Boron-containing pyrimidine compounds, compositions comprising them, methods and uses thereof

Abstract

The present disclosure describes boron-containing pyrimidine compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and medical uses thereof. The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful for the treatment or management of inflammation, autoimmune diseases, cancer, and other disorders and indications in which modulation of JAK is desired. Also described are methods of treating inflammation, autoimmune diseases, cancer, and other conditions that are sensitive to inhibition of Janus kinase by administering the compounds described herein.

Description

Background Art

[0001] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine kinases and serine / threonine kinases. Inappropriate kinase activity, caused by mutation, overexpression, or inappropriate regulation, dysregulation, or deregulation, as well as excessive or insufficient production of growth factors or cytokines, is associated with a wide range of diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, survival, apoptosis, mitosis, cell cycle control, and cell motility, which are associated with the above-mentioned and related diseases. Therefore, protein kinases have become 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) plays a central role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253). Upon receptor binding, cytokines activate JAKs, which then phosphorylate the cytokine receptors, creating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family. This ultimately leads to gene expression, stimulating biological responses such as itch signals. Activation of the JAK-STAT pathway also results in several other ancillary biological activities that contribute to the inflammatory and pruritic processes that lead to acute allergic reactions in animals, but can also exacerbate clinical signs and contribute to chronic allergic reactions.

[0002] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease affecting approximately 20% of children and up to 10% of adults. It imposes a significant financial and societal burden due to direct medical costs and reduced productivity for individuals with AD. The burden of AD appears primarily related to the limited availability of treatments. Furthermore, according to AD treatment guidelines, there is no standard therapy, and treatment may be tailored to individual needs. Topical interventions are the mainstay of AD therapy. To date, topical corticosteroids have been the first-line treatment. However, their use may be limited by potential local and systemic adverse reactions. Topical calcineurin inhibitors are classified as second-line anti-inflammatory therapies for AD, offering advantages in terms of long-term maintenance and specific site application. Topical calcineurin inhibitors inhibit calcineurin-dependent T cell activation; however, black box warnings regarding the potential for malignancy with the use of topical calcineurin inhibitors reduce patient adherence to treatment.

[0003] Psoriasis and psoriatic arthritis are associated with abnormal inflammation and the production of proinflammatory mediators. Psoriasis and psoriatic arthritis are inflammatory diseases with overlapping features and shared immune mechanisms. Psoriasis is a systemic disease because it primarily affects the skin, but up to 40% of individuals with psoriasis may go on to develop psoriatic arthritis. Psoriatic arthritis typically affects peripheral joints and may occasionally affect the spine and sacroiliac region. In patients with joint involvement, enthesitis, dactylitis, and nail changes such as pitting and discoloration are also common manifestations of psoriasis.

[0004] In dogs, pruritus is often a significant clinical sign associated with flea-associated dermatitis. Medical management of pruritus may be sought in cases where the cause of the pruritus cannot be identified or treatment of the underlying condition does not resolve the pruritus. However, controlling pruritus with antihistamines is often ineffective, and while treatment with glucocorticoids may be effective, long-term use is not ideal due to side effects, which include excessive hunger, thirst, and urination, as well as an increased risk of diabetes and urinary tract infections.

[0005] JAK inhibition may provide a therapeutic strategy for a variety of immune and inflammatory diseases, including rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), psoriasis, alopecia areata, atopic dermatitis, vitiligo, palmoplantar pustulosis, the mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, dry eye, secondary hypereosinophilic syndrome (HES), allergies, atopic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer. See Schwartz et al., JAK inhibition as a therapeutic strategy for immune and inflammatory diseases, Nat Rev Drug Discov., 2017 Dec 28., 17(1):78, which is incorporated herein by reference for its rationale for targeting JAKs.

[0006] Various types of compounds have been shown to inhibit JAK enzymes. For example, US 8,133,899 B2 (Pfizer) discloses the use of pyrrolo[2,3-D]pyrimidine compounds as JAK inhibitors. Specifically, oclacitinib (APOQUEL ®) is a cyclohexylaminopyrrolopyrimidine that has been shown to be a Janus kinase inhibitor that can control clinical signs of allergic skin disease in dogs (as disclosed in J. Vet. Pharmacol. Therap. 2014 Aug 37(4): 317-324). JAK inhibitor compounds are described in published patent application numbers US 2020 / 0339585, WO 2009 / 114512 A1, WO 2021 / 003501 A1, and U.S. Patent No. 7,598,257 B2.

[0007] Patent applications filed by Merck Sharp & Dohme Corporation and Intervet Inc. disclosing pyrazolecarboxamide compounds as JAK inhibitors include WO 2013 / 041042 A1, WO 2018 / 108969 A1, WO 2020 / 118597 A1, WO 2020 / 120673 A1, WO 2020 / 120679 A1, and WO 2020221914 A1 (all of which are incorporated herein by reference in their entirety).

[0008] Siu et al., The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties, J. Med. Chem. 2017 Dec 14;60(23):9676-9690, incorporated herein by reference, also describes pyrazolecarboxamide Janus kinase 1 inhibitors.

[0009] There remains a need for therapies that target and modulate JAK kinases for the treatment or management of inflammation, autoimmune diseases, cancer, and other disorders and indications requiring modulation of JAKs.

[0010] Any of the above-referenced applications, all documents cited therein or during their prosecution ("Application Citations"), all documents cited or referenced in said Application Citations, all documents cited or referenced herein ("Herein Citations"), and all documents cited or referenced in the herein Citations, are incorporated herein by reference, as are any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein.

