reaction mixture was passed through a Celite pad, the filtrate concentrated in vacuo to give a residue, which was purified by prep 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-de): 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. 4. 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzo[c][1,2]oxaborol1(3H)-ol H.O. This substance was prepared using General Synthesis Scheme B and following the procedure used for the synthesis of 5-((4-(c¡clopent¡lam¡no)-5-methylp¡r¡m¡n-2- ¡l)am¡no)-7methylbenzo[c][1,2]oxaborol-1(3H)-ol as a white solid. Performance: 8%.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), 1.601.57 (m, 4H), 1.37 (d, J = 6.4 Hz, 1H). MS (ESI): m / z found 339.2 [M+H]+. Purity by HPLC: 97.16% (220 nm), 97.78% (254 nm). 5. 5-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol qq / azn / zznz / q / υιλι 5.1 Preparation of tere-butyl (4-bromo-3-(2-hydroxypropan-2-yl)phenyl)carbamate To a solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)benzoate (10.0 g, 30.4 mmol) in dry THF (50 mL) MeMgBr (50 mL, 150 mmol) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was washed with water, brine, dried over anhydrous Na2SÜ4 and concentrated in vacuo to give a residue, which was purified by chromatography on silica eluting with PE / EA (100 / 1 to 10 / 1) to give ( Tere-butyl 4-bromo-3-(2-hydroxypropan-2-yl)carbamate (7.5 g, 75% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-de): 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. 5.2 Preparation of terebutyl (4-bromo-3-(2-(methoxymethoxy)propan-2-yl)phenyl)carbamate To a solution of tere-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) . MOMCI (2.4 g, 30 mmol) was then added dropwise to the mixture. The resulting mixture was heated at 40°C for 2h. Then, the reaction mixture was cooled to room temperature, washed with sat. NaHCOs. brine, and concentrated in vacuo to give a residue, which was purified by chromatography on silica (PE / EA (30 / 1 to 10 / 1)) to give (4bromo-3-(2-(methoxymethoxy)propan-2- Tere-butylyl)phenyl)carbamate (6.5 g, crude) as yellow oil, which was used directly in the next step without further purification. 5.3 Preparation of tere-butyl (3-(2-(methoxymethoxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl) carbamate Br^^^ || θ I reflux in dioxane \ N OMOM H I / O—v— cn-O S \__ / o ^ \ / IZ >° o λ To a solution of tere-butyl (4-bromo-3-(2-(methoxy¡methoxy¡)propan-2-¡l)phen¡l)carbamate (6.5 g, 17 mmol) in dioxane (50 mL) added KOAc (5.1 g, 52 mol), B2Pin2 (5.1 g, 20.4 mmol) and (dppf)PdCI2DCM (1.4 g, 1.7 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 100°C for 4h, and then cooled to room temperature. The solid of the mixture was removed by filtration, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica chromatography [PE / EA (20 / 1 to 5 / 1)] to give (3-(2 -(methoxymethoxy¡)propan-2-¡l)-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] tere-butyl carbamate (2.4 g, crude) as a yellow oil, qq / Qzn / zznz / q / υιλι which was used directly in the next step without further purification. 5.4 Preparation of tere-butyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl) carbamate HO To a solution of (3-(2-(methoxymethoxy¡)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) carbamate of tere-butyl (2.4 g, 5.7 mmol) in EtOH (15 mL) 2N HCl (5 mL, 10 mol) was added, the resulting reaction mixture was stirred at room temperature for 30 min, then 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, which was purified by column chromatography (PE / EtOAc = 10:1) allowing to obtain (1-hydrox Tere-butyl-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (1.0 g, crude) as a yellow oil, which it is used directly in the next step without further purification. MS: (M-H)-: m / z = 276.0. 5. 5 Preparation of HCl salt of 5-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1 (3H)-ol 4M. HCl (in dioxane) To a solution of terebutyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (1.0 g, 3.6 mmol) in dioxane (4M HCl in dioxane, 6 mL) was stirred at room temperature for 3 h, the precipitate was collected by filtration, dried in vacuo to give (280 mg, 37%) the HCl salt of 5-amino3,3-dimethylbenzo[c][1 ,2]oxaborol-1 (3H)-ol as a white solid.1H NMR (400 MHz, DMSO-de): δ 7.43 (d, J = 7.8 Hz, 1 H), 6.77-6.67 (m, 2H), 1.39 (s, 6H) ppm. 6. 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol This substance was prepared using General Synthesis Scheme B and following the procedure used for the synthesis of 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)-7methylbenzo[c][1,2] oxaborol-1(3H)-ol. Yield: 26%.1H NMR (DMSO-d6, 400 ΜΗζ) 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 found 353.2 [M+H]+. Purity by HPLC: 95.93% (220 nm), 94.50% (254 nm). 7. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7ethylbenzo[c][1,2]oxaborol-1(3H)-ol and 5-((4- (cyclopentylamino)pyrimidin-2-yl)amino)-7-ethylbenzo[c][1,2]oxaborole-1(3H)-ol 7.1 Preparation of Methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2-hydroxybenzoate 100'C,8h To a solution of methyl 5-amino-3-ethyl-2-hydroxybenzoate (600 mg, 3.07 mmol, 1 eq) and 2,5dichloro-N-cyclopentyl-pyrimidin-4-amine (713 mg, 3.07 mmol, 1 eq ) in dioxane (20 mL) was added p-TsOH (794 mg, 4.61 mmol, 1.5 eq) at 20°C. The reaction mixture was stirred at 100°C for 8h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, to which was added sat. NaHCOs. (30 mL) at 0°C, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NasSCU, filtered, and concentrated in vacuo to obtain a residue, which was purified by column chromatography (SIO2, petroleum ether / ethyl acetate =1 / 0 to 5 / 1) to give 5-[[5-chloro-4-(c¡clopent¡lam¡no)p¡r¡mid¡n-2-¡l]am¡no]-3- Methyl ethyl-2-hydroxybenzoate (700 mg, 1.79 mmol, 58.27% yield) as a yellow solid. 1H NMR (DMSO-de, 400 ΜΗζ) 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). 7.2 Preparation of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2(trifluoromethylsulfonyloxy)benzoate QQ! ozn / zznz / q / ΥΙΛΙ To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (658 mg, 1.84 mmol, 1.2 eq) and 5-[[5-chloro-4-(cyclopentylamino) Methyl pyrimidin-2-¡l]amino]-3-ethyl-2-hydroxy¡benzoate (600 mg, 1.54 mmol, 1 eq) in DCM (30 mL) was added DMAP (56 mg, 461 pmol , 0.3 eq) and TEA (311 mg, 3.07 mmol, 427 pL, 2 eq) at 0°C. The mixture was stirred at 25°C for 8h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiOz, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 5-[[ Methyl 5-chloro-4-(cyclopentylamino)pyrmidin-2-l]amino]-3ethyl-2-(trifluoromethylsulfon¡lox¡)benzoate (600 mg, 1.15 mmol , yield 74.75%) as white solid.1H NMR (CDCI3,400 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). 7.3. Preparation of 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl1,3,2-dioxabor¡nan-2-¡l)-3-et Methyl l-benzoate A mixture of methyl 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-ethyl-2(trifluoromethylsulfon¡lox¡)benzoate (150 mg, 287 pmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-5,5-dimethyl-1,3,2-dioxaborinane (194 mg, 860 pmol, 3 eq), KOAc (84 mg, 861 pmol, 3 eq), and Pd(PPh3)2Cl2 (20 mg, 29 pmol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N2 3 times, then The mixture was stirred at 80°C for 2 h under a N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SO2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 5-[[ 5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)- Methyl 3-ethyl-benzoate (450 mg, 924 pmol, 80.57% yield) as a white solid.1H NMR (CDCI3, 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). 7.4 Preparation of N4-cyclopentyl-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)pyrimidin-2,4-diamine and 5-chloro-N4-cyclopentyl-N2-(7 -ethyl-1-hydroxy-3H-2,1-benzoxaborol-5yl)pyrimidin-2,4-diamine NaBH4 MeOH, THF 25°C, 4h qq / ozn / zznz / q / υιλι To a mixture of 5-[[5-chloro-4-(cyclopentylamino)pyrimidín-2-íl]amino]-2-(5,5-dimet¡l- Methyl 1,3,2dioxaboran-2-yl)-3-ethyl-benzoate (150 mg, 308 pmol, 1 eq, 3 batches) in THF (10 mL) and MeOH (0.5 mL) was added NaBH4 (58 mg, 1.54 mmol, 5 eq) in portions at 0°C, then the mixture was stirred at 25°C for 4 h under N2 atmosphere. The reaction was quenched with 1N HCI (1 mL) at 0°C, concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Xtimate C18 100*30mnT3pm; mobile phase: [water(0.1%TFA) -ACN]; B%: 30%-50%, 10min) to give N4-cyclopentyl-N2-(7-ethyl-1 -hydroxy-3H-2,1 benzoxaborol-5-¡l)pyri¡m¡ d¡n-2,4-d¡amine (195 mg, 577 pmol, yield 62.37%).1H NMR (DMSO-de, 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, 2H), 1.98-1.96 (m, 2H ), 1.74-1.72 (m, 2H), 1.64-1.54 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H). MS (ESI): calculated mass. For C18H22BCIN4O2 372.15, m / z found 373.1 [M+H]+. HPLC: 98.74% (220nm), 98.68% (254nm). And 5-chloro-N4-cyclopent¡l-N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-¡l)p¡ñm¡d¡na2,4-diamine (51 mg, 137 pmol, 14.80% yield) as white solid.1H NMR (DMSO-de, 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), 1.761.65 (m, 2H), 1.64-1.48 (m, 4H), 1.19 (t, J = 7.6Hz, 3H). MS (ESI): calculated mass. For C18H23BN4O2 338.19, found m / z 339.2 [M+H]+. HPLC: 98.52% (220nm), 98.84% (254nm). 8. Preparation of 3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborole-1(3H) -ol kOAz. PaíPFh-}.C!. 8.1. Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]benzoate HCI, EtOH 25-100°C, 24h To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (2 g, 9.36 mmol, 1 eq) and methyl 5-amino-2-bromo-benzoate ( 2.15 g, 9.36 mmol, 1 eq) in EtOH (50 mL) HCI (37.4 mmol, 3.72 mL, 36% purity, 4 eq) was added at 25°C, the reaction mixture was heated to 100°C and stirred. for 24 hours. The solvent was then removed to obtain a residue, to which H2O (20 mL) was added, and its pH was adjusted to 5 with aq. NaHCOs. sat, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was triturated with MTBE (10 mL) to give the crude product, then the crude product was triturated with EtOAc (10 mL) to give 2-bromo-5-[[4-(1-ethylpropylamino)- Methyl 5-methyl-p¡r¡m¡n-2yl]amino]benzoate (2.3 g, 5.65 mmol, 60.33% yield) as a white solid. 1H NMR (DMSOde, 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), 3,993.93 (m, 1H), 3.81 (s, 3H) , 1.94 (s, 3H), 1.54-1.49 (m, 4H), 0.75 (t, J = 7.2 Hz, 6H). 8.2. Preparation of 2-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2yl]amino]phenyl]propan-2-ol qq / azn / zznz / q / υιλι A solution of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino] benzoate (500 mg, 1.23 mmol, 1 eq) in THF (10 mL) MeMgBr (3 M, 2.05 mL, 5 eq) was added dropwise at 0°C over a period of 10 min, the resulting mixture was stirred at 25°C for 2 h. The reaction mixture was then poured into H2O (30 mL), and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by short column to give 2[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan. -2-ol (400 mg, 982 pmol, 79.83% yield) as yellow oil.1H NMR (DMSO-de, 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, 1 H),1.99 (s, 3H), 1.58 -1.48 (m, 10H), 0.86 (t, J = 7.6 Hz, 6H). 8.3. Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5methyl-pyrimidin-2,4-diamine KOAc PdiPPh:·l:C¡: dioxane, 25-60'0. 12 noon OH / CF-.COOH To a solution of 2-[2-bromo-5-[[4-(1 -ethylpropylamine)-5-methyl-pyrimidin-2-yl]amino]phenyl]propan-2-ol (350 mg, 859 pmol, 1 eq) 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 eq) in dioxane (7 mL) Pd(PPh3)2Cl2 (60.3 mg, 85.9 pmol, 0.1 eq), KOAc (169 mg, 1.72 mmol, 2 eq) was added at 25°C under atmosphere of N2, 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 prep HPLC (column: ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methylpyrimidine-2,4-dyamine (30 mg, 65.9 pmol, 7.67% yield, 99.8% purity, TFA) as a white solid. Ή 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): calculated mass. For C21H28BF3N4O4 468.22, m / z found 355.2 [M+H]+. HPLC: 99.80% (220nm), 99.99% (254nm) 9. Preparation of 3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι TsOHH.O. ΟΌ»hoop. 2S80‘C. 12r HrRH4ih;□-2b C 3 h KOAo ΡοΡΡύι.Οι. diCxaro. 25-¿Ú:C. 8 a.m. 9.1 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]aminolphenylthanone TsOH.H;O, dioxane, 25 -80cC. 12 noon To a solution of 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.5 g, 7.02 mmol, 1 eq) and 1 -(5amino-2-bromo -phenyl)ethanone (1.50 g, 7.02 mmol, 1 eq) in dioxane (50 mL) was added TSOH.H2O (2.00 g, 10.5 mmol, 1.5 eq) at 25°C, the resulting mixture was heated to 80°C and stirred for 12h. H2O (30 mL) was poured into the above mixture, and its pH was adjusted to 9 with aq. NaHCOs. sat., extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / gradient pet. ether @ 75 mL / min) to give 1- [2-bromo-5-[[4-(1-ethylpropylamino)-5-methylpyrimidin-2-yl]amino]phenyl]ethanone (1.3 g, 3.32 mmol, 47.33% yield) as 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). 9.2 Preparation of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino] phenyl]ethanol NaBH4, MeOH / THF or -------------0-25°C, 3 h To a solution of 1-[2-bromo-5-[[4-(1-ethylpropílam¡no)-5-met¡l-pyr¡m¡d¡n-2-¡l]am¡ no]phenyl]ethanone (700 mg, 1.79 mmol, 1 eq) and MeOH (1.79 mmol, 72.4 pL,1 eq) in THF (5 mL) NaBH4 (102 mg, 2.69 mmol, 1.5 eq) was added to 0 °C, the resulting mixture was stirred at 25°C for 3 h. The reaction mixture was poured into H2O (10 mL), its pH was adjusted to 5 with 2N HCl, and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over NazSCh, filtered, and concentrated in vacuo to give a residue. The residue was purified by short column to give 1-[2-bromo5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-l]amino]phenyl]ethanol (400 mg, 1.02 mmol, 56.98% yield) as white solid.1H NMR (DMSO-de, 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 = 7.6Hz, 6H) 9.3 Preparation of N4-(1-ethylpropyl)-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5methyl-pyrimidin-2,4-diamine CHCOOH To a solution of 1-[2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]ethanol (300 mg, 763 pmol, 1 eq) and 2 -(5,5-dimethyl-1,3,2-dioxaboñnan-2-¡l)-5,5-dimethyl-1,3,2-dioxaborinane (431 mg, 1.91 mmol, 2.5 eq) in dioxane (10 mL ) Pd(PPh3)2Cl2 (53.5 mg, 76.3 pmol, 0.1 eq), KOAc (150 mg, 1.53 mmol, 2 eq) was added at 25°C under N2 atmosphere, 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, which was dissolved in H2O (10 mL), and its pH was adjusted to 5 with 2N HCl, extracted with EtOAc (8 mL x 3). . The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Welch Xtimate C18 100*25mm*3pm; mobile phase: [water(0.1%TFA)-MeOH]; B%: 40%-60%,12min) to give N4-(1 -ethylpropyl)N2-(1-hydroxyl-3-methyl-3H-2,1-benzoxaborol-5-l)-5-methyl-pyrimidin-2,4-dyamine (96 mg, 211 pmol, 27.65% yield, 99.80% purity, TFA) as a white solid.1H NMR (DMSO-de, 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, 1H), 100 5.20 (q, J = 6.8 Hz, 1H), 4.12-4.03 (m, 1H), 2.03 (s, 3H), 1.64-1.59 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 0.880 .82 (m, 6H). MS (ESI): calculated mass. For C20H26BF3N4O4 454.20, m / z found 341.0 [M+H]+. HPLC: 99.80% (220nm), 99.74% (254nm). 10. Preparation of N-(7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)-1,1,1trifluoro-N-(5-methyl-4- (pentan-3-ylamino)pyrimidin-2-yl)methanesulfonamide qq / azn / zznz / q / υιλι K>Ar. 2-re: xvi-er: · •i MrOH BOC Til c-TsOH. a :.xaro, i X’C. 6 r 10.1 Preparation of 3-ethyl-2-hydroxy-benzaldehyde (HCHO)n, MgCI2OH ___________ TEA, MeCN 80°C, 12 h A mixture of 2-ethylphenol (10.0 g, 81.86 mmol, 9.62 mL, 1 eq), MgCl (11.7 g, 122.79 mmol, 5.04 mL, 1.5 eq), TEA (33.1 g, 327.43 mmol, 45.57 mL, 4 eq) and (HCHO)n (4.9 g, 163.71 mmol, 2 eq) in MeCN (100 mL) was degassed and purged with N2 3 times, the reaction mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was then poured into aqueous HCl (200 mL, 1N), and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SiOs, 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 yellow oil.1H NMR (CDCI3, 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 = 7.2Hz, 3H). 10.2 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzaldehyde 101 To a solution of 3-ethyl-2-hydroxyl-benzaldehyde (10.0 g, 66.59 mmol, 1 eq) in AcOH (100 mL) was added HNO3 (14.0 g, 199.97 mmol, 10 mL, 90% purity, 3.00 eq) 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, the yellow solid formed was collected by filtration, dried under vacuum to give 3-ethyl-2-hydroxy-5-nitro-benzaldehyde. (8.60 g, 44.06 mmol, 66.17% yield) as yellow solid.1H NMR (CDCI3, 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). 10.3 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzoic acid 2-methylbut-2-ene I AjDH __________ í J n NaCIO2, NaH2PO4JL °2nt-BuOH, H2O OH 20°C,12h To a solution of 3-ethyl-2-hydroxyl-5-nitro-benzaldehyde (5.00 g, 25.62 mmol, 1 eq) and 2-methyl-2-butene (12.6 g, 179.33 mmol, 19.00 mL, 7 eq) in t- BuOH (50 mL) and H2O (30 mL) were added NaH2PO4 (13.8 g, 115.28 mmol, 4.5 eq) and NaCIO2 (7.00 g, 76.86 mmol, 3 eq) 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, which was poured into ice / water (100 mL) at 0°C. The aqueous phase was extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SÜ4, filtered, and concentrated in vacuo to give 3-ethyl-2-acid. hydroxyl-5-nitro-benzoic acid (5.00 g, 18.94 mmol, 73.94% yield, 80% purity) as a yellow solid. 1H NMR (CDCh, 400 MHz) δ 11.45 (s, 1H), 8.74 (d, J = 2.8 Hz, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 2.78 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H). 