[0011] Citation or identification of any document in this application does not constitute an admission that the document is available as prior art. Summary of the Invention

[0012] The present disclosure provides boron-containing compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and their medical uses. The compounds of the present disclosure are active as Janus kinase (JAK) inhibitors and can be used to treat or control inflammation, autoimmune diseases, cancer, and other disorders and indications requiring JAK modulation. Also described herein are methods for treating inflammation, autoimmune diseases, cancer, and other conditions sensitive to JAK inhibition by administering the compounds of the present disclosure.

[0013] In a first aspect, the present disclosure provides boron-containing pyrimidine compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and medical uses thereof. The compounds disclosed herein have activity as Janus kinase (JAK) inhibitors and are useful for treating or controlling inflammation, autoimmune diseases, cancer, and other disorders and indications requiring JAK modulation.

[0014] In one embodiment, the present disclosure provides a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof; wherein A is selected from benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborol-1-ol and 2H-benzo[e][1,2]oxaborol-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-boronbenzo[cd]azulene, or a derivative thereof, such as a moiety selected from any one of A1-A7 defined herein, and for compounds of formula (I), (Ia) and (Ib), the variable R 1-11 、R 11a and R 12-13 Defined in this article.

[0015] (I),

[0016] (Ia),

[0017] (Ib).

[0018] One embodiment of the present disclosure includes a method of treating a patient suffering from a disease or disorder susceptible to modulation of a JAK, the method comprising administering a therapeutically effective amount of a compound of the present disclosure. In one aspect, the disease or disorder is one or more of atopic dermatitis, flea allergy dermatitis, eczema, pruritus, 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, secondary hypereosinophilic syndrome (HES), allergy, atopic 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, flea allergy dermatitis, psoriasis, and rheumatoid arthritis. In one aspect, the compound is administered in an amount that disrupts an immunomodulatory pathway in a cell. In one aspect, the disruption results in an effect on the JAK-STAT pathway.

[0019] One embodiment of the present disclosure includes a method of inhibiting JAK in a mammalian cell, the method comprising contacting the mammalian cell with a compound of the present disclosure. In one aspect, the mammalian cell is a cell from a subject suffering from an inflammatory disorder.

[0020] One embodiment of the present disclosure includes a composition comprising a compound of the present disclosure and a pharmaceutically or veterinarily acceptable carrier.

[0021] One embodiment of the present disclosure includes a combination comprising a compound of the present disclosure and one or more other pharmaceutically or veterinarily active substances.

[0022] In another aspect, the disclosure provides methods of treating inflammation, autoimmune diseases, cancer, and other conditions sensitive to inhibition of JAKs by administering the compounds described herein.

[0023] In one embodiment of the present disclosure, there is provided a method for treating one or more diseases or disorders in inflammation, autoimmune dysfunction and cancer, the method comprising administering an effective amount of a compound of the present disclosure to a subject in need thereof. In one aspect, the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis or rheumatoid arthritis. In one embodiment, the subject is a mammal. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is selected from livestock mammals, domesticated mammals or companion animals. In one aspect, the subject is selected from cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs and cats. In one aspect, the subject is human.

[0024] One embodiment of the present disclosure includes a compound of the present disclosure for use in medicine.

[0025] One embodiment of the present disclosure includes compounds of the present disclosure for use in the preparation of a medicament for treating one or more diseases or disorders selected from the group consisting of inflammation, autoimmune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

[0026] One embodiment of the present disclosure includes the use of the compounds of the present disclosure for treating 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.

[0027] Although not specifically described, one or more aspects and embodiments may be incorporated into different embodiments. That is, all aspects and embodiments may be combined in any manner or combination.

[0028] The headings used herein are for organizational purposes only and are not meant to limit the scope of the specification or claims. As used throughout this application, the word "may" is used in a permissive sense (i.e., meaning having the potential to), rather than a mandatory sense (i.e., meaning must). Similarly, the word "including" is meant to include, but not be limited to, the described variables.

[0029] These and other embodiments are disclosed or apparent from and encompassed by the following detailed description. DETAILED DESCRIPTION

[0030] In a first aspect, the present disclosure provides boron-containing pyrimidine compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and medical uses thereof.

[0031] The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful in treating or managing inflammation, autoimmune diseases, cancer, and other disorders and indications requiring modulation of JAKs.

[0032] In one embodiment, the present disclosure provides a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof:

[0033] (I),

[0034] (Ia),

[0035] (Ib),

[0036] in

[0037] X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-;

[0038] X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0039] X3 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-, and X2 and X3 cannot both be -O-;

[0040] R1 is selected from hydrogen, halogen (when X3 is -C(R 6 )(R 7 ) when ), hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl (oxy) and C3-7 cycloalkyl (oxy), wherein the above R 1 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0041] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 2 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0042] Each R3 is independently selected from hydrogen, halogen (when X1 is -C(R6 )(R 7 ) when), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 3 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0043] R4 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,

[0044] A is selected from benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborol-1-ol and 2H-benzo[e][1,2]oxaborol-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-boronbenzo[cd]azulene or a derivative thereof, such as a moiety selected from any one of A1-A7:

[0045]

[0046] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), in which, except for hydrogen, R 5 The above members of the group may be optionally substituted independently of one another by one or more substituents selected from C 1-6 Alkyl and halogen, but the halogen cannot be adjacent to a heteroatom;

[0047] R 6 and R 7are independently selected from hydrogen, halogen, hydroxy, -N(R 8 )(R 9 )、-O(R 10 ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3- alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 6 and R 7 The last fifteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and wherein R 6 and R 7 can be joined together to form a ring;

[0048] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl); wherein the above R 8 and R 9 The last fourteen members of the group may optionally be substituted independently of one another by one or more halogens, or R 8 and R 9can be joined together to form a ring;

[0049] R 10 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 10 The last thirteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, provided that the optional substitutions cannot be geminal;

[0050] Each R 11 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 may be linked to provide a fused cycloalkyl group, such as cyclopropyl;

[0051] Each R 11a independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R11 may be linked to provide a fused cycloalkyl group, such as cyclopropyl;

[0052] Each R 12 independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 cycloalkyl; and

[0053] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -N-(R 5 )(R 5 )、-SO2-(R 5 )、-SO2-(R 5 )(R 5 )、-S(O)-(R 5 ) and -S-(R 5 ), wherein the above R 13 The last fourteen members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0054] In one embodiment of the compounds of Formula I described herein

[0055] X1 is -C(R 6 )(R 7 )-;

[0056] X2 is selected from -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0057] X3 is -C(R 6 )(R 7 )-;

[0058] R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0059] R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0060] Each R 3 are independently selected from hydrogen, C 1- 6 alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0061] R4 is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0062] R 6 and R 7 are independently selected from hydrogen, -C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be joined together to form a ring;

[0063] Each R 12 independently selected from hydrogen, halogen and C 1-6 alkyl; and

[0064] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0065] In yet another embodiment of the compounds of Formula I described herein,

[0066] X1 is selected from -O- and -C(R 6 )(R 7 )-;

[0067] X2 is selected from -O- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0068] X3 is -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-;

[0069] R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0070] R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0071] Each R 3 are independently selected from hydrogen, C 1- 6 alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0072] R4 is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0073] R 6 and R 7 are independently selected from hydrogen, -C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be joined together to form a ring;

[0074] Each R 12 independently selected from hydrogen, halogen and C 1-6 alkyl; and

[0075] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0076] In one embodiment of the compounds of Formula I described herein,

[0077] R 1 Selected from hydrogen and C 1-6 alkyl;

[0078] R 2 Selected from hydrogen and C 1-6 alkyl;

[0079] Each R 3 independently selected from hydrogen and C 1-6 alkyl;

[0080] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more halogens;

[0081] R 12 is hydrogen; and

[0082] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0083] In one embodiment of the compounds of Formula I described herein,

[0084] R 1 、R 2 and R 3 It is hydrogen;

[0085] R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0086] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group may be optionally substituted with one or more halogens;

[0087] Each R 11 independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens;

[0088] Each R 11a independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens;

[0089] R 12 is hydrogen; and

[0090] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13 The last three members of the group may optionally be substituted independently of one another by one or more halogens.

[0091] In one embodiment, the present disclosure provides a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, wherein

[0092] X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-;

[0093] X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0094] X3 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be –O-, and X2 and X3 cannot both be -O-;

[0095] R 1 Selected from hydrogen, halogen (when X3 is -C(R 7 )(R 8 )-), hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl (oxy) and C3-7 cycloalkyl (oxy), wherein the above R 1 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0096] R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 2 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0097] Each R 3 are independently selected from hydrogen, halogen (when X1 is -C(R 7 )(R 8 ))、C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 3 The last four members of the group may optionally be substituted independently of one another by one or more halogens;

[0098] R4 is selected from 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;

[0099] A is selected from benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborol-1-ol and 2H-benzo[e][1,2]oxaborol-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-boronbenzo[cd]azulene or a derivative thereof, such as a moiety selected from any one of A1-A7:

[0100]

[0101]

[0102] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), in which, except for hydrogen, R 5 The above members of the group may be optionally substituted independently of one another by one or more substituents selected from C 1-6 Alkyl and halogen, but the halogen cannot be adjacent to a heteroatom;

[0103] R 6 and R 7 are independently selected from hydrogen, halogen, hydroxy, -N(R 8 )(R 9 )、-O(R 10 ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3- alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 6 and R 7The last fifteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and wherein R 6 and R 7 can be joined together to form a ring;

[0104] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 8 and R 9 The last fourteen members of the group may optionally be substituted independently of one another by one or more halogens, or R 8 and R 9 can be joined together to form a ring;

[0105] R 10 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C3-6-cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 10The last thirteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, provided that the optional substitutions cannot be geminal;

[0106] Each R 11 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 may be linked to provide a fused cycloalkyl group, such as cyclopropyl;

[0107] Each R 11a independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 may be linked to provide a fused cycloalkyl group, such as cyclopropyl;

[0108] Each R 12 independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 cycloalkyl; and

[0109] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3-alkyl)-(4-7 membered heterocycloalkyl), -N-(R 5 )(R 5 )、-SO2-(R 5 )、-SO2-(R 5 )(R 5 )、-S(O)-(R 5 ) and -S-(R 5 ), wherein the above R 13 The last fourteen members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0110] In one embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0111] X1 is -C(R 6 )(R 7 )-;

[0112] X2 is selected from -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0113] X3 is -C(R 6 )(R 7 )-;

[0114] R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0115] R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0116] Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0117] R4 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0118] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be linked together to form rings; and