10.4 Preparation of 3-ethyl-2-hydroxy-5-nitro-benzoate χΑχθΗ H2SO4, MeOH χΑ / 0Ηí T ——---* í T80°C'16h oh oh QQ! QZn / ZZnZ / q / ΥΙΛΙ To a solution of 3-ethyl-2-hydroxy-5-nitro-benzoic acid (5.00 g, 18.94 mmol, 1 eq) in MeOH (50 mL) was added H2SO4 (7.4 g, 75.77 mmol, 4.0 mL, 4 eq) drop by drop at 0°C. The mixture was stirred for 16 h at 80°C. The reaction mixture was poured into ice / water (100 mL) at 0°C, and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by column (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 yellow oil. , 400 MHz) δ 11.74 (s, 1H), 8.66 (d, J = 2.4 Hz, 1 H), 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). 10.5 Preparation of methyl 5-amino-3-ethyl-2-hydroxybenzoate 102 NH4CI, Fe / V / OH Yn----- í ToEt0H·H2° H2N ¿ 50°C, 2 h ¿ To a solution of methyl 3-ethyl-2-hydroxy-5-nitro-benzoate (3.50 g, 15.54 mmol, 1 eq) in EtOH (50 mL) and H2O (10 mL) was added NH4Cl (2.50 g, 46.63 mmol , 1.63 mL, 3 eq) and Fe (2.60 g, 46.63 mmol, 3 eq) 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 (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give methyl 5-amino-3ethyl-2-hydroxybenzoate (2.00 g, 10.25 mmol, 65.92% yield). ) as a yellow solid.1H NMR (CDCh, 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). 10.6 Preparation of methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-2hydroxybenzoate p-TsOH, dioxane 100cC, 6 h To a solution of methyl 5-amino-3-ethyl-2-hydroxyl-benzoate (600 mg, 3.07 mmol, 1 eq) in dioxane (20 mL) was added p-TsOH (794 mg, 4.61 mmol, 1.5 eq). ) and 2-chloro-N-(1 -ethylpropyl)-5-methylpyrimidine-4-amine (657 mg, 3.07 mmol, 1 eq) 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 sat. NaHCOs. (30 mL) at 0°C, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SÜ4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SÍO2, petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give 3-ethyl-5-[[4-(1-ethylprop¡lano)-5-methyl-pyrim¡din-2-¡l]am¡ Methyl no]-2-hydroxy-benzoate (700 mg, 1.88 mmol, yield 61.15%) as a yellow solid.1H NMR (DMSO-de, 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). 10.7 Preparation of methyl 3-ethyl-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl](trifluoromethylsulfonyl)amino]-2-(trifluoromethylsulfonyloxy)benzoate Methyl 3-ethyl-5-((5-methyl-4(pentan-3-ylamino)pyrimidin-2-yl)amino)-2-((trifluoromethyl)sulfonyl)oxy)benzoate 103 To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (748 mg, 2.09 mmol, 1.3 eq) and 3-ethyl-5-[[4 Methyl -(1-ethylpropylamino)-5-methyl-pyrimidin-2-l]amino]-2-hydroxy-benzoate (600 mg, 1.61 mmol, 1 eq) In DCM (30 mL), DMAP (59 mg, 483 pmol, 0.3 eq) and TEA (326 mg, 3.22 mmol, 448 pL, 2 eq) were added at 0°C. The reaction mixture was stirred at 25°C for 8 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (S1O2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 3-ethyl- Methyl 5-[[4-(1-ethylpropylamino)-5methyl-pyrim¡din-2-yl]-(trifluoromethylsulfonyl)amino]-2-(trifluoromethylsulfonyloxy)benzoate (300 mg, 471 pmol, 36.91% yield) and 3-ethyl-5-((5-methyl-4-(pentan-3-lamino)pyrimidin-2-l)amino)-2(( Methyl (trifluoromethyl)sulfonyl)oxy)benzoate (300 mg, 595 pmol, 29.25% yield) as white solid. Ή NMR (CDCI3,400 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), 0.900.80 (m, 14H). 10.8 Preparation of 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1-ethylpropylamino)5-methyl-pyrimidin-2-yl Methyl ]-(trifluoromethylsulfonyl)amino]benzoate B2(neop)2 KOAc PdíPPh3);CI;dioxane. 80'C. 2 hours qq / Qzn / zznz / q / υιλι A mixture of 3-ethyl-5-[[4-(1-ethylpropylamine)-5-methyl-pyrimidin-2-yl]-(trifluoromethylsulfonyl)am Methyl]-2(trifluoromethylsulfon¡lox¡)benzoate (100 mg, 157 pmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-5,5-dimet ¡l-1,3,2-d¡oxabor¡nan (106 mg, 471 pmol, 3 eq), KOAc (46 mg, 471 pmol, 3 eq) and Pd(PPh3)2&2 (11 mg, 16 pmol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N2 3 times, then the mixture was stirred at 80°C for 2 h under N2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SIO2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 2-(5 ,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1 ethylpropylamino)-5-methyl-pyrimidin-2-! Methyl l]-(trifluoromethylsulfoníl)amino]benzoate (600 mg, crude) as colorless oil. 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 To a mixture of 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-5-[[4-(1 -ethylpropylamino)-5-methyl Methyl lpyrim¡din-2-¡l]-(trifluoromethylsulfon¡l)amino]benzoate (80 mg, 133.23 pmol, 1 eq) in MeOH (0.1 104 mL) and THF (2 mL), NaBH4 (20 mg, 532.93 pmol, 4 eq) was added at 0°C, and then the mixture was stirred at 20°C for 2 h under N2 atmosphere. The reaction was quenched with HCl (1N, 0.5 mL), concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water (0.1%TFA )-ACN]; B%: 50%-60%, 10min) to give N-(7-ethyl-1-hydroxy-3H-2,1benzoxaborol-5-yl)-N-[4-(1 -ethylpropylamino) -5-methyl-pyrimidin-2-yl]-1,1,1-trifluoro-methanesulfonamide (20 mg, 41.13 pmol, 30.87% yield) as a white solid.1H NMR (DMSO-de, 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): calculated mass. For C20H26BF3N4O4S 486.17, m / z found 487.1 [M+H]+. HPLC: 96.15% (220nm), 90.95% (254nm). 11. Preparation of 7-ethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol qq / ozn / zznz / q / υιλι A mixture of N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N-[4-(1-ethylpropylamino)-5-methylpyrimidedin-2-yl ]-1,1,1-trifluoro-methanesulfonamide (200 mg, 411 pmol, 1 eq) in THF (10 mL) and MeOH (10 mL) K2CO3 (142 mg, 1.03 mmol, 2.5 eq) was added at 0°C , then the mixture was stirred at 20°C for 12 h under a N2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water (0.1%TFA)-ACN] ; B%: 30%-50%,10min) 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 pmol, 15.44% yield) as white solid. 1H NMR (DMSO-de, 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), 4.13-4.07 (m, 1H), 2.78 (q, J = 7.6 Hz, 2H), 2.03 (s, 3H), 1.64-1.56 (m, 4H), 1.90 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.6 Hz, 6H) . MS (ESI): calculated mass. For C19H27BN4O2 354.22, m / z found 355.1 [M+H]+. HPLC: 93.05% (220nm), 95.97% (254nm). 12. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7methylbenzo[c][1,2]oxaborol-1 (3H)-ol •:CAc. either 25'C-íZ*C. '6 hours 105 qq / Qzn / zznz / q / υιλι 12.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid To a mixture of 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 eq) in concentrated H2SO4 (70 mL) was added a solution of KNOa (4.61 g, 45.5 mmol, 0.98 eq) in H2SO4 ( 30 mL), the resulting mixture was stirred for 3 h at 0°C. 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 (50 mL x 2), 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.1H NMR (CDCh, 400 MHz) δ 8.55 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 2.63 (s, 3H). 12.2 Preparation of methyl 2-bromo-3-methyl-5-nitro-benzoate To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.5 g, 32.7 mmol, 1 eq) in MeOH (100 mL) was added thionyl chloride (65.3 mmol, 4.7 mL, 2 eq) to 0°C, the resulting mixture was heated to 80°C and stirred for 15h. The reaction mixture was cooled to room temperature, concentrated in vacuo to give a residue, which was purified by column chromatography (S1O2, petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to give 2-bromo Methyl -3-methyl-5-nitro-benzoate (8.5 g, 31.0 mmol, 94.9% yield) as an off-white solid.1H NMR (CDCh, 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). 12.3 Preparation of Methyl 5-amino-2-bromo-3-methyl-benzoate or or To a mixture of methyl 2-bromo-3-methyl-5-nitro-benzoate (7.5 g, 27.4 mmol, 1 eq) in EtOH (100 mL) and H2O (20 mL) was added NH4Cl (5.86 g, 109 mmol, 4 eq) and Fe (6.11 g, 109 mmol, 4 eq) in one portion at 25°C under N2 atmosphere, 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), the resulting solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 106 to give methyl 5-amino-2-bromo-3-methyl-benzoate (6 g, 24.6 mmol, 89.8% yield) as brown oil.1H NMR (CDCI3,400 MHz) δ 6.79 (s, 1H), 6.67 (s, 1H), 3.90 (s, 3H), 3.72 (br s, 2H), 2.34 (s, 3H). 12.4 Preparation of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine To a mixture of 2,4,5-trichloropinmidine (13 g, 70.8 mmol, 1 eq) in THF (150 mL) cyclopentanamine (106 mmol, 10.5 mL, 1.5 eq) was added dropwise at 0°C, the mixture It 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), the combined organic phase was washed with brine (50 mL x 2), dried over anhydrous NazSCU, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SiOz, petroleum ether / ethyl acetate=20 / 1 to 10 / 1) to give 2,5-dichloro-N-cyclopentyl-pyrimidin-4amine (12.6 g, 54.2 mmol, 76.6% yield) as a white solid. 1H NMR (CDCh, 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). 12.5 Preparation of 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3-methyl methylbenzoate TsOH, dioxane 20cC-80°C. 4 p.m. To a mixture of 2,5-dichloro-N-cyclopentyl-pyrimin-4-amine (2 g, 8.62 mmol, 1 eq) and 5-amino-2bromo-3-methyl- Methyl benzoate (2.1 g, 8.62 mmol, 1 eq) in dioxane (50 mL) TsOH (2.23 g, 12.9 mmol, 1.5 eq) was added dropwise at 20°C under Nz atmosphere. The mixture was heated to 80°C and stirred for 16h. The reaction mixture was poured into NaHCO3ac. sat. (100 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with brine (50 mL x 2), dried over anhydrous NazSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether / ethyl acetate=3 / 1 to 1 / 1) to give 2-bromo-5-[[5-chloro4-(cyclopent¡lamino)pyrim¡ Methyl d¡n-2-¡l]am¡no]-3-methyl-benzoate (1.5 g, 3.41 mmol, 39.6% yield) as a white solid.1H NMR (DMSO-de.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). 12.6 Preparation of 5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-2-(5,5-dimethyl1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate methyl 107 To a mixture of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-¡l]amino]-3-methyl-benzoate (500 mg, 1.14 mmol, 1 eq) In dioxane (15 mL), KOAc (279 mg, 2.84 mmol, 2.5 eq), Pd(PPh3)2Cl2 (79 mg, 113 pmol, 0.1 eq) and 2-(5,5-dimethyl-1,3,2) were added. -dioxaborinan-2-¡l)-5,5-dimethyl¡l-1,3,2dioxaborinane (513 mg, 2.27 mmol, 2 eq) in one portion at 25°C under N2 atmosphere, then the mixture was heated to 80°C and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 5-[[5-chloro-4-(cyclopent¡lamino)pyr¡midín-2-¡l]amino]- Methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylbenzoate (700 mg, crude) as brown solid. MS (ESI): calculated mass. For C23H30BCIN4O4 472.20, m / z found 473.2 [M+H]+. 12.7 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy¡-7-methyl-3H-2,1-benzoxaborol-5yl)pyrimidin-2,4-diamine qq / Qzn / zznz / q / υιλι To a mixture of 5-[[5-chloro-4-(cyclopent¡lamino)pyr¡m¡d¡n-2-¡l]amino]-2-(5,5-dimet¡ Methyl l-1,3,2dioxaborinan-2-yl)-3-methylbenzoate (700 mg, crude) and MeOH (0.1 mL, 1.67 eq) in THF (8 mL) NaBH4 (168 mg, 4.44 mmol, 3 eq) in portions at 0°C, then the reaction was 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 (2N), which was extracted with ethyl acetate ( 5mL x 3). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water (0.1%TFA)-ACN]; B%: 20%-50%, 10min) to give the product with TFA residue. The product was dissolved in ice-water (w / w = 1 / 1) (8 mL), and the pH of the aqueous phase was adjusted to 7 with NaHCOs (2N), extracted with ethyl acetate (5 mL x 3 ), the combined organic phase was washed with brine (5 mL x 2), dried over anhydrous NapSCk, filtered and concentrated in vacuo to give 5-chloro-N4-cyclopentyl-N2-(1hydroxy-7-methyl-3H- 2,1-benzoxaborol-5-yl)pyrimidin-2,4-diamine (16 mg, 42 pmol, 2.82% yield, 93.73% purity) as a yellow solid.1H NMR (DMSO-de, 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): calculated mass. For C17H20BCIN4O2 358.14, m / z found 359.1 [M+H]+. HPLC: 93.73% (220nm), 94.52% (254nm). 13. Preparation of 7-chloro-3,3-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2yl)amino) benzo[c][1,2] oxaborol-1( 3H)-ol 108 o2n 13.1 Preparation of methyl ci 2-amino-3-chloro-5-nitro-benzoate To a mixture of methyl 2-amino-5-nitro-benzoate (12 g, 61.17 mmol, 1 eq) in DMF (120 mL) was added NCS (10.6 g, 79.5 mmol, 1.3 eq) in portions at 20°C . The mixture was stirred at 20°C for 12 hours. The mixture was stirred at 20°C for 12 h. The reaction mixture was poured into H2O (200 mL), then the yellow precipitate was collected by filtration, dried in vacuo to give methyl 2-amino-3-chloro-5-nitrobenzoate (13 g, 56.37 mmol, yield 92.15 %) as yellow solid.1H NMR (DMSO-de, 400 ΜΗζ) δ 8.52 (dd, J = 6.8, 2.8 Hz, 1 H), 8.29 (dd, J = 7.6, 2.4 Hz, 1H), 3.88 (s, 3H). 13.2 Preparation of methyl 2-bromo-3-chloro-5-nitro-benzoate o2n ci CL NH2CuBr2, t-BuONO or Tf MeCN, 65°C, 0.5 h O2N either To a mixture of t-BuONO (8.94 g, 86.7 mmol, 10.3 mL, 2 eq) and CuBrz (14.53 g, 65.0 mmol, 3.0 mL, 1.5 eq) in MeCN (100 mL) was added 2-amino-3-chloro Methyl-5-nitro-benzoate (10 g, 43.4 mmol, 1 eq) in portions at 65°C. The mixture was stirred at 65°C for 30 min. The reaction mixture was poured into H2O (150 mL), the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with aq Na2SOa. sat. (100 mL x 3), the combined organic layers were washed with brine (100 mL x 2), dried over anhydrous NasSCU, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 120 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give methyl 2-bromo-3-chloro-5-nitro-benzoate ( 11 g, 37.3 mmol, yield 86.14%) as a yellow solid. 1H NMR (CDCb, 400 ΜΗζ) δ 8.43-8.42 (m, 2H), 4.01 (s, 3H). 13.3 Preparation of methyl ci 5-amino-2-bromo-3-chloro-benzoate Cl o2n 109 To a mixture of methyl 2-bromo-3-chloro-5-nitro-benzoate (11 g, 37.4 mmol, 1 eq) in EtOH (110 mL) and H2O (30 mL) was added Fe (6.26 g, 112 mmol , 3 eq) and NH4CI (3.00 g, 56.0 mmol, 1.5 eq) in one portion at 20°C. The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was dissolved in DCM (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-amino-2-bromo Methyl -3-chloro-benzoate (10 g, crude) as yellow oil. Ή NMR (CDCI3,400 ΜΗζ) δ 6.90-6.89 (m, 1H), 6.86-6.85 (m, 1H), 3.92 (s, 3H). 13.4 Preparation of methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2yl]amino]benzoate qq / Qzn / zznz / q / υιλι To a mixture of methyl 5-amino-2-bromo-3-chloro-benzoate (2.72 g, 10.3 mmol, 1.1 eq) and 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin- 4-amine (2 g, 9.36 mmol, 1 eq) in dioxane (20 mL) was added to TSOH.H2O (2.67 g, 14.0 mmol, 1.5 eq) in one portion at 20°C. The mixture was heated to 80°C and kept stirring for 10 h. The reaction mixture was cooled to room temperature and its pH was adjusted to 7 with NaHCO3ac. sat., the aqueous phase was extracted with EtOAc (20 mL x 3). 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, which was purified by flash chromatography on silica gel (ISCO®; Flash column of 40 g SepaFlash® silica, eluent 0-40% gradient ethyl acetate / petroleum ether @ 75 mL / min) to give 2-bromo-3-chloro-5-[[4-(1-ethylprop¡ Methyl lam¡no)-5-methyl-p¡r¡m¡d¡n-2-¡l]am¡no] benzoate (2.1 g, 4.75 mmol, yield 50.80%) as a yellow solid.1H NMR ( DMSO-de, 400 ΜΗζ) 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). 13.5 Preparation of 2-[2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2yl]amino]phenyl]propan-2-ol Methyl 2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-i]amino]benzoate was added (1 g, 2.26 mmol, 1 eq) to MeMgBr (3 M, 11.3 mL, 15 eq) in portions at 0°C, the resulting mixture was stirred at 0°C for 4 h. The reaction mixture was poured into sat. NH4CI. ac. (20 mL), and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by chromatography. 110 flash on silica gel (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-60% gradient ethyl acetate / petroleum ether @ 75 mUmin) to give 2-[2-bromo-3-chloro -5-[[4-(1-ethylpropylamino)-5methyl-pyrim¡din-2-yl]amino]phenyl] propan-2-ol (0.6 g, 1.36 mmol, yield 59.99%) as a solid yellow.1H NMR (CDCh, 400 MHz) δ 8.33 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 4.284.26 (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). 13.6 Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-(1ethylpropyl)-5-methyl-pyrimidin-2,4-damine qq / ozn / zznz / q / υιλι To a mixture of 2-[2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimiden-2yl]amino ]phenyl]propan-2-ol (0.6 g, 1.36 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaboran-2-yl)-5,5 -dimethyl1,3,2-dioxaborinane (614 mg, 2.72 mmol, 2 eq) in dioxane (10 mL) KOAc (333 mg, 3.40 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (95 mg, 135.81 pmol, 0.1 eq) in one portion at 20°C, the resulting mixture was stirred at 100°C for 12 h under a N2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water (0.1%TFA)-ACN] ; B%: 25%-50%, 10min) to give N2-(7-chloro-1-hydroxy-3,3-dimethyl2,1-benzoxaborol-5-íl)-N4-(1-ethylpropyl) -5-methyl-pyridine-2,4-dymine (202 mg, 519.68 pmol, 38.27% yield) as white solid. 1H NMR (DMSO-de, 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): calculated mass. For C19H26BCIN4O2 388.18, m / z found 389.2 [M+H]+. HPLC: 99.84% (220nm), 99.83% (254nm). 14. Preparation of 7-chloro-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H) -ol 14.1 Preparation of [2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]phenyl]methanol To a mixture of 2-bromo-3-chloro-5-[[4-(1-ethllprop¡lano)-5-methyl-pyr¡m¡d¡n-2-¡l]amino]benzoate of methyl (1.5 g, 3.40 mmol, 1 eq) in THF (20 mL) DIBAL-H (1 M, 13.6 mL, 4 eq) was added. 6 mL, 4 eq) dropwise at 0°C, the resulting mixture was stirred at 0°C for 1 h. NazSCU.IOhW (5 g) was then added to the above mixture, the resulting mixture was stirred at 25°C for 10 min. The mixture was filtered and the filtrate was concentrated in vacuo to give [2-bromo-3-chloro-5-[[4-(1-ethylpropylamino)-5-methyl-piñm¡din- 2yl]amino]phenyl]methanol (1 g, 2.42 mmol, 71.18% yield) as a yellow solid.1H NMR (DMSO-de, 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). 