[0119] Each R 12 independently selected from hydrogen, halogen and C 1-6 alkyl; and

[0120] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0121] In another embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0122] R 1 Selected from hydrogen and C 1-6 alkyl;

[0123] R 2 Selected from hydrogen and C 1-6 alkyl;

[0124] Each R 3 independently selected from hydrogen and C 1-6 alkyl;

[0125] R4 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0126] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more halogens;

[0127] R 12 is hydrogen; and

[0128] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0129] In yet another embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0130] R 1 、R 2 and R 3 It is hydrogen;

[0131] R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0132] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group may be optionally substituted with one or more halogens;

[0133] Each R 11 independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens;

[0134] Each R 11a independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens;

[0135] R 12 is hydrogen; and

[0136] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13The last three members of the group may optionally be substituted independently of one another by one or more halogens.

[0137] In yet another embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0138] X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-;

[0139] X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3;

[0140] X3 is -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-;

[0141] R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0142] R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0143] Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the aforementioned group may be optionally substituted independently of each other by one or more halogens;

[0144] R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0145] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl(oxy), wherein the last four members of the above group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be linked together to form rings; and

[0146] Each R 12 independently selected from hydrogen, halogen and C 1-6 alkyl.

[0147] In another embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0148] X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-;

[0149] X2 is selected from -O- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-, or X2 contains the bond between X1 and X3;

[0150] X3 is -C(R 6 )(R 7 )-;

[0151] R 1 Selected from hydrogen and C 1-6 alkyl;

[0152] R 2 Selected from hydrogen and C 1-6 alkyl;

[0153] Each R 3 independently selected from hydrogen and C 1-6 alkyl;

[0154] R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0155] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0156] R 12 is hydrogen; and

[0157] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the R13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

[0158] In another embodiment of the compounds of Formula (Ia) or (Ib) described herein,

[0159] X2 is -C(R 6 )(R 7 )-;

[0160] X3 is -C(R 6 )(R 7 )-;

[0161] R 1 、R 2 and R 3 It is hydrogen;

[0162] R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl;

[0163] R 6 and R 7 independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0164] Each R 11 independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 11 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0165] Each R 11a independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 11 The last two members of the group may optionally be substituted independently of each other by one or more halogens;

[0166] Each R 12 is hydrogen; and

[0167] Each R 13 independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13 The last three members of the group may optionally be substituted independently of one another by one or more halogens.

[0168] In one embodiment, the present disclosure relates to a compound selected from the compounds shown in Table 1 below:

[0169] Table 1

[0170]

[0171]

[0172]

[0173] In one embodiment, the present disclosure relates to a compound selected from the compounds shown in Table 2 below:

[0174] Table 2

[0175]

[0176]

[0177]

[0178] In one embodiment, the present disclosure provides a compound selected from Examples 1-24 and Examples 25-50 (Tables 1 and 2), and having the trans relative stereochemistry represented in Formulas (Ia) and (Ib):

[0179] (Ia) and (Ib).

[0180] In one embodiment, the present disclosure provides a compound selected from Examples 1-25 (as shown in Table 1) and Examples 26-50 (as shown in Table 2) and having the trans relative stereochemistry represented in Formula (Ia).

[0181] In one embodiment, the present disclosure provides a compound selected from Examples 1-25 (as shown in Table 1) and Examples 26-50 (as shown in Table 2) and having the trans relative stereochemistry represented in Formula (Ib).

[0182] definition

[0183] Unless otherwise specified, the terms used herein have their customary meanings in the art. The organic moieties mentioned in the definitions of the variables of the compounds of formulae (I), (Ia), and (Ib), like the term halogen, are collective terms for individual lists of the members of the respective groups. The prefix Cn-Cm (or Cn-m) in each case indicates the possible number of carbon atoms in the group in question.

[0184] As used herein, the term "animal" includes all mammals, birds, and fish, as well as all vertebrates. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. It also includes individual animals at all stages of development, including embryonic and fetal stages. In some embodiments, the animal will be a non-human animal.

[0185] The term "enriched" refers to a weight:weight ratio of at least about 1.05 or greater in favor of the enantiomer that exhibits significant in vitro and in vivo activity (the eutomer).

[0186] In one embodiment, the compounds of the present disclosure are selective JAK1 inhibitors relative to JAK2. For a given JAK1 inhibitory compound, the determination of relative selectivity is defined as (JAK2 IC 50 Value / JAK1 IC 50 In one embodiment, for a given compound, (JAK2 IC 50 Value / JAK1 IC 50 In yet another embodiment, for a given compound, the relative ratio of (JAK2 IC 50 Value / JAK1 IC 50 In another embodiment, the relative ratio of the JAK2 IC values ​​is at least 5. 50 / JAK1 IC 50 The relative ratio of JAK2 to IC is preferably at least 10. 50 / JAK1 IC 50 The ratio is greater than 10.

[0187] The term "treating" includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.

[0188] "Therapeutically effective amount" means the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0189] The term "composition" as used in the context of a pharmaceutical composition is intended to encompass a product comprising an active ingredient and an inert ingredient (a pharmaceutically acceptable excipient) constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present disclosure include any composition prepared by mixing a compound of Formula (I), (Ia), and (Ib), or a mixture thereof, with a pharmaceutically acceptable excipient.

[0190] The term "optionally substituted" means "unsubstituted or substituted," thus, the general formulae described herein encompass compounds containing the specified optional substituents as well as compounds without the specified optional substituents.