14.2 Preparation of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-N4(diethylpropyl)-5-methyl-pyrimidin-2,4-diamine qq / Qzn / zznz / q / υιλι To a mixture of [2-bromo-3-chloro-5-[[4-(1 -ethylpropylamino)-5-methyl-pyrimidin-2-!l]amino]phenyl]methanol ( 0.9 g, 2.18 mmol, 1 eq) in THF (10 mL) was added TBSOTf (863 mg, 3.26 mmol, 750 pL, 1.5 eq) and 2,6-dimethylpyridine (396 mg, 3.70 mmol, 430 pL, 1.7 eq) in one portion at 25°C. The mixture was stirred at 25°C for 3 h. The reaction mixture was poured into H2O (20 mL), and the aqueous phase was extracted with EtOAc (20 mL x 3). 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, which was purified by flash chromatography on silica gel (ISCO®; Flash column of 20 g SepaFlash® silica, eluent 0~20% gradient ethyl acetate / petroleum ether @ 36 mL / min) to give N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl] -5-chloro-phenyl]-N4-(1-ethylpropyl)-5-methyl-pyrimidin-2,4-dyamine (0.7 g, 1.33 mmol, 60.95% yield) as a yellow solid.1H NMR (DMSO-ds, 400 MHz) δ 9.30 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H ), 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). 14.3 Preparation of N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4-(1-ethylpropyl)-5methyl-pyrimidin-2,4-diamine To a mixture of N2-[4-bromo-3-[[tert-butíl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-N4-(1 -ethylpropyl)-5methyl-pyrm ¡din-2,4-diamine (0.6 g, 1.14 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-d¡oxaborinan-2-¡l)-5, 5-dimethyl1,3,2-dioxaborinane (513 mg, 2.27 mmol, 2 eq) in dioxane (10 mL) was added KOAc (335 mg, 3.41 mmol, 3 eq) and Pd(PPh3)2Cl2 (80 mg, 114 pmol, 0.1 eq) in one serving at 25°C. The mixture was stirred at 80°C. 112 for 16 h under N2 atmosphere. The reaction mixture was filtered, HCl (2N, 1 mL) was added to the filtrate, which was concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Phenomenex Luna C18 150*30mm*5pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%-40%, 12min) to give N2-(7 -chloro-1 -hydroxy-3H-2,1 -benzoxaborol-5-yl)-N4-(1 -ethylpropyl)-5-methyl-pyrimidin-2,4-diamine (103 mg, 285.60 pmol, 25.13% yield) as white solid.1H NMR (DMSO-de, 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): calculated mass. For C17H22BCIN4O2 360.15, m / z found 361.1 [M+H]+. HPLC: 99.83% (220nm), 99.82% (254nm). 15. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3,3,7trimethylbenzo[c][1,2]oxaborol-1(3H)-ol KüA. b-inéüpr i.·;:!· doxane 1C3:C 7 h 15.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3methyl-benzoate h dioxane, 25-80cC. I2 h To a mixture of methyl 5-amino-2-bromo-3-methylbenzoate (2.31 g, 9.45 mmol, 1 eq) and 2,5dichloro-N-cyclopentyl-pyrimidin-4-amine (2.19 g, 9.45 mmol, 1 eq) in dioxane (60 mL) TsOH (1.79 g, 10.4 mmol, 1.1 eq) was added at 25°C under a N2 atmosphere, 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, which was purified by recrystallization from MTBE (40 mL) at 25°C to give 2-bromo-5-[[5-chloro-4- Methyl (cyclopentylamino)pyrimidin-2-¡l]amino]-3-methyl-benzoate (3.00 g, 6.82 mmol, yield 72.18%) as white solid. 1H NMR (DMSO- ds, 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). 15. 2 Preparation of 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3methyl-phenyl]propan-2-ol 113 MeMgBr THF, 0-25°C, 2 h qq / Qzn / zznz / q / υιλι To a mixture of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamine)pyrimidin-2-l]amino]-3-methyl-benzoate (1.00 g, 2.27 mmol, 1 eq) in THF (6 mL) MeMgBr (3 M, 4.60 mL, 6 eq) was added in one portion at 0°C under N2 atmosphere, the resulting mixture was stirred at 25°C sat. NH4Cl was added for 2 h. (50 mL) to the previous 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 Na2SO4, filtered, and concentrated in vacuo to give 2-[2-bromo-5-[[5-chloro-4-(c¡ clopentylamino)pyrimidin-2-l]amino]-3-methyl-phenyl]propan-2-ol (0.85 g, 1.93 mmol, yield 84.99%) as yellow oil, which was used directly without further ado. purification in the next step. 15. 3 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol5-yl)pyrimidin-2,4-diamine To a mixture of 2-[2-bromo-5-[[5-chloro-4-(cyclopentalamino)pyrimidin-2-yl]arnino]-3-methylphenyl]propan-2 -ol (0.85 g, 1.93 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxabor¡nan-2-¡l)-5,5-dimethyl-1,3, 2dioxaborinane (1.09 g, 4.83 mmol, 2.5 eq) in dioxane (20 mL) was added KOAc (0.474 g, 4.83 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (0.135 g, 193.28 pmol, 0.1 eq) in one portion 25°C under N2 atmosphere, 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 (SI02, petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3, 7-trimethyl2,1-benzoxaborol-5-yl)pyrimidin-2,4-damine (0.09 g, 232.75 pmol, yield 12.04%) as white solid. Ή NMR (DMSO-d6, 400 MHz) 6 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, 3H), 1.98-1.97 (m, 2H), 1.76-1.75 (m, 2H), 1.67-1.66 (m, 2H), 1.55-1.54 (m, 2H) , 1.43 (s, 6H). MS (ESI): calculated mass. For C19H24BCIN4O2 386.17, m / z found 387.1 [M+H]+. HPLC: 97.21% (220nm), 88.55% (254nm). 16. Preparation of 2-(2-bromo-3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2yl)amino)phenyl)propan-2-ol and 1-(2 -bromo-3-methyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2yl)amino)phenyl)ethanone To a mixture of 2-bromo-3-methyl-5-((5-methyl-4-(pentan-3-lam¡no)p¡r¡m¡din-2-yl)am¡ methyl no)benzoate (2.00 g, 4.75 mmol, 1 eq) in THF (6 mL) was added MeMgBr (3 M, 9.50 mL, 6 eq) in one portion to 114 0°C under N2, the mixture was stirred at 25°C for 2h. The reaction mixture was quenched with aq. NH4CI. sat. (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 Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1 ) to give 2[2-bromo-5-[[4-(1-et¡lprop¡lam¡no)-5-met¡l-p¡ñmid¡n-2-¡l]am¡no]-3-met l-phenyl]propan-2-ol (1.30 g, 3.09 mmol, yield 64.99%) as yellow oil.1H NMR (DMSO-de, 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). Y 1-[2-bromo-5-[[4-(1-ethylprop¡lam¡no)-5-methyl-pyr¡m¡n-2yl]amino]-3-methyl-phenyl ] ethenone (0.400 g, 987 pmol, 20.79% yield) as a yellow oil. 17. Preparation of 3,3,7-trimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborole- 1(3H)-ol qq / Qzn / zznz / q / υιλι To a mixture of 2-[2-bromo-5-[[5-chloro-4-(ethylpropylamino)pyrimidin-2-l]amino]-3-ethyl-phenyl] propan2-ol (1.00 g, 2.26 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)5,5-dimethyl 1-1,3,2 -dioxaborinane (1.28 g, 5.66 mmol, 2.5 eq) in dioxane (20 mL) KOAc (0.555 g, 5.66 mmol, 2.5 eq) and Pd(PPh3)zCl2 (0.159 g, 226 pmol, 0.1 eq) were added in one portion at 25°C under N2 atmosphere, 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 prep HPLC (column: Welch -trimethyl-5-((5-methyl-4-(pentan3-lamino)pyrimidin-2-l)amino)benzo[c][1,2]oxaborol-1(3H )-ol (0.111 g, 286 pmol, yield 12.62%) as white solid.1H NMR (DMSO-de, 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, 1 H), 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): calculated mass. For C20H29BN4O2 368.24, m / z found 369.2 [M+H]+. HPLC: 98.87% (220nm), 99.07% (254nm). 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 18.1 Preparation of 1-[5-[[5-chloro-4-(1-ethylpropylamino)pyrimidin-2-yl]amino]-2-(5,5dimethyl-1,3,2-dioxaborinan-2-yl)- 3-methyl-phenyl]ethanone 115 To a mixture of 1-[2-bromo-5-[[5-chloro-4-(1-¡ethylprop¡lano)pyr¡m¡d¡n-2-yl]amino]- 3-methylphenyl]ethanone (400 mg, 940 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaboran-2-yl)-5,5-dimethyl- 1,3,2dioxaborinane (531 mg, 2.35 mmol, 2.5 eq) in dioxane (20 mL) was added KOAc (231 mg, 2.35 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (66 mg, 94.0 pmol, 0.1 eq) in a portion at 25°C under N2 atmosphere, 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 (SiOz, petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give 1-[5-[[5-chloro-4-(ethylpropylamino)p ¡ñm¡din-2-¡l]am¡no]2-(5,5-dimethyl-1,3,2-dioxaboñnan-2-¡l)-3-methyl-phen¡l]ethanone (350 mg, 763 pmol, yield 81.20%) as yellow oil, which was used directly in the next step. 18.2 Preparation of 3,7-dimethyl-5-((5-methyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborole-1(3H)- ol qq / ozn / zznz / q / υιλι To a mixture of 1 -[2-(5,5-dimethyl-1,3,2-dioxaboñnan-2-íl)-5-[[4-(1 -ethylpropylamino)-5-methylpyrimidin-2-yl] amino]-3-methyl-phenyl]ethanone (300 mg, 684 pmol, 1 eq) in THF (10 mL) and MeOH (1 mL) NaBH4 (65 mg, 1.71 mmol, 2.5 eq) was added in one portion to 25°C under N2 atmosphere, the resulting mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H2O (10 mL), its pH was adjusted to 5 with 2N HCl, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Welch -5-((5-methyl-4-(pentan-3-yl amino)p¡r¡m¡d¡n-2-yl)amino)benzo[c][1,2]oxaborol-1( 3H)-ol (23 mg, 64.9 pmol, 9.49% yield) as white solid. Ή 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 = 6.8 Hz, 1H), 4.16-4.13 (m, 1H), 2.36 (s, 3H), 1.95 (s, 3H), 1.65-1.53 ​​(m, 4H ), 1.37 (d, J = 6.4 Hz, 3H), 0.90-0.85 (m, 6H). MS (ESI): calculated mass. For C19H27BN4O2 354.22, m / z found 355.2 [M+H]+. HPLC: 97.41% (220nm), 96.99% (254nm). 19. Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4cyclopentyl-pyrimidin-2,4-damine TSCiT-, C.í-d'netlphd na ΤΗΓ 3 h i'C PI>hH <(l?KüAc 116 19.1 Preparation of methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]benzoate dioxane, 80°C, 10 h CL To a mixture of methyl 5-amino-2-bromo-3-chloro-benzoate (2.13 g, 8.06 mmol, 1.1 eq) and 2,5dichloro-N-cyclopentyl-pyrimidin-4-amine (1.7 g, 7.32 mmol, 1 eq) in dioxane (20 mL) TsOH.HzO (2.09 g, 10.99 mmol, 1.5 eq) was added in one portion at 20°C, 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 by aq. NaHCOa. sat. The mixture was filtered and the filter cake was dried under vacuum to give 2-bromo-3-chloro-5-[[5-chloro-4(cyclopent¡lano)piñm¡din-2-¡ Methyl l]amino]benzoate (3 g, 6.52 mmol, 89.02% yield) as a yellow solid. Ή NMR (CDCh, 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 ). 19.2 Preparation of [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]phenyl]methanol To a mixture of 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentalamino)pyrmidin-2-l]amino]benzoate methyl (2 g, 4.35 mmol, 1 eq) in THF (20 mL) DIBAL-H (1 M, 22 mL, 5 eq) was added dropwise at 0°C, the resulting mixture was stirred at 25°C for 2 hours The reaction mixture was poured into H2O (150 mL), Na2SO4.10H2O (5 g) was added to the above mixture, the resulting mixture was filtered to remove the insoluble substance. The filtrate was dried in vacuo to give [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimiden-2yl]amino]phenyl]methanol ( 1.1 g, 2.55 mmol, 58.56% yield) as yellow solid.1H NMR (DMSO-de, 400 MHz) δ 9.58 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H) , 7.82 (d, J = 2.4 Hz, 1H), 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), 1.761.68 (m, 2H), 1.63-1.58 (m, 4H). 19.3 Preparation of N2-[4-bromo-3-[[tert-butyl (dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5chloro-N4-cyclopentyl-pyrimidin-2,4-diamine To a mixture of [2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylam¡no)pyr¡m¡d¡n-2-¡l]amino]phenyl]methanol (1 g, 2.31 mmol, 1 eq) in THF (12 mL) TBSOTf (918 mg, 3.47 mmol, 800 pL, 1.5 eq) and 2,6dimethylpyridine (422 mg, 3.93 mmol, 460 pL, 1.7 eq) were added in one portion at 25°C. The mixture was stirred at 25°C for 3 h. The reaction mixture was poured into H2O (20 mL), the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NazSCh, filtered and concentrated in vacuo to obtain the crude product, which was triturated with EtOAc at 25°C for 10 min, then the product Crude was collected by filtration, dried under vacuum to give N2-[4bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-chloro-N4-cyclopentyl-pyrimidin -2,4-diamine (0.7 g, 1.28 mmol, 55.36% yield) as white solid.1H NMR (DMSO-de, 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). 19.4 Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-N4cyclopentyl-pyrimidin-2,4-damine qq / ozn / zznz / q / υιλι To a mixture of N2-[4-bromo-3-[[tert-butyl(dimethyl)sil¡l]oxymethyl]-5-chloro-phenyl]-5-chloro-N4cyclopent¡l-p¡r m¡d¡n-2,4-d¡amine (0.6 g, 1.10 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5 ,5dimethyl-1,3,2-dioxaborinane (496 mg, 2.20 mmol, 2 eq) in dioxane (10 mL) was added KOAc (323 mg, 3.29 mmol, 3 eq) and Pd(PPh3)2Cl2 (77 mg, 109.81 pmol, 0.1 eq) in one portion at 25°C. The mixture was stirred at 80°C for 16 h under N2 atmosphere. The reaction mixture was filtered and HCl (2N, 1 mL) was added to the filtrate. The resulting mixture was concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Welch Xtimate C18 100*25mm*3pm; mobile phase: [water(0.1%TFA)-MeOH]; B%: 45%- 65%, 12min) to give 5-chloro-N2-(7-chloro-1 -hydroxy-3H-2,1 -benzoxaborol-5-íl)-N4-cyclopentyl-pyrimidín- 2,4diamine (25 mg, 65.95 pmol, 6.01% yield) as white solid.1H NMR (DMSO-de, 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): calculated mass. For C16H17BCI2N4O2 378.08, m / z found 379.1 [M+H]+. HPLC: 94.64% (220nm), 97.36% (254nm). 20. Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4cyclopentyl-pyrimidin-2,4-damine 20.1 Preparation of 2-[2-bromo-3-chloro-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]phenyl]propan-2-ol 118 To a mixture of methyl 2-bromo-3-chloro-5-[[5-chloro-4-(cyclopent¡lamino)pyr¡m¡dln-2-¡l]amino]benzoate (1 g, 2.17 mmol, 1 eq) MeMgBr (3 M, 10.9 mL, 15 eq) was added in portions at 0°C, the resulting mixture was stirred at 0°C for 4 h. The reaction mixture was poured into aq NH4Cl. sat. (20 mL), and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SÜ4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ISCO®; Flash column of 20 g SepaFlash® silica, eluent 0~30% gradient ethyl acetate / petroleum ether @ 75 mL / min) to give 2-[2-bromo-3chloro-5-[[5-chloro-4-(c clopentylamino)pyrimidin-2-l]amino]phenyl]propan-2-ol (0.6 g, 1.30 mmol, yield 59.99%) as a yellow solid.1H NMR (CDCI3,400 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). 20.2 Preparation of 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-íl)-N4cyclopentyl-pyrimidin-2,4-damine 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 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2dioxaborinan (491 mg, 2.17 mmol, 2 eq ) in dioxane (10 mL) KOAc (267 mg, 2.72 mmol, 2.5 eq) and Pd(PPh3)2Cb (76 mg, 108.65 pmol, 0.1 eq) were added in one portion at 20°C, the resulting mixture was stirred at 120°C for 16 h under N2 atmosphere. The reaction mixture was filtered and HCl (2N, 1 mL) was added to the filtrate. The resulting mixture was concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Xtimate C18 100*30mm*3pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 30%-50 %, 10min) to give 5-chloro-N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-N4-cyclopentyl-pyrimidin-2,4-diam na (53 mg, 130.19 pmol, 11.98% yield) as off-white solid.1H NMR (DMSO-ds, 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), 2,031.99 (m, 2H), 1.76-1.74 (m, 2H) , 1.65-1.55 (m, 4H), 1.43 (s, 6H). MS (ESI): calculated mass. For C18H21BCI2N4O2 406.11, m / z found 407.1 [M+H]+. HPLC: 98.76% (220nm), 98.54% (254nm). 21. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-3methylbenzo[c][1,2]oxaborol-1 (3H)-ol 119 ’&c-f -re. s pray·:· 25-óO’C 12 h l· Wi \ Μ*: H Ti 4 aOAC. 3íGX310. 25-32'C 3 hours qq / Qzn / zznz / q / υιλι 21.1 Preparation of 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]phenyl]ethanone To a solution of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 8.62 mmol, 1 eq) and 1-(5amino-2-bromo -phenyl)ethanone (1.84 g, 8.62 mmol, 1 eq) in dioxane (60 mL) TSOH.H2O (2.46 g, 12.9 mmol, 1.5 eq) was added at 25°C under a N2 atmosphere, 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 H2O (30 mL), and its pH was adjusted to 9 with aq. NaHCOs. sat, and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SÜ4, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (ISCO®; flash column of SepaFlash® silica 40 g, eluent 0-17% gradient ethyl acetate / petroleum ether @ 75mL / min) to give 1-[2-bromo-5-[[5-chloro-4-(cyclopent¡lamino)p ¡r¡midín-2yl]amino]phenyl]ethanone (2.5 g, 6.10 mmol, 70.82% yield) as a yellow solid.1H NMR (DMSOde, 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). 21.2 Preparation of [1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]amino]phenyl]ethanol To a solution of 1 -[2-bromo-5-[[5-chloro-4-(cyclopent¡lamino)pyr¡m¡d¡n-2-yl]amino]phen¡l] ethanone (500 mg, 1.22 mmol, 1 eq) and MeOH (1.28 mmol, 51.7 pL,1 eq) in THF (10 mL) NaBH4 (72.5 mg, 1.92 mmol, 1.5 eq) was added at 0°C, the resulting mixture It was stirred at 25°C for 3 h. The reaction was inactivated 120 adding 2N HCl, H2O (10 mL) was poured into the above mixture, and its pH was adjusted to 5 with 2N HCl, then the aqueous phase was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by short column to give 1-[2-bromo-5-[[5-chloro-4(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]ethanol (400 mg, 972 pmol, 76.05% performance) as yellow oil. Ή 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). 21.3 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5yl)pyrimidin-2,4-diamine B / neop)., qq / Qzn / zznz / q / υιλι KO Ac. Pd(PPh3)2CL· dioxane. 