[0191] When referring to the compounds disclosed herein, the following terms have the following meanings unless otherwise indicated. The following definitions are intended to clarify, not to limit, the defined terms. If a particular term is not specifically defined as used herein, the term should not be considered ambiguous. Instead, the term is used within the scope of its generally accepted meaning.

[0192] As used herein, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The hydrocarbon chain can be straight or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Similarly, "alkenyl" refers to an alkyl group having one or more double bonds in the chain, and "alkynyl" refers to an alkyl group having one or more triple bonds in the chain.

[0193] As used herein, "halogen" or "halo" refers to halogen. In some embodiments, halogen is preferably Br, Cl or F.

[0194] As used herein, "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, wherein at least one hydrogen atom is replaced by a halogen, including but not limited to a perhalogenated group in which all hydrogen atoms are replaced by halogen atoms. The haloalkyl chain can be straight or branched. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, "haloalkenyl" refers to a haloalkyl group having one or more double bonds in the chain, while "haloalkynyl" refers to a haloalkyl group having one or more triple bonds in the chain.

[0195] Furthermore, an "alkylene" linker group refers to a divalent alkyl group, i.e., (CH2) x , wherein x is 1 to 20, preferably 1 to 8, preferably 1 to 6, more preferably 1 to 3.

[0196] As used herein, "hydroxyalkyl" refers to an alkyl group as defined herein that is substituted with one or more -OH groups. Similarly, "hydroxyalkenyl" refers to a hydroxyalkyl group having one or more double bonds in the chain, and "hydroxyalkynyl" refers to a hydroxyalkyl group having one or more triple bonds in the chain.

[0197] As used herein, "aryl" refers to a substituted or unsubstituted carbocyclic aromatic ring system, whether pendant or fused, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indane or biphenyl. Preferred aryl is phenyl.

[0198] As used herein, "cycloalkyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and partially saturated forms thereof such as cyclohexenyl and cyclohexadienyl. In addition, bridged rings, such as adamantane, are also included in the definition of "cycloalkyl."

[0199] As used herein, the term "heterocyclyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms, wherein one or more carbon atoms are replaced by a heteroatom selected from O, N, S or Si, wherein each N, S and Si can be oxidized, and wherein each N can be quaternized. A heterocyclyl group can be attached to the rest of the molecule through a heteroatom. Heterocyclyl groups do not include heteroaryl groups.

[0200] As used herein, the term "heteroaryl" or "heteroaromatic" refers to an aromatic ring group having 5 to 14 ring atoms selected from carbon and at least one (typically 1-4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, sulfur, or silicon). They include monocyclic and polycyclic rings in which a monocyclic heteroaromatic ring is fused to 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), isobutyl pyridyl (e.g., 4-imidazolyl, 5-imidazolyl), cyclopentyl (e.g., cyclopentyl), isobutyl pyrid ... Azolyl (e.g. 3-iso oxazolyl, 4-iso Azolyl, 5-iso oxazolyl), Oxazolyl (e.g. 2- oxadiazole, 5- Oxazolyl), Azolyl (e.g. 2- Azolyl, 4- Azolyl, 5- 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyridyl (e.g., 2-pyrrolyl, 3-pyrrolyl, 4-pyridyl), pyrimidyl (e.g., 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of monocyclic six-membered nitrogen-containing heteroaryl groups include pyrimidyl, pyridyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzo oxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl or benzisoquinolyl Azolyl.

[0201] The terms "arylalkyl," "heteroarylalkyl," and "heterocyclylalkyl" refer to groups in which an aryl, heteroaryl, or heterocyclyl group is attached via an alkyl group. Examples include benzyl, phenethyl, pyridylmethyl, and the like. The term also encompasses alkyl linker groups in which a carbon atom, such as a methylene group, has been replaced by, for example, an oxygen atom. Examples include phenoxymethyl, pyridin-2-yloxymethyl, 3-(naphthalen-1-yloxy)propyl, and the like. Similarly, the term "benzyl," as used herein, refers to a group in which a phenyl group is attached to a CH2 group, thus a CH2Ph ​​group. A benzyl group may be substituted or unsubstituted. The term substituted benzyl refers to a group in which the phenyl group or CH2 contains one or more substituents. In one embodiment, the phenyl group may have from 1 to 5 substituents, or in another embodiment, from 2 to 3 substituents.

[0202] As used herein, "optionally substituted" refers to the replacement of an otherwise existing hydrogen atom with a substituent. When discussing ring systems, optional substitution typically refers to the replacement of a normally existing hydrogen with one, two, or three substituents. However, when referring to straight and branched moieties, the number of substitutions may be greater and may occur wherever a hydrogen is present. The substitutions may be the same or different.

[0203] Exemplary substituents (wherein multiple substituents can be the same or different) include halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O) (alkyl substituted with one or more of halogen, haloalkyl, NH2, OH, SH, CN, and NO2), 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, NHCO2 H, 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', Si(R')3, each of the foregoing can be connected by a divalent alkylene linker (CH2)x, where x is 1, 2 or 3. In embodiments where a saturated carbon atom is optionally substituted with one or more substituents, the substituents may be the same or different and further include =0, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =N-CN, =NH, or =NR'. For each of the foregoing, each may be linked by an alkylene linker (CH2)x, where x is 1, 2, or 3. R' is the same or different at each occurrence and, in some embodiments, represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, in some embodiments, when two R' are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing 4 to 6 ring atoms.

[0204] As used herein, the phrases veterinary or veterinary or pharmaceutical or pharmaceutically acceptable salt refer to any salt of the compounds disclosed herein that retains its biological properties and has no toxic or other adverse effects for veterinary or pharmaceutical use. The general usage of the terms pharmaceutical or pharmaceutically is also intended to apply to veterinary or veterinary use. Where the context permits, the terms can be used interchangeably.

[0205] Such salts can be derived from various organic and inorganic counterions known in the art. Such salts include those with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethyl ester ... Acid addition salts formed by acids such as 1,2-dimethylthiocarbamate, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinic acid, and mucofuric acid.

[0206] Salts also include, by way of example only, salts of non-toxic organic or inorganic acids, for example, halides such as chlorides and bromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandelates, phthalates, laurates, Salt, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate, mucofurate, etc.

[0207] Examples of inorganic bases useful for forming 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.

[0208] Examples of organic bases useful for forming base addition salts include, but are not limited to, metal alkoxides such as lithium, sodium, and potassium alkoxides, including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium hydroxides such as choline hydroxide; and amines including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, aromatic amines, heteroaromatic amines, basic amino acids, amino sugars, and polyamines.

[0209] The base can be a quaternary ammonium hydroxide, wherein one or more alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that can be used according to the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide, preferably choline hydroxide. The alkylamine base can be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that can be used according to the present disclosure include methylamine, ethylamine, diethylamine and triethylamine. Substituted alkylamine bases can be substituted with one or more hydroxyl groups, preferably 1 to 3 hydroxyl groups. Non-limiting examples of substituted alkylamine bases that can be used according to the present disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (diethanolamine), tromethamine, ethanolamine and diethanolamine.

[0210] Stereoisomers and polymorphs

[0211] In some cases, the depicted substituents may give rise to optical isomers and / or stereoisomerism. Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or in the arrangement of their atoms in space, are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers." When a compound has an asymmetric center, such as when it is bonded to four different groups, a pair of enantiomers is possible. Molecules with at least one stereocenter can be characterized by the absolute configuration of their asymmetric center and designated as (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 (Errata: Angew. Chem., Int. Ed. Engl. 5: 511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: 657-668), or can be characterized by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., a (+)- or (-)-isomer, respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture."

[0212] In certain embodiments, the compounds disclosed herein may have one or more asymmetric centers, and thus such compounds may be produced as racemic mixtures, enantiomerically enriched mixtures, or as individual enantiomers. Unless otherwise indicated, for example by specifying stereochemistry at any position in the formula, the description or naming of a particular compound in this specification and claims is intended to include individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0213] In certain embodiments, the compounds disclosed herein are "stereochemically pure." A stereochemically pure compound has a level of stereochemical purity that one skilled in the art would consider "pure." Of course, such purity levels may be less than 100%. In certain embodiments, "stereochemically pure" refers to a compound that is substantially (i.e., at least about 85% or more) free of alternative isomers. In specific 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.

[0214] In addition, the compounds disclosed herein ("active agents") may exist as hydrates or solvates, wherein a stoichiometric amount of water or solvent is associated with the molecule in a crystalline form. The compositions disclosed herein may include hydrates and solvates of the active agents. In some embodiments, the compositions disclosed herein may include up to 15% (w / w), up to 20% (w / w), or up to 30% (w / w) of a particular solid form.

[0215] As used herein, the terms "subject" and "patient" are used interchangeably herein. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal, such as a dog or cat. In another embodiment, the subject is an animal, such as a sheep, a cow, a horse, a goat, a fish, a pig, or poultry (e.g., a chicken, a turkey, a duck, or a goose). In another embodiment, the subject is a primate, such as a monkey, such as a cynomolgus monkey, or a chimpanzee.

[0216] In addition, the present disclosure also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I), formula (Ia) and formula (Ib). A pharmaceutically acceptable prodrug refers to a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solvent decomposition or under physiological conditions. Examples of groups forming prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198. Throughout this specification, the term prodrug is used to describe any pharmaceutically acceptable form of a compound that provides an active compound after administration to a patient. A pharmaceutically acceptable prodrug refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of the present disclosure. Typical examples of prodrugs include compounds having a biologically unstable protective group on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.

[0217] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds of the present disclosure include isotopes of hydrogen such as 2 H and 3 H, carbon isotopes such as 11 C. 13 C and 14 C. Isotopes of chlorine, e.g. 36 Isotopes of Cl and fluorine, such as 18 F, Iodine isotopes such as 123 I and 125 I. Isotopes of nitrogen such as 13 N and 15 N, oxygen isotopes such as 15 O. 17 O and 18 O, phosphorus isotopes such as 32 P and sulfur isotopes such as 35 Certain isotopically labeled compounds of the present disclosure, for example compounds incorporating radioactive isotopes, are useful in tissue distribution studies of drugs or substances. 3 H) and carbon-14 (i.e. 14C) is particularly suitable for this purpose because of its ease of incorporation and readily available means of detection. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. 11 C. 18 F. 15 O and 13 N substitution may facilitate positron emission topographies (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously used. In one aspect, the present disclosure provides a method for preparing compounds of any embodiment of Formula (I), Formula (Ia), and Formula (Ib) as described herein.