25-80:C. 8 hours To a solution of 1-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-l]amino]phenyl]ethanol (300 mg, 729 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (411 mg, 1.82 mmol, 2.5 eq) in dioxane (10 mL) Pd(PPh3)2Cl2 (51 mg, 72.9 pmol, 0.1 eq) and KOAc (143 mg, 1.46 mmol, 2 eq) were added at 25°C under atmosphere of N2, 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 H2O (10 mL), and its pH was adjusted to 5 with 2N HCl. EtOAc (10 mL) was added to the above mixture, the precipitate formed was collected by filtration, dried under vacuum to give the crude product, which was purified by prep HPLC (column: Welch Xtimate C18 100*25mm*3pm; mobile phase : [water(0.1%TFA)-MeOH]; B%: 40%-60%,12min) to give 5-chloro-N4-cyclopentyl-N2-(1 -h hidroxy -3-methyl-3 H-2, 1 -be nzoxaborol-5-i l)pi r¡ m id i n2,4-diamine (147 mg, 405 pmol, 55.60% yield, 98.84% purity) as white solid.1H 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, 1 H), 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), 1.571.53 (m, 2H ), 1.38 (d, J = 6.4 Hz, 3H). MS (ESI): calculated mass. For C17H20BCIN4O2 358.14, m / z found 359.1 [M+H]+. HPLC: 98.84% (220nm), 97.83% (254nm). 22. Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5yl)pyrimidine-2,4-diamine 25-=G’C. 12Ί 121 22.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2yl]aminobenzoate °\ TsOH.H^O, dioxane, 25-80°C, 12 h To a solution of 2,5-dichloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 8.62 mmol, 1 eq) and methyl 5-amino2-bromo-benzoate ( 2.38 g, 10.3 mmol, 1.2 eq) in dioxane (60 mL) TSOH.H2O (2.46 g, 12.9 mmol, 1.5 eq) was added at 25°C under N2 atmosphere, the reaction was heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to give a residue, which was dissolved in H2O (30 mL), and its pH was adjusted to 9 with aq. NaHCOs. sat, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (ISCO®; flash column SepaFlash® silica 40 g, eluent 0-20% gradient ethyl acetate / petroleum ether @75mL / min) to give 2-bromo-5-[[5-chloro-4-(cyclopent¡lamino)p Methyl hm¡d¡n-2-yl]amino] benzoate (3.30 g, 7.75 mmol, 89.96% yield) as a yellow solid.1H NMR (DMSO-de, 400 ΜΗζ) 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 ). 22.2 Preparation of methyl 2-[2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]propan-2-ol A solution of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)piñmidín-2-¡l]amino]benzoate (2.00 g, 4.70 mmol, 1 eq) in THF (20) was added. mL) to the MeMgBr solution (3 M, 7.90 mL, 5 eq) at 0°C dropwise for 30 min, the resulting mixture was stirred at 25°C for 1.5 h. The reaction mixture was then poured into a mixture of H2O (15 mL) and sat. NH4CI. (10 mL), the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g silica flash column, eluent 0-55% gradient ethyl acetate / petroleum ether @ 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, yield 64.99%) as yellow oil. Ή NMR (DMSO-de, 400 ΜΗζ) δ 9.28 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.91 (s, 1H), 7.54 (dd, J = 8.8, 2.8 Hz, 1H) , 7.39 (d, J = 8.8 Hz, 1H), 6.78-6.75 (m, 1H), 5.10 (s, 1H), 4.52-4.45 (m 1H), 1.961.63 (m, 4H), 1.60 (s, 6H), 1.58-1.52 (m, 4H). 122 22.3 Preparation of N2-[4-bromo-3-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl]phenyl]-5-chloro-N4- TBSOTf, 2.6-!itidine DCM. 40-60nC 8h To a solution of 2-[2-bromo-5-[[5-chloro-4-(cyclopent¡lamino)pyr¡m¡d¡n-2-¡l]amino] phenyl] propane -2-ol (300 mg, 705 pmol, 1 eq) and 2,6-dimethylpyridine (2.11 mmol, 246 pL, 3 eq) in DCM (10 mL) was added [tert-butyl(dimethyl)silyl trifluoromethanesulfonate ] (1.76 mmol, 405 pL, 2.5 eq) at 25°C, the resulting mixture was stirred at 40°C for 6 h. Next, an additional part of [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (352 pmol, 81.0 pL, 0.5 eq) was added to the above mixture in one portion at 25°C, the reaction mixture was stirred at 60 °C for 2 h. H2O (15 mL) was added to the reaction mixture, and the aqueous phase was extracted with DCM (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 36 mL / min) to give N2-[4 -bromo-3-[1[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]phenyl]-5-chloro-N4-cyclopentyl-pyrimidin-2,4-diamine (400 mg, 741 pmol, 52.56% yield) as yellow oil.1H NMR (DMSO-de, 400 MHz) δ 9.25 (s, 1H), 7.90 (s, 1H), 7.57 (dd, J = 8.4, 2.4 Hz , 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.42-4.37(m, 1H), 1.961.93 (m, 2H), 1.74-1.71 ( m, 8H), 1.58-1.52 (m, 4H), 0.89 (s, 9H), 0.10 (s, 6H). 22.4 Preparation of 5-chloro-N4-cyclopentyl-N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5yl)pyrimidine-2,4-diamine To a solution of N2-[4-bromo-3-[1 -[tert-butyl(dimethyl)sil¡l]ox¡-1 -methyl-ethyl]phenyl]-5-chloro-N4cyclopent¡l-pyrim¡dine -2,4-dyamine (400 mg, 741 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-íl)-5,5dimethyl-1, 3,2-Dioxaborinan (418 mg, 1.85 mmol, 2.5 eq) in dioxane (10 mL) was added PdíPPhajsClz (52.0 mg, 74.1 pmol, 0.1 eq) and KOAc (145 mg, 1.48 mmol, 2 eq) at 25°C under a N2 atmosphere, 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 prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-45%, 10min) to give 5-chloro -N4-cyclopentyl-N2-(1 -hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)primidine-2,4-diamine (102 mg , 267 pmol, 36.04% yield, 97.54% purity) as white solid.1H NMR (DMSO-de, 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), 4.52-4.42 (m, 1H), 1.98-1.96 (m, 2H), 1.77 -1.71 (m, 2H), 1.66-1.60 (m, 2H), 1.55-1.51 (m, 2H), 1.42 123 (s, 6H). MS (ESI): calculated mass. For C18H22BCIN4O2 372.15, m / z found 373.1 [M+H]+. HPLC: 97.54% (220nm), 96.29% (254nm) 23. Preparation of 3,3-dimethyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol 23.1 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate To a solution of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (1.50 g, 6.83 mmol, 1 eq) and methyl 5-amino-2bromo-benzoate ( 1.73 g, 7.51 mmol, 1.1 eq) in dioxane (60 mL) was added TSOH.H2O (1.95 g, 10.2 mmol, 1.5 eq) at 25°C under N2 atmosphere, the resulting mixture was stirred at 90°C for 12 h. The reaction mixture was cooled to room temperature and filtered, the filter cake dissolved in H2O (30 mL), and its pH adjusted to 9 with sat. NaHCOs. NaHCOs, and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous NazSCU, filtered, and concentrated in vacuo to give a residue, which was triturated with EtOAc (20 mL) to give 5[(4-an Methyl l¡no-5-methyl¡l-pymmidín-2-l)amino]-2-bromo-benzoate (1.70 g, 4.11 mmol, 60.24% yield) as a light yellow solid.1H NMR (DMSO-de, 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). 23.2 Preparation of 2-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl] propan-2- To a solution of methyl 5-[(4-an¡lino-5-methyl-p¡ñm¡n-2-¡l)am¡no]-2-bromo-benzoate (500 mg, 1.21 mmol, 1 eq) in THF (10 mL) MeMgBr (3 M, 2.10 mL, 5 eq) was added dropwise at 0°C over a period of 30 min, the resulting mixture was stirred at 25°C for 1.5 h. The reaction was quenched by adding sat. NH4Cl. (15 mL), and the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous NazSO4, filtered, and concentrated to 124 empty to give 2-[5-[(4-an¡l¡no-5-met¡l-pyr¡m¡n-2-¡l)am¡no]-2-bromo-fen¡l ]propan-2-ol (350 mg, 847 pmol, 69.99% yield) as a yellow solid.1H NMR (DMSO-de, 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). 23.3 Preparation of N2-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine B?neop? KO Ac. Pd(PPh,j;CI;dioxane. 25-8ÓsC. 8 h OH / To a solution of 2-[5-[(4-anil¡no-5-methyl-p¡r¡m¡n-2-¡l)am¡no]-2-bromo-phenyl]propan-2 -ol (300 mg, 726 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-¡l)-5,5-dimethyl-1,3, 2-dioxaborinane (401 mg, 1.81 mmol, 2.5 eq) in dioxane (10 mL) Pd(PPh3)2CÍ2 (51 mg, 72.6 pmol, 0.1 eq) and KOAc (143 mg, 1.45 mmol, 2 eq) were added to 25 °C under N2 atmosphere, 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 H2O (10 mL), and its pH was adjusted to 5 with 2N HCl, and the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by prep HPLC (column: Welch Xtimate C18 100*25mm*3pm ; mobile phase: [water (0.1%TFA)-ACN]; B%: 20%-30%,12min) to give N2-(1h¡drox¡-3,3-dimet¡l-2,1- benzoxaborol-5-l)-5-methyl-N4-phenyl-pyrimidin-2,4-damine (103 mg, 286 pmol, 39.39% yield, 100% purity) as white solid.1H NMR (DMSO-de, 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): calculated mass. For C20H21BN4O2 360.18, m / z found 361.0 [M+H]+. HPLC: 100.00% (220nm), 99.77% (254nm). 24. Preparation of 3-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol B r-oop oh i 125 24.1 Preparation of 1-(5-amino-2-bromo-phenyl)ethanone oNBS* h2n DMF, 25°C, 2 h A solution of 1-(3-aminophenyl)ethanone (10.0 g, 74.0 mmol, 1 eq) in DMF (70 mL) was added dropwise to a solution of NBS (13.2 g, 74.0 mmol, 1 eq) in DMF (70 mL) at 25°C for 1 h, the resulting mixture was stirred at 25°C for 1 h. The reaction mixture was poured into H2O (100 mL), and the aqueous phase was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with aq. NaHCOs. sat. (20 mL x 3), H2O (15 mL x 3) and brine (10 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give 1-(5-amino-2-bromo-phenyl) ethanone (15.0 g, 70.1 mmol, 94.71% yield) as brown oil.1H NMR (CDCh, 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). 24.2 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-benzoate TsOH H;O. dioxane 25-90°C. 12 noon To a solution of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (2.00 g, 9.10 mmol, 1 eq) and methyl 5-amino-2bromo-benzoate ( 2.30 g, 10.0 mmol, 1.1 eq) in dioxane (60 mL) TSOH.H2O (2.60 g, 13.7 mmol, 1.5 eq) was added at 25°C under N2 atmosphere, the resulting mixture was stirred at 90°C for 12 h. The reaction mixture was filtered, the filter cake was dissolved in H2O (30 mL), and its pH was adjusted to 9 with aq. NaHCOs. sat, extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over NazSO4, filtered and concentrated in vacuo to give a residue. The residue was triturated with EtOAc (20 mL), the precipitate was collected by filtration, dried in vacuo to give 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo -methyl benzoate (2.00 g, 4.84 mmol, yield 53.15%) as brown solid.1H NMR (DMSO-de, 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, 1 H), 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). 24.3 Preparation of 1-[5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-phenyl]ethanol NaBH4, MeOH / THF 0-25°C, 12h To a solution of 1-[5-[(4-an¡lino-5-met¡l-pyr¡m¡din-2-¡l)amino]-2-bromo-phen¡l]ethanone (1.60 g, 4.03 mmol, 1 eq) and MeOH (4.03 mmol, 163 pL, 1 eq) in THF (25 mL) NaBH4 (229 mg, 6.04 mmol, 1.5 eq) was added at 0°C, the resulting mixture was stirred at 25°C for 12 h. The reaction was inactivated by adding 2N HCl, H2O (25 mL) was added to the previous mixture, its pH was adjusted to 5 with 2N HCl, the aqueous phase was 126 extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, 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, dried under vacuum to give 1-[5-[(4anílino-5-methyl-pyrimidín- 2-l)amino]-2-bromo-phenl]ethanol (1.00 g, 2.50 mmol, 62.18% yield) as brown solid.1H NMR (CDCh, 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) 24.4 Preparation of N2-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine B2neopzqq / Qzn / zznz / q / υιλι KO Ac. Pd(PPh3)2Ch dioxane, 25-120:C, 5 h OH Yo To a solution of 1-[5-[(4-an¡lino-5-methyl-pyrim¡din-2-¡l)amino]-2-bromo-phen¡l]ethanol (600 mg, 1.50 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (849 mg, 3.76 mmol, 2.5 eq) in dioxane (12 mL) Pd(PPh3)2Ch (105 mg, 150 pmol, 0.1 eq) and KOAc (295 mg, 3.01 mmol, 2 eq) were added at 25°C under atmosphere of N2, the resulting mixture was stirred at 120°C for 5 h. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in H2O (15 mL), and its pH was adjusted to 5 with 2N HCl, the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by prep HPLC (column: Welch Xtimate C18 100*25mm*3pm ; mobile phase: [water (0.1%TFA)-MeOH]; B%: 35%-55%, 12min) to give N2-(1-hydroxy¡-3-methyl-3H-2,1-benzoxaborole-5- ¡l)-5-methyl-N4-phen¡l-pyr¡mid¡n-2,4diamine (140 mg, 384 pmol, 25.54% yield, 94.91% purity) as a white solid.1H NMR (DMSO- d6, 400 MHz) δ 10.26 (s, 1H), 9.69 (s, 1H), 8.98 (brs, 1H), 7.93 (s, 1H), 7.56-7.53 (m, 4H), 7.43 (t, J = 8.4 Hz, 2H), 7.32-7.29 (m, 2H), 5.02 (q, J = 6.8 Hz, 1H), 2.18 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H). MS (ESI): calculated mass. For C19H19BN4O2 346.16, m / z found 347.1 [M+H]+. HPLC: 94.91% (220nm), 93.77% (254nm). 25. Preparation of N4-(1-ethylpropyl)-N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol5-yl]-5-methyl-pyrimidin-2,4-damine 127 Η Sil, M»DH i h \K.N f C' <.·ι c : n qq / Qzn / zznz / q / υιλι 25.1 Preparation of methyl 2-amino-3-(trifluoromethyl)benzoate H2SO4, MeOH 80°C, 16 h To a solution of 2-amino-3-(trifluoromethyl)benzoic acid (10.0 g, 48.75 mmol, 1 eq) in MeOH (150 mL) was added H2SO4 (4.00 g, 41.15 mmol, 2.2 mL) slowly at 0° c. After addition, the resulting mixture was stirred for 16 h at 80°C. The reaction mixture was poured into ice / water (300 mL) at 0°C, and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by column (S1O2, petroleum ether / ethyl acetate=1 / 0 at 10 / 1) to give methyl 2-amino3-(trifluoromethyl)benzoate (8.00 g, 36.50 mmol, 74.88% yield) as yellow oil.1H NMR (CDCI3, 400 ΜΗζ) 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 (brs, 2H), 3.89 (s, 3H). 25.2 Preparation of methyl 2-bromo-3-(trifluoromethyl)benzoate NaNO2, CuBr, HBr MeCN / H2O 0~60°C, 2h To a solution of methyl 2-amino-3-(trifluoromethyl)benzoate (5.00 g, 22.81 mmol, 1 eq) in MeCN (50 mL) and HBr (46.0 g, 228.14 mmol, 31 mL, 40% purity, 10 eq) was NaNO added? (1.90 g, 27.38 mmol, 1.2 eq, in 10 mL of H2O) drop by drop for 15 min at 0°C. Then CuBr (3.93 g, 27.38 mmol, 833.81 pL, 1.2 eq) was added in portions to the above mixture at 0°C, the resulting mixture was stirred for 2 h at 60°C. The reaction mixture was poured into ice / water (100 mL) at 0°C, and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), 128 were dried over Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SIO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to give 2-bromo- Methyl 3(trifluoromethyl)benzoate (5.20 g, 18.37 mmol, 80.53% yield) as yellow oil.1H NMR (CDCh, 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). 25.3 Preparation of methyl 2-bromo-5-nitro-3-(trifluoromethyl)benzoate To a solution of methyl 2-bromo-3-(trifluoromethyl)benzoate (5.00 g, 17.67 mmol, 1 eq) in H2SO4 (50 mL) was added fuming HNO3 (3.70 g, 53.05 mmol, 2.70 mL, 90% purity, 3.00 eq) dropwise at 0°C, 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 formed was collected by filtration, dried under vacuum to give methyl 2-bromo5-nitro-3-(trifluoromethyl)benzoate. (5.00 g, 15.24 mmol, 86.28% yield) as yellow solid. Ή NMR (DMSO-de, 400 MHz) δ 8.77 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H). 25.4 Preparation of methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate NH4CI, Fe EtOH, H2O 50°C, 2 h To a solution of methyl 2-bromo-5-nitro-3-(trifluoromethyl)benzoate (5.00 g, 15.24 mmol, 1 eq) in a mixture of H2O (10 mL) and EtOH (100 mL) was added NH4Cl (2.50 g, 45.7 mmol, 1.60 mL, 3 eq) and Fe (2.80 g, 45.7 mmol, 3 eq) sequentially at 20°C, 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, which was poured into ice / water (100 mL) at 0°C, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (4.10 g, 13.76 mmol, yield 90.25%) as white solid. Ή NMR (CDCI3, 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). 25.5 Preparation of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3(trifluoromethyl)benzoate p-TsOH, dioxane 100=C.6h To a solution of methyl 5-amino-2-bromo-3-(thfluoromethyl)benzoate (1.50 g, 5.03 mmol, 1 eq) 129 and 2-chloro-N-(1-ethylpropyl)-5-methyl-pyrimidin-4-amine (1.10 g, 5.0 mmol, 1 eq) in dioxane (30 mL) were added p-TsOH (1.30 g, 7.6 mmol, 1.5 eq) at 20°C, the resulting mixture was stirred at 100°C for 6 h. The reaction mixture was poured into sat. NaHCOs. (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, which was purified by column chromatography (SÍO2, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-piñm¡din-2yl]amino]-3-(trifluoromethyl) methyl benzoate (1.60 g, 3.37 mmol, 66.89% yield) as white solid. Ή NMR (DMSO-ds, 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, 1 H), 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= 7.6Hz, 6H). 25.6 Preparation of [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-yl]amino]-3(trifluoromethyl)phenyl]methanol qq / Qzn / zznz / q / υιλι A mixture of methyl 2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidín-2-íl]amino]-3(trifluoromethyl)benzoate (1.00 g, 2.10 mmol, 1 eq) in THF (20 mL) DIBAL-H (1 M, 10.5 mL, 5 eq) was added dropwise at 0°C, and then the mixture was stirred at 20°C for 2 h under N2 atmosphere. The reaction was quenched by adding Na2SO4.10H2Q (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, yield 63.76%) as yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 9.35 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 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), 1.601.42 (m, 4H), 0.84 (t, J = 7.2 Hz, 6H). 25.7 Preparation of N4-(1-ethylpropyl)-N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol5-yl]-5-methyl-pyrimidin-2,4-damine B2(neop)2. KOAc A mix of Pd(PPh3)2CL dioxane. 80'C, 6 hcf3 OH / [2-bromo-5-[[4-(1-ethylpropylamino)-5-methyl-pyrimidin-2-l]amino]-3 (trifluoromethyl)phenyl ]methanol (200 mg, 447.14 pmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dloxaborinan-2-yl)-5,5-dimethyl1,3,2-dioxaborinan (152 mg, 670.70 pmol, 1.5 eq), KOAc (132 mg, 1.34 mmol, 3 eq) and Pd(PPh3)2Cl2 (32 mg, 44.71 pmol, 0.1 eq) in dioxane (10 mL) were degassed and purged with N2 3 times, then the reaction mixture was stirred at 80°C for 6 h under N2 atmosphere. The reaction mixture was poured into sat. NH4CI. (20 mL), and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous NasSO4, concentrated in vacuo to give a residue, which was 130 purified by TLC prep (SÍO2, petroleum ether / ethyl acetate=2 / 1) and HPLC prep (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-55%, 10min) to give N4-(1ethylpropyl)-N2-[1 -hydroxy-7-(trifluoromethyl)3H-2,1 -benzoxaborol-5-yl]-5-methyl-p¡ rimídin-2,4-diamine (112 mg, 284.12 prnol, 21.18% yield) as white solid.1H NMR (DMSO-de, 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): calculated mass. For C18H22BF3N4O2 394.18, m / z found 395.1 [M+H]+. HPLC: 98.77% (220nm), 99.23% (254nm). 26. Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7- (trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol qq / ozn / zznz / q / υιλι 26.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3(trifluoromethyl)benzoate p-TsOH, dioxane 100cC, 8 h The substance was prepared using the procedure used for the synthesis of 2-bromo-5-[[4(1-et¡lprop¡lamino)-5-methyl-p¡r¡m¡n-2-¡l] Methyl am¡no]-3-methyl-benzoate (1.40 g, 2.84 mmol, 56.35% yield) as a white solid.1H NMR (DMSO-de, 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), 1.941.73 (m, 2H), 1.72-1.62 (m, 2H), 1.59-1.53 ​​(m, 4H). 26.2 Preparation of [2-bromo-5-[[5-chloro-4-(cyclopentylamino)pyrimidin-2-yl]amino]-3(trifluoromethyl)phenyl]methanol either The substance was prepared using the procedure used for the synthesis of [2-bromo-5-[[4(1-et¡lprop¡lam¡no)-5-methyl-pyr¡midin-2-yl]amino]-3 -(trifluoromethyl)phenyl]methanol (600 mg, 1.29 mmol, 63.61% yield) as a yellow solid.1H NMR (DMSO-de, 400 MHz) δ 9.72 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.57 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 131 5.6 Hz, 1 Η), 4.50-4.45 (m, 1 Η), 1.99-1.95 (m, 2H), 1.71 -1.66 (m, 2H), 1.59-1.54 (m, 4H). 26.3 Preparation of 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)-7qq / Qzn / zznz / q / υιλι (trifluoromethyl)benzo[c][1,2]oxaborol- 1(3H)-ol 32Íneop)j. KOAc Pd(PPh3)2Cl2 dioxane, 80’C, 6 h ΗH The substance was prepared using the procedure used for the synthesis of N4-(1-ethylpropyl)N2-[1-hydroxy-7-(trifluoromethyl)3H-2,1-benzoxaborol-5-yl]-5-methyl -pyrimidine-2,4-dyamine (60 mg, 145.42 pmol, yield 13.54%) as a white solid.1H NMR (DMSO-de, 400 MHz) 6 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): calculated mass. For C17H17BCIF3N4O2 412.11, m / z found 413.0 [M+H]+. HPLC: 98.46% (220nm), 98.87% (254nm). 27. Preparation of 7-methyl-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol 27.1 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-methyl-benzoate To a mixture of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (0.9 g, 4.10 mmol, 1 eq) and 5-amino-2bromo-3-methyl- Methyl benzoate (1.00 g, 4.10 mmol, 1 eq) in dioxane (20 mL) was added TsOH.HzO (1.17 g, 6.15 mmol, 1.5 eq), the resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, and cold Na2CO3 solution (10 mL) was added, the aqueous phase was extracted with EtOAc (50 mL) twice. The combined organic layers were washed with cold water, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by recrystallization from EtOAc / petroleum ether (1:2) to give 5-[(4-anilino-5-methyl-pyrimidin-2-l)amino]-2-bromo-3-methyl-benzoate. pure methyl (1.71 g, 4.00 mmol, 97.68% yield) as a gray solid.1H NMR (DMSO, 400 MHz) 6 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 132 = 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 ). 27.2 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate methyl To a mixture of methyl 5-[(4-anilino-5-methyl-p¡r¡m¡din-2-¡l)amino]-2-bromo-3-methyl-benzoate (380 mg, 889 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (803 mg, 3.56 mmol, 4 eq) in anhydrous dioxane (20 mL), KOAc (175 mg, 1.78 mmol, 2 eq) and PdíPPhsjzClz (31.2 mg, 44.4 pmol, 0.05 eq) were added, the resulting mixture was bubbled with nitrogen for 10 minutes, then sealed and stirred at 80°C for 8 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g silica flash column, eluent of 20%~100% ethyl acetate / ethyl ether gradient). petroleum @ 50 mL / min) to give 5-[(4-anilino-5-methyl-p¡r¡m¡din-2-yl)amino]-2-(5,5-dimethyl-1 Methyl 3,2-dioxaborinan-2-yl)-3-methylbenzoate (290 mg, 630 pmol, 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). 27.3 Preparation of N2-(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine To a mixture of 5-[(4-an¡lino-5-methyl-pyrim¡din-2-¡l)amino]-2-(5,5-dimet¡ -1, Methyl 3,2-dioxaborinan-2-1)-3methyl-benzoate (240 mg, 521.3 pmol, 1 eq) and MeOH (33 pL, 1.6 eq) in THF (6 mL) was added NaBH4 (59 mg, 1.56 mmol, 3 eq) in portions at 0°C, 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), the pH of the aqueous phase was adjusted to 3-4 with HCl (2N), extracted with (5 mL x 3 ). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous NazSCU, filtered and concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 15%-35%, 10min) to give N2-(1-hydroxy-7-methyl-3H-2,1 -benzoxaborole- 5-l)-5-methyl-N4-phenyl-pyrimidin-2,4diamine (84 mg, 219 pmol, yield 42.0%, purity 90.25%) as a gray solid. 1H NMR (DMSO- de, 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, 2H), 7.22-7.17 (m, 2H), 6.54(s, 2H), 4.76 (s, 2H), 2.30 (s, 3H), 2.14 (s , 3H). MS (ESI): calculated mass. For C19H19BN4O2 346.16, m / z found 347.1 [M+H]+. HPLC: 90.25% (220nm), 88.74% (254nm). 133 28. Preparation of 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl)benzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι 28.1 Preparation of methyl 2-bromo-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-3(trifluoromethyl)benzoate CH I dioxane, HCl, 100°C. 16 A mixture of 2-chloro-5-methyl-N-phenyl-pyrimidin-4-amine (500 mg, 2.28 mmol, 1 eq) and methyl 5-amino-2bromo-3-(trifluoromethyl)benzoate (712 mg , 2.39 mmol, 1.05 eq) 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 sat. NaHCOs. (20 mL), the organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. After grinding with MTBE (10 mL), the precipitate was collected by filtration, dried in vacuo to give 5-[(4-anilino-5-methyl-pyrimidin-2-l)am! Methyl no]-2-bromo-3-(trifluoromethyl)benzoate (670 mg, 1.39 mmol, 61.16% yield) as a gray solid.1H NMR (DMSO-de, 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). 28.2 Preparation of [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-(trifluoromethyl)phenyl]methanol DIBAL THF, 0-25°C, 1 h To a solution of 5-[(4-anílino-5-methyl-pyrimádin-2-íl)amino]-2-bromo-3-(trifluoromethyl)benzoate methyl (500 mg, 1.04 mmol, 1 eq) in THF (10 mL) DIBAL (1 M, 4.20 mL, 4 eq) was added dropwise at 0°C, the resulting mixture was stirred at 0-25°C for 1 hour. The reaction was quenched by adding Na2SO4.10H2O (5 g) in portions at 0°C, 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-5 134 methyl-pyrimidin-2-l)amino]-2-bromo-3-(trifluoromethyl)phenyl]methanol (420 mg, 926.63 pmol, 89.19% yield) as yellow oil. 28.3 Preparation of benzo[c][1,2]oxaborol-1 (3H)-ol 5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino)-7-(trifluoromethyl) qq / ozn / zznz / q / υιλι CF, Pd(PPh3)2CI2. KOAc dioxane. 80:C. 10 hCf3 OH / ΗH A mixture of [5-[(4-an¡lino-5-methyl-p¡r¡m¡n-2-yl)amino]-2-bromo-3-(t¡fluoromethyl)phenyl] methanol (400 mg, 882.51 pmol, 1 eq), 5,5,5',5'-tetramethyl-2,2'-b¡(1,3,2-dioxaborinane) (997 mg, 4.41 mmol, 5 eq) , Pd(PPh3)2&2 (124 mg, 176.50 pmol, 0.2 eq) and KOAc (433 mg, 4.41 mmol, 5 eq) 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 in vacuo to give a residue, which was purified by prep HPLC (column: Phenomenex Luna C18 150*30mm*5pm; mobile phase: [water (0.05% HCI)-ACN], B%: 15%-30%, 12min) to give 5-((5-methyl-4(fen¡lam¡no)pinm¡n¡n-2-yl)amino)-7- (trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (54 mg, 134.95 pmol, 15.29% yield) as a white solid.1H NMR (DMSO-de, 400 ΜΗζ) 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, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 4.86 (s, 2H), 2.15 (s, 3H). MS (ESI): calculated mass. For C19H16BF3N4O2 400.13, found m / z 401.1 [M+H]+. HPLC: 99.28% (220nm), 99.80% (254nm). 29. Preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol 5-yl)-5-methyl N4-phenylpyrimidin-2,4-diamine Methyl 5-[(4-an¡l¡no-5-methyl·pyrimidin-2-¡l)am¡no]-2-bromo-3-methyl·benzoate (500 mg , 1.17 mmol, 1 eq) to MeMgBr (3 M, 7.80 mL, 20 eq) at 0°C for 30 min, the resulting mixture was stirred at 25°C for 6.5 h. The reaction mixture was then poured into aq. NH4Cl. sat. (15 mL), and the aqueous phase was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g silica flash column, eluent 0-100% gradient ethyl acetate / petroleum ether @ 36 mL / min) to give 2-[5 -[(4-anilino5-methyl-pyrimidin-2-¡l)amino]-2-bromo-3-methyl-phenyl]propan-2-ol (250 mg, 585 pmol , performance 49.99%) 135 as a yellow solid. 29.2 Preparation of N2-(1-hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2.4-diamine To a solution of 2-[5-[(4-an¡l¡no-5-methyl-pyrimidin-2-¡l)am¡no]-2-bromo-3-methyl-phen ¡l]propan-2-ol (50 mg, 117 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3 ,2-dioxaborinane (66.1 mg, 293 pmol, 2.5 eq) in dioxane (3 mL) KOAc (23.0 mg, 234 pmol, 2 eq), Pd(PPh3)2Cl2 (8.21 mg, 11.7 pmol, 0.1 eq) was added to 25°C under a N2 atmosphere, 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 prep HPLC (column: Welch -hydroxy-3,3,7-trimethyl-2,1-benzoxaborol-5-yl)5-methyl-N4-phenyl-pyrimidin-2,4-diamine (8.4 mg, 19.18% yield) as a white solid.1H NMR (DMSO-de, 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): calculated mass. For C21H23BN4O2 374.19, m / z found 375.1 [M+H]+. HPLC: 100.00% (220nm), 100.00% (254nm). 30. Preparation of 7-chloro-5-((5-methyl-4-(phenylamino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol 30.1 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chloro-benzoate dioxane, 80:C, 6 h CL 136 To a mixture of methyl 5-amino-2-bromo-3-chloro-benzoate (3.97 g, 15.0 mmol, 1.1 eq) and 2chloro-5-methyl-N-phenyl-pyrimidin-4- amine (3 g, 13.7 mmol, 1 eq) in dioxane (30 mL) TsOH.HLO (3.90 g, 20.49 mmol, 1.5 eq) was added in one portion at 25°C, the resulting mixture was stirred at 80° C for 6 hours. 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 aq. NaHCOs. sat., the precipitate of the mixture was collected by filtration and dried in vacuo to give 5-[(4-an¡lino-5-methyl-pyr¡m¡din-2-¡l) Methyl amino]-2-bromo-3-chlorobenzoate (2.5 g, 5.58 mmol, yield 40.89%) as a yellow solid.1H NMR (CDCl3,400 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). 30.2 Preparation of phenyl]methanol [5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-2-bromo-3-chlorocyl DIBAL-H THF, 0°C, 1 h To a mixture of methyl 5-[(4-anil¡no-5-methyl-p¡ñm¡d¡n-2-¡l)amino]-2-bromo-3-chloro-benzoate (1.2 g, 2.68 mmol, 1 eq) in THF (20 mL) DIBAL-H (1 M, 13.40 mL, 5 eq) was added dropwise at 0°C, the resulting mixture was stirred at 0°C for 1 h. The reaction mixture was poured into H2O (150 mL), Na2SO4.10H2O (5 g) was added to the above mixture, the resulting mixture was stirred at 25°C for 10 min. The insoluble substance was removed by filtration, and the filtrate was concentrated in vacuo to give [5-[(4-anilino-5methyl-pyrn¡din-2-¡l)amino]-2- brorno-3-chloro-phenyl]methanol (0.7 g, 1.67 mmol, 62.23% yield) as a yellow solid.1H 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). 30.3 Preparation of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-methylN4-phenyl-pyrimidin-2,4-d-amine ci ΤΗΓ, 25% 3 Ί TBSOTf. 2,6-dimethylpyridine CL To a mixture of [5-[(4-anilino-5-methyl·pyrimidín-2-íl)amino]-2-bromo-3-chloro-pheníl]methanol (0.6 g, 1.43 mmol, 1 eq) in THF (10 mL) TBSOTf (567 mg, 2.14 mmol, 500 pL, 1.5 eq) and 2,6dimethylpindine (260 mg, 2.43 mmol, 280 pL, 1.7 eq) were added in one portion at 25 °C, the resulting mixture was stirred at 25°C for 3 h. The reaction mixture was poured into H2O (10 mL), and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SÜ4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ISCO®; Flash column of SepaFlash® silica 20 g, eluent 0-30% gradient ethyl acetate / petroleum ether @ 75 mL / min) to give N2-[4-bromo-3-[[tert 137 butyl(dimethyl)sil¡l]oxymethyl]-5-chloro-phenyl]-5-methyl-N4-phenyl-pyrimidin-2,4-diamine (450 mg, 842.76 pmol , 58.95% yield) as a yellow solid.1H NMR (DMSO-de, 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). 30.4 Preparation of N2-(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine To a mixture of N2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]-5-methyl-N4-phenylpyrmidin-2 ,4-diamine (0.35 g, 655.48 pmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxabor¡nan-2-¡l)-5,5-dimethyl- 1,3,2dioxaborinane (296 mg, 1.31 mmol, 2 eq) in dioxane (8 mL) was added KOAc (193 mg, 1.97 mmol, 3 eq) and PdíPPhejzCla (46 mg, 65.55 pmol, 0.1 eq) in one portion 25°C, the resulting mixture was stirred at 80°C for 16 h under a Nz atmosphere. The reaction mixture was cooled to room temperature, the precipitate was removed by filtration, then HCl (2N, 1 mL) was added to the filtrate, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Phenomenex Luna C18 150*30mm*5pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 15%-35%, 12min) to give N2-(7 -chloro-1h¡droxy¡-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phen¡l-pyr¡m¡na-2,4-d¡amine (78 mg, 212.76 pmol, 32.46% yield) as white solid.1H NMR (DMSO-de, 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): calculated mass. For C18H16BCIN4O2 366.11, found m / z 367.1 [M+H]+. HPLC: 96% (220nm), 98.16% (254nm). 31. Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4phenyl-pyrimidin-2,4-diamine To a solution of methyl 5-[(4-an¡lino-5-methyl-p¡r¡m¡n-2-¡l)amino]-2-bromo-3-chloro-benzoate (1 g , 2.23 mmol, 1 eq) in THF (10 mL) was added MeMgBr (3 M, 11.2 mL, 15 eq), the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was then poured into aq. NH4CI. sat. (20 mL), the 138 aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SÜ4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ISCO®; Flash column of SepaFlash® silica 20 g, eluent 0~60% ethyl acetate / petroleum ether gradient @ 75 mL / min) to give 2-[5-[(4-an¡l¡no-5-methyl-p¡r ¡m¡n-2-¡l)amino]-2-bromo-3-chloro-phenyl]propan-2-ol (0.8 g, 1.79 mmol, 79.99% yield) as a yellow solid.1H NMR (DMSO-de, 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), 7.077.04 (m, 1H), 5.23 (s, 1H), 2.13 (s, 3H), 1.61 (s, 6H). 31.2 Preparation of N2-(7-chloro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4phenyl-pyrimidin-2,4-diamine ci dioxane. 100!C. 4 p.m. B?(-ecp:,. HdiHPh-,)CI?KOAc To a mixture of 2-[5-[(4-an¡lino-5-met¡l-p¡rim¡d¡n-2-¡l)am¡no]-2-bromo-3-chloro-fen¡l ]propan-2-ol (0.7 g, 1.56 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaboránan-2-yl)-5,5-dimethyl-1 ,3,2-dioxaborinane (706 mg, 3.13 mmol, 2 eq) in dioxane (10 mL) KOAc (460 mg, 4.69 mmol, 3 eq) and Pd(PPh3)2Cl2 (110 mg, 156 pmol, 0.1 eq) were added ) in one portion at 25°C, the resulting mixture was stirred at 80°C for 16 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and filtered, HCl (2N, 1 mL) was added to the filtrate, the resulting mixture was concentrated in vacuo to give a residue. The residue was purified by prep HPLC (column: Phenomenex Luna C18 150*30mm*5pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%-40%,12min) to give N2-(7 -chloro-1 -hydroxy¡-3,3-dimethyl-2,1-benzoxaborol-5-yl)-5-methyl-N4-phen¡lp¡rímidín-2,4-d¡amine ( 220 mg, 557.44 pmol, 35.66% yield) as white solid.1H NMR (DMSOde, 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): calculated mass. For C20H20BCIN4O2 394.14, m / z found 395.1 [M+H]+. HPLC: 96.13% (220nm), 98.95% (254nm). 32. Preparation of N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine and N-(4-anilino-5 -methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5i I )-1,1,1-trif fluoro-methanesulfonamide p-’SCH 310Χ3ΓΟ ZCC. :r Na3H. MvÜH Ή1 / Ί 139 32.1 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)amino]-3-ethyl-2-hydroxy-benzoate 100'0.8h qq / ozn / zznz / q / υιλι To a solution of methyl 5-amino-3-ethyl-2-hydroxybenzoate (600 mg, 3.07 mmol, 1 eq) and 2-chloro5-methyl-N-phenyl-pyrimidina- 4-amine (675 mg, 3.07 mmol, 1 eq) in dioxane (20 mL) was added p-TsOH (793 mg, 4.60 mmol, 1.5 eq) at 20°C, the resulting mixture was stirred at 100°C for 8 h. The reaction mixture was cooled to room temperature and filtered, the filtrate concentrated in vacuo to give a residue, which was poured into sat. NaHCOs. here (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 NazSO4, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SIO2, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give 5-[(4-an¡lino-5-methyl-pyrimidin-2-yl) Methyl am¡no]-3-ethyl-2-hydroxybenzoate (750 mg, 1.98 mmol, 64.56% yield) as a yellow solid.1H NMR (CDCh, 400 ΜΗζ) 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). 32. 2 Preparation of methyl 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate To a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (213 mg, 594.57 pmol, 1.5 eq) and 5-[(4-anyl Methyl -5-methyl-pyrimidin-2-l)amino]-3-ethyl-2-hydroxybenzoate (150 mg, 396.38 pmol, 1 eq) in DCM (10 mL) DMAP (24 mg, 198.19 pmol, 0.5 eq) and TEA (120.33 mg, 1.19 mmol, 165.52 pL, 3 eq) were added at 0°C, 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 (SiOz, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 5-[( Methyl 4-anilino-5-methyl-pyrimidin-2-yl)(trifluoromethylsulfonyl)amino]-3-ethyl-2-(trifluoromethylsulfonyloxy)benzoate (440 mg, 684.77 pmol, 34.55 % yield) as yellow oil. 32. 3 Preparation of 5-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2(5,5-dimethyl-1,3,2-dioxaborinan-2-yl) Methyl -3-ethyl-benzoate 140 A mixture of 5-[(4-anílino-5-methyl-pyrimídin-2-íl)-(trifluoromethylsulfoníl)amino]-3-ethyl-2(trifluoromethylsulfonyloxy¡)benzoate methyl (100 mg, 157.09 pmol, 1 eq, 4 lots), 2-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)-5,5-dimethyl-1,3 ,2-dioxaborinane (107 mg, 471.27 pmol, 3 eq), KOAc (46.25 mg, 471.27 pmol, 3 eq) and Pd(PPh3)2Cl2 (11.03 mg, 15.71 pmol, 0.1 eq) in dioxane (10 mL) was degassed. and purged with N2 3 times, then stirred at 80°C for 2 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo to give 5-[(4-anilino-5-methylpyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2-(5.5 Methyl-dimethyl-1,3,2-dioxaborinan-2-l)-3-ethyl-benzoate (600 mg, 494.71 pmol, 78.73% yield, 50% purity) as black oil. 32. 4 Preparation of N2-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-5-methyl-N4-phenylpyrimidin-2,4-diamine and N-(4-anilino- 5-methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5i I)-1,1,1-trifluoro-methanesulfonamide qq / ozn / zznz / q / υιλι A mixture of [4-[(4-anilino-5-methyl-pyrimidin-2-yl)-(trifluoromethylsulfonyl)amino]-2-ethyl-6methoxycarbonyl-phenyljborinic acid (200 mg, 191.46 pmol, 1 eq ) in MeOH (1 mL) and THF (10 mL) NaBH4 (72.43 mg, 1.91 mmol, 10 eq) was added in portions at 0°C, the resulting mixture was stirred at 25°C for 2 h under a N2 atmosphere. The reaction was inactivated by adding HCl (1M, 5 mL) at 0°C, the mixture was concentrated in vacuo to give a residue, which was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 8pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 50%-70%, 10min and column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 50 %-80%,10.5min) to give N2-(7-ethyl-1 hydroxy¡-3H-2,1-benzoxaborol-5-¡l)-5-methyl-N4-phenyl-pyr¡m Din-2,4-diamine (10 mg, 27.76 pmol, 4.83% yield) as a yellow solid. 1H NMR (DMSO-de, 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, 2H), 7.24 ( s, 1H), 7.11 (t, J = 8.0 Hz, 1H), 4.78 (s, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.10 (t, J = 7.6Hz, 3H). MS (ESI): calculated mass. For C20H21BN4O2 360.18, m / z found 361.1 [M+H]+. HPLC: 92.87% (220nm), 94.53% (254nm); and N-(4-anilino-5-methyl-pyrimidin-2-yl)-N-(7-ethyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)-1,1,1-trifluoromethanesulfonamide (60 mg, 121.88 pmol, 21.22% yield, 20 mg supplied) as a white solid. Ή NMR (DMSC-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 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1 H), 4.98 (s, 2H), 2.85 (q, J = 7.6 Hz , 2H), 2.17 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H). MS (ESI): calculated mass. For C21H20BF3N4O4S 492.13, m / z found 493.1 [M+H]+. HPLC: 99.84% (220nm), 99.87% (254nm). Part 2-1: General synthesis schemes for compounds of Formula (IA) General synthesis scheme A: 141 KOAc, Pd(PPh;);CI;dioxane. 25eC-80eC, 16h NaDlh MeOH -----► 2. 6N HCI Xs NH. NR¿ O, S R s H. llkyl The detailed procedure is as shown in the preparation of 5-((5-fluoro-4-(hexan-3ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborole -1 (3H)-ol. See also Example 7 below. General synthesis scheme B: r2xh TEA, THF The detailed procedure is as follows: Sample oxaborol-1 (3H)-ol To a mixture of 5-chloro-N-(1-hydroxy-3H-2,1-benzoxaborol-5-l)-4-methylsulfonyl-pyrimidin-2-amine (200 mg, 588.99 pmol, 1 eq) and cyclohexanamine (64 mg, 647.89 pmol, 74.15 pL, 1.1 eq) in dioxane (3 mL) TEA (149 mg, 1.47 mmol, 204.95 pL, 2.5 eq) was added in one portion at 25°C under N2 atmosphere, the resulting reaction mixture was stirred at 25°C for 2 h. H2O (10 mL) was then added to the reaction mixture, and its pH was adjusted to 5 with 2N HCl, the aqueous phase was extracted with EtOAc (20 mL x 3). 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. The residue was purified by prep HPLC (column: Nano-micro Kromasil C18 100*30mm 5pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%-45%, 10min) to give 5-chloro -N4-cyclohex¡l-N2-(1-hydroxy¡-3H-2,1-benzoxaborol-5-¡l)pyrim¡din-2,4-d¡amine (47 mg, 131.05 pmol, 22.25% yield) as a white solid. PART 2-2: Synthesis examples for compounds of Formula (IA) Example 1: 5-((5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol h RuCI3,NalO4 THF, H2O, 25°C, 2 h 142 To a mixture of 5-chloro-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-4-methylsulfaníl-piñmidin-2-amine (250 mg, 812.84 pmol, 1 eq) in THF (8 mL) and H2O (2 mL) NalÜ4 (522 mg, 2.44 mmol, 135.12 pL, 3 eq) and RuCh (17 mg, 81.28 pmol, 5.42 pL, 0.1 eq) were added at room temperature under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then filtered and water (20 mL) was added to the filtrate obtained. The resulting mixture was extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by HPLC prep (column: Welch Droxy-3H-2,1-benzoxaborol-5-yl)-4-methylsulfonyl-pyrimidin-2-amine (0.041 g, 120.74 pmol, 14.85% yield) as a white solid. 1H 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 found 338.0 [M-H]'. Purity by HPLC: 89.32% (220 nm) , 88.4% (254 nm). Example 2: 5-((5-chloro-4-(cyclohex¡lamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)ol QQ / Q7n / 77n7 / q / ΥΙΛΙ This substance was prepared following General Synthesis Scheme B by reacting 5-((5chloro-4-(methylsulfon¡l)pyrim¡din-2-¡l)amino)benzo[c][1,2] oxaborol-1 (3H)-ol with cyclohexanamine in the presence of TEA in THF.1H NMR (DMSO-Ó6, 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 found 359.1 [M+H]+. Purity by HPLC: 94.33% (220 nm), 96.85% (254 nm). Example 3: 5-((5-chloro-4-(propylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme B starting with 5-((5chloro-4-(methylsulfonyl)pyrimid¡n-2-¡l)amino)benzo[c][1,2]oxaborol-1( 3H)-ol with propylamine in the presence of TEA in THF. Ή 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 found 319.1 [M+H]+. Purity by HPLC: 98.74% (220 nm), 99% (254 nm). Example 4: 5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-ol 143 This substance was prepared following the General Synthesis Scheme A,1H 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 found 278.0 [M+H]+. Purity by HPLC: 95.22% (220 nm), 93.22% (254 nm). Example 5: 5-((4-(benzylamino)-5-chloropyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol qq / ozn / zznz / q / υιλι This substance was prepared following General Synthesis Scheme B, starting with 5-((5chloro-4-(methylsulfonyl)pyrimidin-2-¡l)amino)benzo[c][1,2]oxaborole -1(3H)-ol and benzylamine using the procedure of Example 2.1H 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 found 367.0 [M+H]+. Purity by HPLC: 99.08% (220 nm), 98.63% (254 nm). Example 6: 5-((5-chloro-4-(cyclopentylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)ol This substance was prepared following General Synthesis Scheme B, starting with 5-((5chloro-4-(methylsulfon¡l)pyr¡m¡d¡n-2-¡l)amino)benzo[c][1 ,2]oxaborol-1(3H)-ol and cyclopentylamine using the procedure of Example 2. Ή 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 found 345.1 [M+H]+. Purity by HPLC: 84.75% (220 nm), 86.81% (254 nm). Example 7: 5-((5-fluoro-4-(hexan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)ol FIA. FIOH 'NhCI ;·.ΟΗ iBPir FdicppfiCl. AdCK doxane V MeCH ·- ON Cl H H To a solution of 2,4-dichloro-5-fluoropyrimidine (1.6 g, 10.0 mmol) and hexan-3-amine (0.73 g, 10.0 mmol) 144 mmol) in EtOH (15 mL) EtsN (2.8 mL, 20.0 mmol) was added at room temperature. The reaction was heated at 50°C for 2h, then the reaction mixture was concentrated in vacuo to give a residue, which was purified by column chromatography (ΡΕ / EtOAc = 10 / 1) to give 2-chloro-5-fluoro -N-(hexan-3yl)pyrimidin-4-amine (1.1 g, 88% yield) as an off-white solid. 1H NMR (400 MHz, CDCb): 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). To a solution of 2-chloro-5-fluoro-N-(hexan-3-¡l)pyrimidín-4-amine (1.1 g, 5 mmol) in EtOH (20 mL) was added 5- methyl amino-2-bromobenzoate (1.15 g, 5 mmol) and HCl (1.5 N, 4 mL). The resulting reaction mixture was heated at reflux for 3 h. 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, which was triturated with EtOAc: PE= 1:5 to give methyl 2-bromo-5-((5-fluoro-4-(hexan-3-ylamino)pyrimidín-2-l)amino)benzoate (1.4 g, yield 80%) as white solid.1H NMR (400 MHz, DMSO-Ó6): 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). To a solution of methyl 2-bromo-5-((5-fluoro-4-(hexan-3-ylamino)p¡ñm¡din-2-¡l)benzoate (1.2 g, 3 mmol) in THF (20 mL) KOAc (412 mg, 9 mol), (BPin)2 (1.1 g, 4.2 mmol) and (dppf)PdCI2 (937 mg, 1.2 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was added. heated at 100°C overnight, then the solid was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with PE / EtOAc (100 / 1 to 20 / 1) to give 5 -((5fluoro-4-(hexan-3-ylam¡no)p¡ñm¡d¡n-2-¡l)amino)-2-(4,4,5,5-tetramet¡l-1,3 Crude methyl ,2-dioxaborolan-2-yl)benzoate (1.0 g, 52% yield) as a white solid. 1H 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). To a solution of 5-((5-fluoro-4-(hexan-3-¡lam¡no)p¡ñmidín-2-¡l)amino)-2-(4,4,5,5 Crude methyl-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (700 mg, 1.7 mmol) in MeOH (15 mL) NaBH4 (532 mg, 14.0 mmol) was added at 30°C in small portions. The reaction was stirred at 30°C for 30 min, 6N HCl (3 mL) was added and stirred for another 20 min. Then neutralized with saturated aqueous NaHCOs and filtered, the filter cake was purified by trituration with MeOH and water (v / v=5:1) to give 5-((5-fluoro-4-(hexane-3ylamino )pymidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (117 mg, 20% yield) as a white solid. Ή 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, 2H), 4.17-3.97 (m, 1H), 1.65-1.42 (m, 4H), 1.41-1.21 (m, 2H), 0.88 (t, J = 7.3 Hz, 6H). Purity by HPLC: 97.79% at 210 nm and 97.96% at 254 nm. MS: m / z = 345.2, (M+H)+. Example 8: 5-((5-methyl-4-((3-methylcyclohexyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol QQ / Q7n / 77n7 / q / ΥΙΛΙ 145 QQ / Q7n / 77n7 / q / ΥΙΛΙ 5Pr 5CC'C2C -TV: ''y-?^V·»· :yrh(?• Ύχτ Π c. ' · ,Ci ' T ' 1 .· I c To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added 3methylcyclohexane-1-amine (1.7 g, 15 mmol, cis-trans mixture ) and EtsN (2.0 g, 20.0 mmol) at room temperature. The reaction was refluxed overnight, then the solvent was removed in vacuo to give a residue which was purified by chromatography on silica with PE / EtOAc (20 / 1 to 5 / 1) to give 2chloro-5-methyl-N -(3-methylcyclohexyl)pyrimidine-4-amine (1.6 g, yield 67%, cis:trans = 3:1) as a yellow solid, which was used directly for the next step. 5-Amino Methyl -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 and extracted with DCM, the combined organic phase washed with water, brine concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 10 / 1) to give 2-bromo-5-((5-methyl-4-((3-methylclohex Methyl ¡l)amino)p¡hm¡d¡n-2yl)amino)benzoate (1.0 g, 56% yield) as a yellow solid. To a solution of 2-bromo-5-((5-methyl¡l-4-((3-met¡lc¡clohex¡l)amino)p¡r¡m¡d¡n-2-yl) methyl am¡no)benzoate (1.0 g, 2.3 mmol) in THF (15 mL) was added KOAc (676 mg, 6.9 mmol), (BPin)2 (864 mg, 3.4 mmol) and (dppfjPdCL (734 mg, 0.9 mmol) at room temperature under a nitrogen atmosphere The resulting mixture was refluxed overnight, then the solid formed was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give 5-((5-methyl¡l-4-((3-methylcyclohex¡l)amino)pyrimid¡n-2-yl) Crude methyl amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, contain 40% Br product in LCMS) as a solid black, which was used directly in the next step. MS: m / z =481.3, (M+H)+. To a solution of 5-((5-methyl-4-((3-met¡lc¡clohex¡l)amino)pyrim¡din-2-¡l)amino)-2-(4,4 Crude methyl ,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (700 mg, crude) in MeOH (20 mL) was added NaBH4 (437 mg, 11.5 mmol) at 25°C in little portions. The reaction was stirred at 25°C for 30 min, 6N HCl (3 mL) was added and stirred for another 20 min. It was then neutralized by adding aq. NaHCOs. saturated, extracted with DCM and the combined organic phase washed with water, brine and concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was triturated with CHsCN and water to give 5-((5-methyl-4-((3methylcyclohexyl)amino)pyr¡m¡din-2-¡l)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), 146 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). Purity by HPLC: 98.33% at 210 nm and 99.03% at 254 nm. MS: m / z = 353.2, (M+H)+. Example 9: 5-((4-((4-fluorobenzyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol QQ / Q7n / 77n7 / q / ΥΙΛΙ 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 EtaN (2.0 g , 20.0 mmol) at room temperature. The reaction was refluxed overnight, then the solvent was removed in vacuo to give a residue which was purified by chromatography on silica with 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. To a solution of 2-chloro-N-(4-fluorobenzyl)-5-methylp¡rmidin-4-amine (1.6 g, 6.4 mmol) in EtOH (6 mL) Methyl 5-amino-2-bromobenzoate (1.5 g, 6.4 mmol) and HCl (1.5 N, 4 mL) were added. 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 2-bromo-5-((4 Methyl -((4-fluorobenzyl)amino)-5methylpyrimidin-2-yl)amino)benzoate (1.6 g, 57% yield) as a white solid. 1H NMR (400 MHz, DMSO-ds):6 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. To a solution of methyl 2-bromo-5-((4-((4-fluorobenzyl)amino)-5-met¡lp¡r¡míd¡n-2-¡l)amino)benzoate ( 1.6 g, 3.6 mmol) in THF (15 mL) KOAc (1.1 g, 10.8 mmol), (ΒΡίη)ζ (1.4 g, 5.4 mmol) and (dppf) PdCIs (1.1 g, 1.4 mmol) were added at low room temperature nitrogen atmosphere. The mixture was heated to reflux overnight, then the solid formed was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give 5((4-((4-fluorobenzyl)amino)-5-methylpyrmiden-2-l)amino)-2-(4,4,5,5 Methyl -tetramethyl-1,3,2-dioxaborolan-2yl)benzoate (1.3 g, contains 30% of -Br product in LCMS) as a black solid, which was directly used for the next step. MS: m / z =493.3, (M+H)+. To a solution of 5-((4-((4-fluorobenzyl)amino)-5-methílp¡nmidín-2-íl)amino)-2-(4,4, Crude methyl 5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (1.3 g, crude) in MeOH (20 mL) was added NaBH4 (722 147 mg, 19.0 mmol) at 30°C in small portions. The reaction was stirred at 30°C for 30 min, then 6N HCl (3 mL) was added, the resulting mixture was kept stirring for another 20 min. The reaction mixture was neutralized with aq. NaHCOs. saturated, extracted with EtOAc, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue which was purified by chromatography on silica with 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-methyl!pyrimidin-2-!l)amino) benzo[c][1,2]oxaborol-1 (3H)-ol (186 mg, 14% yield) as a yellow solid.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 98.97% at 254 nm. MS: (M+H)+: m / z = 365.1. Example 10: 5-((5-methyl-4-((4-methylcyclohex¡l)amino)pyrimidin-2yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι To a solution of 2,4-dichloro-5-methylpyrimidine (1.6 g, 10.0 mmol) in EtOAc (20 mL) was added 3methylcyclohexane-1-amine (1.7 g, 15 mmol, cis mixture -trans) and EtaN (2.0 g, 20.0 mmol) at room temperature. The reaction was refluxed overnight, then the solvent was removed in vacuo to give a residue which was purified by chromatography on silica with PE / EtOAc (20 / 1 to 5 / 1) to give 2chloro-5-methyl-N. -(4-met¡lc¡clohex¡l)p¡nmidin-4-amine (1.6 g, 67% yield, cis : trans = 1:1) as a yellow solid. To a solution of 2-chloro-5-methyl-N-(4-methylcyclohexyl)pyrimidin-4-amine (1.0 g, 4.2 mmol) in EtOH (6 mL ) methyl 5-amino-2-bromobenzoate (1.0 g, 4.2 mmol) and HCl (1.5 N, 4 mL) were added. The reaction was subjected to microwave irradiation (90°C, 30 min), then cooled to room temperature, poured into water and the aqueous phase was extracted with DCM, the combined organic phase was washed with water, brine, concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 10 / 1) to give 2-bromo-5-((5-methyl-4-((4-methyl Methyl ¡clohexyl)amino)p¡ñm¡d¡n-2yl)amino)benzoate (1.0 g, 56% yield) as a yellow solid. To a solution of 2-bromo-5-((5-methyl¡l-4-((4-methylcyclohex¡l)amino)p¡r¡m¡d¡n-2-¡l)amino )methyl benzoate (1.0 g, 2.3 mmol) in THF (15 mL) KOAc (676 mg, 6.9 mmol), (BPin)2 (864 mg, 3.4 mmol) and (dppfjPdCh (734 mg, 0.9 mmol) were added to room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux overnight, then the solid was removed by filtration and the filtrate was concentrated in vacuo to give a residue that was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give 5-((5-met¡l-4-((4-met¡lc¡clohex¡l)amino)pyrim¡din-2-¡l)amino) Crude methyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (700 mg, contain 40% of-Br product in LCMS) as 148 a black solid, which was used directly for the next step. MS: (M+H)+: m / z =481.3. To a solution of 5-((5-met¡l-4-((4-rnet¡lc¡clohex¡l)amino)p¡rm¡d¡n-2-¡l)amino Crude methyl )-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (700 mg, crude) in MeOH (20 mL) NaBH4 (437 mg, crude) was added. 11.5 mmol) at 25°C in small portions. The reaction was stirred at 25°C for 30 min, then 6N HCl (3 mL) was added, and the resulting mixture was kept stirring for another 20 min. The reaction mixture was neutralized by adding aq. NaHCOs. saturated, extracted with DCM, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue which was purified by chromatography on silica with 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.1H NMR (400 MHz, DMSO-de): 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. Example 11: 5-((4-(cyclobutylamino)-5-methylpyrimidine-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol qq / ozn / zznz / q / υιλι 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 EtsN (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, which was triturated with CH3CN and H2O to give 2-chloro-N-cyclobutyl-5-methylpyrimidin-4-amine. (1.6 g, 80% yield) as a light yellow solid. 1H NMR (300 MHz, CDCI3): 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. 