[0218] Compositions and methods of administration

[0219] In certain embodiments, the compounds of Formula (I), (Ia), and (Ib) used in the methods disclosed herein can be administered using veterinary or pharmaceutical compositions comprising at least one compound of Formula (I), (Ia), and (Ib) (in salt form, where appropriate), alone or in combination with one or more compatible and veterinary or pharmaceutically acceptable carriers (e.g., diluents or adjuvants) or another pharmaceutical agent. The present invention provides compositions comprising compounds of Formula (I), (Ia), and (Ib), or derivatives of their salts, and an acceptable excipient, carrier, or diluent. The compositions can also take various forms, including, but not limited to, oral formulations, injectable formulations, and topical, dermal, or subcutaneous formulations. The specific route chosen by the practitioner depends on a variety of factors, such as the physicochemical properties of the drug or therapeutic agent, the condition of the host, and economic factors.

[0220] In one aspect, the present disclosure provides a method of treating a patient suffering from a disease or disorder sensitive to modulation of a JAK, comprising administering a therapeutically effective amount of a compound described herein, including any embodiment of a compound according to Formula (I), (Ia), or (Ib).

[0221] In one embodiment, the present disclosure provides a method of treating a patient suffering from a disease or disorder that can be ameliorated by selective inhibition of the Janus kinase JAK 1 relative to JAK 2.

[0222] In one embodiment, the present disclosure provides a method of treating a patient suffering from a disease or disorder using a therapeutically effective amount of a compound that is an embodiment of Formula (I), Formula (la), and Formula (lb), wherein the disease or disorder is one or more of atopic dermatitis, flea allergy dermatitis, eczema, pruritus, 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, secondary hypereosinophilic syndrome (HES), allergy, atopic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer.

[0223] In one embodiment, the present disclosure provides a method of treating a patient as described above, wherein the disease or disorder is one or more of atopic dermatitis, flea allergy dermatitis, psoriasis, and rheumatoid arthritis.

[0224] According to one embodiment, the present disclosure provides a method of treating a patient suffering from a disease or disorder sensitive to modulation of JAK, comprising administering a compound according to the invention in an amount that disrupts an immunomodulatory pathway in a cell. In one such embodiment, the disruption results in an effect on the JAK-STAT pathway.

[0225] In one aspect, the present disclosure provides a method of inhibiting JAK in a mammalian cell, the method comprising contacting the mammalian cell with a compound according to any embodiment of Formula (I), (Ia) or (Ib). In certain embodiments, the mammalian cell is a cell from a subject with an inflammatory condition.

[0226] In one aspect, the present disclosure provides a composition comprising a compound according to any embodiment of Formula (I), Formula (la) and Formula (lb) and a pharmaceutically or veterinarily acceptable carrier.

[0227] The composition can be in a form suitable for oral administration, for example as a dietary supplement, lozenge, buccal tablet, chewable tablet, tablet, hard or soft capsule, emulsion, aqueous or oily suspension, aqueous or oily solution, dispersible powder or granule, syrup or elixir. The composition for oral use can be prepared according to any method known in the art for preparing veterinary or pharmaceutical compositions, and such compositions can contain one or more agents selected from sweeteners, bittering agents, flavorings, coloring agents and preservatives to provide a preparation that is particular about palatability. In some cases, it is convenient and efficient to orally administer veterinary drugs by placing the therapeutic agent in a solid or liquid matrix suitable for oral delivery. These methods include chewing drug delivery formulations. The problem associated with administering oral formulations to animals is that the therapeutic agent typically provides unpleasant taste, fragrance or texture, causing the animal to reject the composition. This situation is further exacerbated because the composition is hard and difficult to swallow.

[0228] Oral veterinary compositions in the form of palatable soft chewable compositions ("soft chews") or chewable tablets are often convenient to administer to certain animals, particularly cats and dogs, and can be effective for administering veterinary drugs to these animals. However, many oral compositions containing active agents with a bitter or unpleasant taste are not well tolerated by cats and dogs. Furthermore, when the bioavailability of the active agent from the oral dosage form is insufficient or variable, the required exposure of the active ingredient to the animal may be insufficient to provide the desired therapeutic effect. Issues such as these often result in low or suboptimal efficacy and parasite control.

[0229] Chewable dosage forms for drug delivery are well known in pharmaceutical technology. The act of chewing is known in the pharmaceutical industry to increase the surface area of ​​the available active ingredient and may improve the absorption rate of the digestive tract. In the case where it is necessary to make the active ingredient locally available in the oral cavity or throat area to produce a local effect and / or systemic absorption, a chewable system is also advantageous. In addition, chewable dosage forms are also used to facilitate the administration of drugs for pediatric and elderly patients. Examples of chewable dosage forms can be found in U.S. Patents 6,387,381, 4,284,652, 4,327,076, 4,935,243, 6,270,790, 6,060,078, 4,609,543 and 5,753,255, all of which are incorporated herein by reference.

[0230] When providing a dosage form or matrix for an active drug or pharmaceutical, palatability and "mouthfeel" are important characteristics to consider. Unfortunately, many drugs and other active ingredients have a bitter or other unpalatable taste or unacceptable mouthfeel due to the gritty or chalky feel of the compound, or both. These characteristics make it difficult to incorporate such active ingredients into chewable dosage forms of the current state of the art, as the objectionable taste and / or mouthfeel make it unlikely that users will comply. Oral veterinary dosage forms that are unpalatable to the animals being treated result in low animal acceptance of the drug and low compliance. Therefore, there is a need for improved oral veterinary dosage forms that are palatable and widely accepted by the animals being treated.