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, poured into water, the solid formed was collected by filtration, dried under vacuum to give 2-bromo-5-( Methyl (4(cyclobutylamino)-5-methylp¡r¡m¡d¡n-2-¡l)amino)benzoate (2.1 g, 68% yield) as a yellow solid. Ή NMR (400 MHz, CDCI3): δ 10.73 (s, 1H), 8.27 (d, J = 2.7 Hz, 1H), 7.59-7.50 (m, 1H), 7.507.29 (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. 149 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) was added KOAc (1.2 g, 12.3 mmol), (BPin)2 (1.5 g, 6.1 mmol), and (dppf)PdCl2 (1.3 g, 1.6 mmol) at room temperature under a nitrogen atmosphere. The mixture was refluxed overnight, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue, which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1). to give 5-((4-(cyclobutylamine)-5-methylpyrimidin-2-l)amino)-2-(4,4,5,5-tetramethyl- Crude methyl 1,3,2-dioxaborolan-2yl)benzoate (1.1 g, 70% purity in LCMS) as a black solid, which was directly used for the next step. MS: (M+H)+: m / z =439.3. To a solution of 5-((4-(cyclobutylamino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3, Crude methyl 2dioxaborolan-2-yl)benzoate (1.1 g, crude) in MeOH (20 mL) was added NaBH4 (760 mg, 20.0 mmol) at 30°C in small portions. The reaction was stirred at 30°C for 30 min, then 6N HCI (3 mL) was added, and the resulting mixture was allowed to stir another 20 min. The reaction mixture was neutralized by adding saturated aqueous NaHCOs, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was triturated. with CH3CN and water to give 5-((4-(cyclobutylamno)-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-de): 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% at 210 nm and 98.69% at 254 nm. MS: (M+H)+: m / z = 311.1. Example 12: 5-((4-(sec-butylamino)-5-chloropyrimidin-2-yl)amino)benzo[c][1,2]oxaborole-1(3H)ol QQ! ozn / zznz / q / ΥΙΛΙ This substance was prepared following the general synthesis scheme B, starting with 5-((5chloro-4-(methylsulfonyl)pyrimidin-2-1)amino)benzo[c][1,2]oxaborole-1 (3H)-ol and butan-2-amine using the procedure of Example 2.1H 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 found 333.1 [M+H]+. HPLC purity: 97.93% (220 nm), 95.61% (254 nm). Example 13: 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol 150 QQ / Q7n / 77n7 / q / ΥΙΛΙ ==- KIAí --F •e'L.C > J Μ**1'·' .·. Λ i,. . - Y ~ j YvV 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 EtsN (1.4 g, 14.0 mmol) to room temperature. The reaction was refluxed overnight, then the solvent was removed in vacuo to give a residue, which was triturated with CH3CN and H2O to give 2-chloro-5-methyl-N-(1-phenylpropyl)p¡ r¡m¡n-4-amine (1.2 g, 67% yield) as a white solid. 1H NMR (400 MHz, CDCI3): 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. 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 5 methyl -amino-2-bromobenzoate (1.1 g, 4.6 mmol) and HCI (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, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give 2-bromo-5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2yl)amino) methyl benzoate (1.0 g, yield 48%) as yellow solid.1H NMR (400 MHz, CDCI3): 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. To a solution of methyl 2-bromo-5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-l)benzoate (1.0 g, 2.1 mmol) in THE (15 mL) KOAc (617 mg, 6.3 mmol), (BPin)z (787 mg, 3.1 mmol) and (dppf)PdCl2 (653 mg, 0.8 mmol) were added at room temperature under atmosphere nitrogen The mixture was refluxed overnight, then the solid was filtered off and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-l)amino)-2-(4,4,5, Crude methyl 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 for the next step MS: (M +H)+: m / z =503.3. To a solution of 5-((5-methyl-4-((1-phenylpropyl)amino)pyrimidin-2-l)amino)-2-(4,4,5 Crude methyl,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (800 mg, crude) in MeOH (10 mL) was added NaBH4 (380 mg, 10.0 mmol) at 30°C in small portions. The reaction was stirred at 30°C for 30 min, then 6N HCl (3 mL) was added, and the resulting mixture was kept stirring for another 20 min. The reaction mixture was neutralized by adding saturated aqueous NaHCOs, and the aqueous phase was extracted with EtOAc, the combined organic phase was washed with water, brine, and concentrated under reduced pressure to give a residue, which was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give the product 151 crude, which was triturated with CH3CN and water to give 5-((5-methyl-4-((1-phenylpropyl)amino)p¡r¡m¡din-2yl)amino)benzo[c][1,2 ]oxaborol-1(3H)-ol (77 mg, 10% yield) as a white solid.1H NMR (400 MHz, DMSO-de): 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. Purity by HPLC: 96.48% at 210 nm and 98.14% at 254 nm. MS: (M+H)+: m / z = 375.2. Example 14: 5-((5-chloro-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol qq / ozn / zznz / q / υιλι This substance was prepared following general synthesis scheme B, starting with 5-((5chloro-4-(methylsulfonyl)pyrimidin-2-!l)amino)benzo[c][1 ,2]oxaborol-1 (3H)-ol and pentan-3-amine using the procedure of Example 2.1H 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 found 347.0 [M+H]+. Purity by HPLC: 95.31% (220 nm), 99.07% (254 nm). Example 15: 5-((5-chloro-4-((1-hydroxybutan-2-yl)amino)pyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following the general synthesis scheme B, starting with 5-((5chloro-4-(methylsulfon¡l)pyrimid¡n-2-¡l)amino)benzo[c][1,2]oxaborole -1(3H)-ol and 2-aminobutan-1-ol using the procedure of Example 2.1H 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 (s, 2H), 4.10-4.09 (m,1H), 3.59-3.55 (m, 1H), 3.52-3.51 (m, 1H) 1.71-1.66 (m, 1H), 1.62-1.57 (m, 1H), 0.92-0.89 (m, 3H). MS (ESI): m / z found 349.0 [M+H]+. Purity by HPLC: 91.87% (220 nm), 95.66% (254 nm). Example 16: 5-((4-(cyclopentylamino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol I.NaBH4. MeOH. ta HCI H.O. To a solution of 5-((4-(cyclopentalamino)-5-methylpyrimidín-2-íl)amino)-2-(4,4,5,5-tetramethyl Methyl -1,3,2 dioxaborolan-2-yl)benzoate (5.4 g, crude), which was prepared using the experimental procedure Generally, in MeOH (50 mL) NaBH4 (4.6 g, 0.12 mol) was added at room temperature in small portions. The reaction was stirred at room temperature for 1 h, then 6N HCl (10 mL) was added and stirred for another 20 min. The reaction mixture was neutralized by adding saturated NaHCO3, and the aqueous phase was extracted with EtOAc, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by silica chromatography with MeOH / DCM (100 / 1 to 50 / 1) to give the crude product, which was triturated with MeCN / HsO (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. Ή 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, 1H), 4.91 (s, 2H), 4.51-4.32 (m, 1H), 2.09-1.87 (m, 2H), 1.93 (s, 3H), 1.81- 1.65 (m, 2H), 1.65 -1.46 (m, 4H). HPLC purity: 98.40% at 210 nm and 97.77% at 254 nm. MS: (M+H)+: m / z = 325.1. Example 17: 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol qq / Qzn / zznz / q / υιλι To a solution of 2,4-dichloro-5-methylpyrimidine (2.0 g, 12.3 mmol) in EtOAc (20 mL) was added 2aminobutan-1-ol (2.2 g, 24.6 mmol) and Et3N (2.5 g, 24.6 mmol) at room temperature. The reaction was refluxed overnight and then the solvent was removed in vacuo to give a residue, which was triturated with water and MeOH to give 2-((2-chloro-5-methylpyrimidin-4-yl)amino)butan. -1-ol (2.1 g, yield 81%) as a light yellow solid.1H NMR (300 MHz, CDCh): 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. To a solution of 2-((2-chloro-5-methylpinmidin-4-¡l)amino)butan-1-ol (1.3 g, 6.0 mmol) in EtOH (6 mL) was added 5-amino-2 -methyl 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 organic was washed with water, brine, concentrated under reduced pressure to give a residue that was purified. by chromatography on silica with DCM / MeOH (100 / 1 to 10 / 1) to give 2-bromo-5-((4-((1hydroxy¡butan-2-yl)amino)-5-met¡ Methyl lp¡r¡m¡din-2-¡l)amino)benzoate (1.4 g, 58% yield) as a yellow solid. Ή NMR (300 MHz, CDCh): 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. To a solution of 2-bromo-5-((4-((1-hydroxy¡butan-2-yl)amino)-5-methylpyr¡m¡din-2-¡l)am¡ methyl no)benzoate (1.4 g, 3.4 mmol) in THF (15 mL) was added KOAc (1.0 g, 10.2 mmol), (BPin)2 (1.3 g, 5.1 mmol) and (dppf)PdCh (1.1 g, 1.3 mmol) at room temperature under a nitrogen atmosphere. The mixture is 153 was heated to reflux overnight, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 20 / 1) to give the 5-((4-((1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3 Crude methyl ,2-dioxaborolan-2-yl)benzoate (1.0 g, contains 45% de-Br product in LCMS) as a black solid. (M+H)+: m / z =457.2. To a solution of 5-((4-((1-hydroxy¡butan-2-yl)am¡no)-5-methylp¡ñm¡din-2-¡l)amino)-2-(4, Methyl 4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, crude) in MeOH (20 mL) was added NaBH4 (570 mg, 15.0 mmol) at 30°C in small portions . The reaction was stirred at 30°C for 30 min, then 6N HCI (3 mL) was added and stirred for another 20 min. The reaction mixture was neutralized by adding saturated NaHCOs and extracted with EtOAc, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was further purified by prep HPLC (0.1% TFA in MeCN and H2O) to give 5-((4-((1 -hydroxybutan-2-¡l) amino)-5-methylp¡r¡m¡n-2yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol (90 mg, 9% yield) as a white solid .1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 99.94% at 254 nm. MS: (M+H)+: m / z = 329.2. Example 18: 5-((4-((3-(hydroxymethyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol To a solution of 3-((2-((1 -hydroxy¡-1,3-dihydrobenzo[c][1,2]oxaborol-5-¡l)amino)-5-methylpyr¡m¡d¡ Ethyl n-4yl)amino)benzoate (500 mg, 1.2 mmol), which was prepared as shown in Example 61, in THF (10 mL) was added DIBAL-H (1.5 N, 4 mL) at 0°C under N2 atmosphere, the reaction was stirred at 0 °C for 2h, then quenched by adding 6N HCI, poured into water, neutralized by adding aq. NaHCOs, extracted with EtOAc. The combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by chromatography on silica with DCM / MeOH (100 / 1 to 10 / 1) to give the crude product, which was purified further by HPLC prep (0.1% TFA in MeCN) to give 5-((4-((3-(hydroxymethyl)phenyl)amino)-5-methyl!rimidin-2-! l)amino)benzo[c][1,2]oxaborol-1 (3H)-ol (62 mg, 14% yield) as a white solid.1H NMR (400 MHz, DMSO-de): 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, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 5.21 (s, 1H), 4.79 (s, 2H), 4.51 (s, 2H), 2.12 ( s, 3H) ppm. HPLC purity: 98.72% at 210 nm and 98.83% at 254 nm. MS: (M+H)+: m / z = 363.1. Example 19: 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol 154 v- · » _ . r res,b'•ν^'χ ·:8>·Λ|0 .1^.. ----------- ----------- To a solution of cyclopentanone (5.0 g, 59.5 mmol) in MeOH (50 mL) was added NaBH4 (4.5 g, 0.12 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with DCM, and the combined organic phase was washed with water, brine, and concentrated in vacuo to give the crude cyclopentanol (3.0 g, yield 51 %) as a clear oil.1H NMR (400 MHz, CDCI3): 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. To a solution of 2,4-dichloro-5-methylpyrimidine (3.7 g, 23.0 mmol) in DMF (20 mL) was added cyclopentanol (2.0 g, 23 mmol) and NaH (1.8 g, 46 mmol) at room temperature. The reaction was heated to 60 °C overnight, then the mixture was quenched by adding water, extracted with EA, and the combined organic phase washed with brine (3x50 mL), concentrated in vacuo to give a residue, which was Purified by chromatography on silica with PE / EtOAc (20 / 1 to 10 / 1) to give 2-chloro-4-(cyclopentyloxy¡)-5-methylpyrimidine (2.2 g, 45% yield) as a yellow solid. 1H NMR (400 MHz , CDCb): δ 8.07 (s, 1H), 5.61 -5.47 (m, 1 H), 2.08 (s, 3H), 2.03-1.93 (m, 2H), 1.86-1.78 (m, 4H), 1.70-1.62 (m, 2H)ppm. To a solution of 2-chloro-4-(cyclopentylox¡)-5-methyl¡lprím¡dine (1.1 g, 5 mmol) in EtOH (10 mL) was added 5-amino-2-bromobenzoate. methyl (1.15 g, 5 mmol) and HCl (1.5 N, 4 mL). The resulting mixture was heated to 80°C for 5h, then cooled to room temperature, poured into water, the solid collected by filtration, dried in vacuo to give 2-bromo-5-((4-(cyclopentyloxy) Methyl -5-met¡lp¡rmid¡n-2yl)amino)benzoate (1.0 g, 61% yield) as a white solid.1H NMR (400 MHz, CDCI3): 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. 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) was added KOAc (706 mg , 7.2 mmol), (BPin)2 (914 mg, 3.6 mmol) and (dppf)PdCl2 (800 mg, 1.0 mmol) at room temperature under a nitrogen atmosphere. The mixture was refluxed overnight, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography on silica with PE / EA (10 / 1 to 3 / 1) to give 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-l)amino)-2-(4,4,5,5-tetramethyl-1,3 Crude methyl ,2-dioxaborolan-2yl)benzoate (650 mg, 70% purity) as a colorless oil.1H NMR(400 MHz, DMSO): δ 9.62 (s, 1 H), 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. To a solution of 5-((4-(cyclopentyloxy)-5-methylpyrimidin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -methyl-yl)benzoate (650 mg, 1.3 mmol) in MeOH (10 mL) NaBH4 (380 mg, 10.0 mmol) at room temperature in small portions. The reaction was kept stirring at room temperature for 30 min, then 6N HCl (3 mL) was added and stirred for another 20 min. The reaction mixture was neutralized by adding saturated NaHCOs, extracted with EtOAc, the combined organic phase was washed with water, brine and concentrated under reduced pressure to give a residue, which was purified by silica chromatography with DCM / MeOH (100 / 1 to 20 / 1) to give the crude product, which was triturated with CH3CN and water to give 5-((4-(cyclopent¡lox¡)-5-met¡lp¡rímidin-2-¡l )amino)benzo[c][1,2]oxaborol1 (3H)-ol (236 mg, 56% yield) as a white solid.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 95.01% at 254 nm. MS: (M+H)+: m / z = 326.2. Example 20: 5-((4-(cyclopentyl(methyl)amino)-5-methylpyrimidin-2-yl)amino) benzo[c][1,2]oxaborol-1 (3H)-ol QQ / Q7n / 77n7 / q / ΥΙΛΙ This substance was prepared using the above scheme and the general procedure described in General Synthesis Scheme A.1H NMR (300 MHz, DMSO-de): 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, 1H), 2.90 (s, 3H), 2.16 (s, 3H), 1.95-1.75 (m, 2H), 1.75-1.44 (m, 6H) ppm. HPLC purity: 98.74% at 210 nm and 98.51% at 254 nm. MS: (M+H)+: m / z = 339.2. Example 21: 5-((5-chloro-4-((2-cyclopropylethyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol This substance was prepared following General Synthesis Scheme B, starting with 5-((5chloro-4-(methylsulfon¡l)pyrimidin-2-¡l)amino)benzo[c][1,2]oxaborole -1(3H)-ol and pentan-3-amine using the procedure of Example 2.1H 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 found 345.1 [M+H]+. Purity by HPLC: 97.31% (220 nm), 98.41% (254 nm). Example 22: 5-((5-chloro-4-(2-ethylaziridín-1-yl)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1(3H)ol 156 TEA, THF This substance was prepared following General Synthesis Scheme B, from 5-((5-chloro-4 (methylsulfon¡l)pyr¡m¡d¡n-2-¡l)amino)benzo[c] [1,2]oxaborol-1(3H)-ol, which was prepared following the procedure of Example 2, and 2-ethylaziridine.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, 1 H), 1.81-1.72 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS (ESI): m / z found 331.0 [M+H]+. HPLC purity: 99.26% (220 nm), 99% (254 nm). Example 23: 5-((4-(cyclopentylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol ΗH This substance was prepared using the general experimental procedure as shown in General Synthesis Scheme A.1H NMR (400 MHz, DMSO-de): 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 Hz, 1H), 4.91 (s, 2H), 4.23-4.22 (m , 1H), 1.99-1.93 (m, 2H), 1.70-1.24 (m, 6H) ppm. HPLC purity: 98.05% at 210 nm and 98.18% at 254 nm. MS: (M+H)+: m / z = 311.1. Example 24: 5-((4-(cyclohexylamino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol ΗH This substance was prepared using the general experimental procedure as shown in General Synthesis Scheme A.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 98.18% at 254 nm. MS: (M+H)+: m / z = 325.2. Example 25: 5-((5-methyl-4-((2-(trifluoromethyl)phenyl)amino)pyrimidin-2-yl)amino)benzo[c][1,2]oxaborol-1 (3H)-ol OH This substance was prepared using the general experimental procedure as shown in 157 General synthesis scheme A.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 99.84% at 254 nm. MS: (M+H)+: m / z = 401.1. Example 26: 5-((4-((2-ethylphenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared using the general experimental procedure as shown in the following General synthesis scheme A.1H NMR (400 MHz, DMSO-de): 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% at 210 nm and 98.32% at 254 nm. MS: (M+H)+: m / z = 361.2. Example 27: 5-((4-((2-fluorotophenyl)amino)-5-methylpyrimidín-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-ol This substance was prepared using the general experimental procedure as shown in General Synthesis Scheme A.1H NMR (400 MHz, DMSO-de): 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, 3H), 7.29-7.24 (m, 2H), 4.68 (s, 2H) , 2.12 (s, 3H) ppm. HPLC purity: 97.19% at 210 nm and 97.7% at 254 nm. MS: (M+H)+: m / z = 351.1. Example 28: 5-((4-((2-methoxyphenyl)amino)-5-methylpyrimidin-2-yl)amino)benzo[c][1,2]oxaborol1(3H)-Ol This substance was prepared using the general experimental procedure as shown in General Synthesis Scheme A.1H NMR (400 MHz, DMSO-de): 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, 1H), 7.21-7.19 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.02-6.98 (m, 1H), 4.77 (s, 2H), 3.79 (s, 3H), 2.10 (s, 3H) ppm. HPLC purity: 99.72% at 210 nm and 99.74% at 254 nm. ...

Claims

qq / azn / zznz / q / uili 1. A compound of formula (I): wherein: A is selected from the group consisting of: and X is selected from the group consisting of: NH, O and S; when present, R1 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, partially or fully halogenated cyclopropyl, O(C1-C3 alkyl) and O(C1-C3 haloalkyl); when present, each R1b 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);When present, each of R2 and R3 is independently selected from the group consisting of: C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and, when present, R2 and R3 taken together form a 3-membered cycloalkyl ring; and when present, each of R2a and R3a, is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and R2a and R3a taken together form a 3-membered cycloalkyl ring, RB is selected from the group consisting of: substituted phenyl, unsubstituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Ci-Ce alkenyl, substituted Ci-Ce alkenyl, unsubstituted Ci-Cs alkynyl, substituted Ci-Ce alkynyl, unsubstituted Cs-Ce cycloalkyl, substituted Cs-Ce cycloalkyl, and unsubstituted arylalkyl, substituted arylalkyl;and Rc 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 veterinary or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein: when present, R1 is 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).

3. A compound of formula (IA) qq / azn / zznz / q / υιλι wherein: X is selected from the group consisting of: NH, O and S; R1 is selected from the group consisting of: hydrogen and fluorine; RB is selected from the group consisting of: substituted phenyl, unsubstituted phenyl, unsubstituted O-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Ci-Ce alkenyl, substituted Ci-Ce alkenyl, unsubstituted C1-C5 alkynyl, substituted Ci-Ce alkynyl, unsubstituted Cs-Ce cycloalkyl, substituted Cs-Ce cycloalkyl, unsubstituted arylalkyl and substituted arylalkyl; and Rc 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 veterinary or pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein Rc is selected from the group consisting of: halogen, C1-C3 alkyl and C1-C3 haloalkyl.

5. The compound according to claim 3, wherein Rc is selected from the group consisting of: CH3, CF3, F and Cl.

6. The compound according to any of claims 1 to 5, wherein X is NH.

7. The compound according to any one of claims 1 to 6, wherein RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted Cs-Ce cycloalkyl, unsubstituted arylalkyl, and substituted arylalkyl.

8. The compound according to claim 7, wherein RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted C3-C6 alkyl, substituted C3-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted benzyl, and substituted benzyl.

9. The compound according to claim 8, wherein each of the substituted phenyl, substituted Ci-Ce 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(CiC3), OH, CH2OH, Cs-Ce cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, halogen, O(C1C3 alkyl) and O(C1-C3 haloalkyl).

10. The compound according to claim 7, wherein RB is selected from the group consisting of: unsubstituted Ci-Ce alkyl and unsubstituted C3-Ce cycloalkyl.

11. The compound according to any of claims 1-10, wherein R1 is hydrogen.

12. The compound according to any of claims 1-10, wherein R1 is fluorine.

13. A compound selected from the group consisting of: 222 qq / ozn / zznz / q / υιλι 223 OH OH 224 225 qq / ozn / zznz / q / υιλι 226 qq / ozn / zznz / q / υιλι 227 qq / ozn / zznz / q / υιλι 228 or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

14. A compound is selected from the group consisting of: 229 OH 230 qq / ozn / zznz / q / υιλι 231 or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

15. A compound of formula (IB): wherein: A is selected from the group consisting of: 232 qq / azn / zznz / q / υιλι X is selected from the group consisting of: NH, O and S; RB is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Cs-Ce alkenyl, substituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, substituted C2-C6 alkynyl, unsubstituted Cs-Ce cycloalkyl, substituted Cs-Ce cycloalkyl and unsubstituted arylalkyl, substituted arylalkyl; Rc 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, C2C3 haloalkynyl, and partially or totally halogenated cyclopropyl;Each R1, when 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 R1b, when 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); each of R2 and R3, when present, is independently selected from the group consisting of: C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and, when present, R2 and R3 taken together form a 3-membered cycloalkyl ring;and each of R2a and R3a, when present, is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and R2a and R3a taken together form a 3-membered cycloalkyl ring, or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

16. A compound according to claim 15, wherein A is selected from the group consisting of: 233 17. The compound according to claim 15, wherein A is selected from the group consisting of:

18. The compound according to any of claims 15-17, wherein, when present, R1 is selected from the group consisting of: chlorine, bromine, iodine, C1-C3 alkyl, and C1-C3 haloalkyl.

19. The compound according to any of claims 15-17, wherein, when present, R1b is selected from the group consisting of: hydrogen, halogen, Ci-Cs alkyl, and C1-C3 haloalkyl.

20. The compound according to any of claims 15-17, wherein, when present, R1b is selected from the group consisting of: halogen, C1-C3 alkyl, and C1-C3 haloalkyl.

21. The compound according to any of claims 15-17, wherein, when present, each of R2 and R3 is methyl.

22. The compound according to any of claims 15-21, wherein A is:

23. The compound according to any of claims 15-22, wherein X is NH.

24. The compound according to any of claims 15-23, wherein RB is unsubstituted phenyl, substituted phenyl, unsubstituted Ci-Ce alkyl, substituted Ci-Ce alkyl, unsubstituted Cs-Ce cycloalkyl or substituted Cs-Cs cycloalkyl.

25. The compound according to claim 24, wherein RB is unsubstituted phenyl, unsubstituted Ci-Ce alkyl, or unsubstituted O3-Oβ cycloalkyl.

26. The compound according to claim 24, wherein RB is an unsubstituted Ci-Ce alkyl or an unsubstituted C3-C6 cycloalkyl.

27. The compound according to any of claims 15-23, wherein RB is an unsubstituted C2-C6 alkyl, a substituted C2-C6 alkyl, an unsubstituted C2-C6 alkenyl, a substituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, a substituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or a substituted C3-C6 cycloalkyl.

28. The compound according to any of claims 24 or 27, wherein substituted is selected from one or more of CH2OH, C1-C3 alkyl, C1-C3 haloalkyl and SO2(C1-C3 alkyl).

29. The compound according to any of claims 15-28, wherein Rc is selected from the group consisting of: halogen, C1-C3 alkyl and partially or totally halogenated C1-C3 alkyl.

30. The compound according to claim 29, wherein Rc is selected from the group consisting of: CH3, CF3, F and Cl.

31. A compound selected from the group consisting of: 235 qq / ozn / zznz / q / υιλι 236 OH OH qq / ozn / zznz / q / υιλι 237 or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

32. A compound selected from the group consisting of: 238 qq / ozn / zznz / q / υιλι 239 OH qq / ozn / zznz / q / υιλι 240 or a stereoisomer, enantiomer or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

33. A method for treating a patient having 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 according to claims 1-32.

34. The method according to claim 33, wherein the additional enzyme is also a tyrosine kinase.

35. The method according to claim 34, wherein the additional tyrosine kinase is one or more of TrkA and Syk.

36. The method according to claim 33, wherein the additional enzyme is PDE4.

37. The method according to any one of claims 33-36, wherein the disease or disorder is one or more of the following: 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, arteriosclerosis, and cancer.

38. The method according to claim 37, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis.

39. The method according to any of claims 33-38, wherein the compound is administered in an amount to disrupt an immune regulatory pathway in a cell.

40. The method according to claim 39, wherein the disturbance results in an effect on the JAK-STAT pathway.

41. A method of JAK inhibition alone or in combination with the inhibition of one or more additional mechanisms in a mammalian cell comprising contacting the mammalian cell with a compound according to any of claims 1-32.

42. The method according to claim 41, wherein the additional mechanism is also the inhibition of a tyrosine kinase.

43. The method according to claim 42, wherein the tyrosine kinase is one or more TrkA and Syk.

44. The method according to claim 41, wherein the additional mechanism is the inhibition of PDE4.

45. A method for treating a patient having a disease or disorder susceptible to JAK modulation, either alone or with dual modulation with PDE4, comprising administering a therapeutically effective amount of a compound according to claims 1-32.

46. ​​The method according to claim 45, wherein 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, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, disease cardiovascular disease, arteriosclerosis, and cancer.

47. The method according to claim 46, wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis.

48. The method according to any of claims 45-47, wherein the compound is administered in an amount to disrupt an immune regulatory pathway in a cell.

49. The method according to claim 48, wherein the disturbance results in an effect on the JAK-STAT pathway.

50. A method of JAK inhibition in combination with PDE4, in a mammalian cell comprising contacting the mammalian cell with a compound according to any of claims 1-14.

51. The method according to any of claims 33 - 50, wherein JAK is JAK-1.

52. The method according to claim 51, wherein the inhibition is selective for JAK-1.

53. The method according to claim 50-52, wherein the mammalian cell is a cell from a subject having an inflammatory condition.

54. A method of inhibiting JAK alone or with one or more of TrkA and Syk, in a mammalian cell comprising contacting the mammalian cell with a compound according to any of claims 1 or 15-32.

55. The method according to claim 54, wherein JAK is JAK-1.

56. The method according to claim 55, wherein the inhibition is selective for JAK-1.

57. The method according to claim 54-56, wherein the mammalian cell is a cell from a subject having an inflammatory condition.

58. A method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer comprising administering to a subject in need an effective amount of a compound according to any one of claims 1-32.

59. The method according to claim 58, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

60. The method according to any of claims 33-59, wherein the subject is a mammal.

61. The method according to claim 60, wherein the mammal is selected from 242 humans, livestock mammals, domestic mammals, or companion mammals.

62. The method according to claim 60 or 61, wherein the mammal is human.

63. The method according to claim 60 or 61, wherein the mammal is one or more of cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, and cats.

64. A composition comprising a compound according to any of claims 1-32, and a veterinary or pharmaceutically acceptable vehicle.

65. A combination comprising a compound according to any of claims 1-32, and one or more pharmaceutical or veterinary active substances.

66. A compound according to any of claims 1-32, for use in medicine.

67. A compound according to any of claims 1-32, for the manufacture of a medicament for the treatment of one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer.

68. The compound according to claim 67, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

69. Use of a compound according to any of claims 1-32, for the treatment of one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer.

70. Use according to claim 69, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis. qq / Qzn / zznz / q / υιλι

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