[0231] Another challenge with oral veterinary compositions, particularly soft chew compositions, is that the release and dissolution of the active agent from the composition after ingestion by the animal can be variable and incomplete. This results in variability in the amount of drug absorbed from the animal's digestive tract.

[0232] US Patent No. 7,955,632, incorporated herein by reference, describes palatable, edible soft chewable pharmaceutical vehicles and methods for their preparation for delivering pharmaceutically acceptable active ingredients to animals.

[0233] Additionally, US 2004 / 0037869 A1, US 2004 / 0151759 A1, WO 2005 / 062782, and WO 2004 / 016252 to Cleverly et al. (incorporated herein by reference) describe chewable veterinary formulations and tablets containing at least one pharmaceutically active agent, and WO 2009 / 02451 A2 and US 2011 / 0059988 to Heckeroth et al. describe various compositions for oral administration to animals (all incorporated herein by reference).

[0234] Traditionally, palatability has been achieved in veterinary formulations by incorporating animal by-products or animal-derived flavorings into the formulation. For example, excipients such as chicken meal, liver meal, beef, ham, fish, or rawhide-derived products are often included in dog chews to make the chews appealing and palatable to dogs. See, for example, U.S. Patents 6,086,940, 6,093,441, 6,159,516, 6,110,521, 5,827,565, and 6,093,427, all to Axelrod et al. (each incorporated herein by reference).

[0235] Particularly palatable soft chew oral veterinary compositions that provide high bioavailability of the active agent are described in US Pat. No. 9,259,417; US Pat. No. 9,233,100; US Pat. No. 9,931,320; US Pat. No. 10,596,156, all to Soll et al., each incorporated herein by reference.

[0236] Lozenges are solid compositions containing one or more active ingredients that are designed to dissolve or disintegrate slowly in the mouth, either passively by incubation in the mouth or actively by sucking or chewing. They can be used for systemic action if the drug is absorbed through the lining of the mouth or esophagus or swallowed. In particular, soft lozenges can be chewed or allowed to dissolve slowly in the mouth. These dosage forms offer the advantages of flavoring and are therefore easy to administer to both human and animal patients; formulations are easily adaptable and can be patient-specific; can deliver precise amounts of active ingredients to the oral cavity and digestive system; and allow the drug to remain in contact with the oral or esophageal lumen for extended periods of time.

[0237] Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrant agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period.

[0238] Formulations for oral use may be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. The capsules may also be soft gelatin capsules in which the active ingredient is mixed with water or a miscible solvent such as propylene glycol, PEG and ethanol, or with an oil medium such as peanut oil, liquid paraffin or olive oil.

[0239] The composition can also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil or a mineral oil such as liquid paraffin, or a mixture of these oils. Suitable emulsifiers can be naturally occurring phosphatides, such as soybean lecithin, lecithin, and esters or partial esters derived from fatty acids and hexanol anhydride such as sorbitan monooleate, and condensation products of the partial ester and ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, bittering agents, flavorings, and preservatives.

[0240] In one embodiment of the formulation, the composition takes the form of a microemulsion. Microemulsions are well-suited as liquid carrier vehicles. Microemulsions are quaternary systems consisting of an aqueous phase, an oil phase, a surfactant, and a cosurfactant. They are translucent, isotropic liquids. Microemulsions consist of a stable dispersion of aqueous phase droplets in an oil phase, or conversely, a stable dispersion of oil phase droplets in an aqueous phase. These droplets are less than 200 nm in size (1,000 to 100,000 nm for emulsions). The interfacial film, composed of alternating surfactant molecules (SA) and cosurfactant molecules (co-SA), allows the spontaneous formation of the microemulsion by reducing interfacial tension. In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, unsaturated polyglycolyzed glycerides or triglycerides, or 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, such as C8-C 10 Caprylic / capric triglyceride. In another embodiment, the oil phase will comprise a % v / v range selected from about 2 to about 15%, about 7 to about 10%, and about 8 to about 9% v / v of the microemulsion. The aqueous phase comprises, for example, water or a glycol derivative such as propylene glycol, glycol ether, polyethylene glycol, or glycerol. In one embodiment of a glycol derivative, the glycol is selected from propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Typically, the aqueous phase comprises about 1 to about 4% v / v of the microemulsion. Surfactants used in microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyethylene glycol-C8 ... 10 Glyceride or polyglycerol-6-dioleate.Except these surfactants, the cosurfactant comprises short chain alcohols, for example ethanol and propyl alcohol.Some compound is that the three components discussed above for example water, surfactant and cosurfactant are total.Yet, use different compounds for every kind of component of same preparation, within the skill level of practitioner completely.In one embodiment, for example, for the amount of surfactant / cosurfactant, the ratio of cosurfactant and surfactant can be about 1 / 10 to about 1 / 2.In another embodiment of the amount of cosurfactant, there will be about 25 to about 75% v / v surfactant and about 10 to about 55% v / v cosurfactant in the described microemulsion.

[0241] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as sucrose, saccharin or aspartame, bittering agents and flavorings may be added to provide a palatable oral formulation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid or other known preservatives.

[0242] Aqueous suspensions can contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersants or wetting agents can be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols (such as heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners and / or bittering agents, such as those described herein.

[0243] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, such as sweeteners, bittering agents, flavorings, and coloring agents, may also be present.

[0244] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulsifiers, preservatives, flavoring and coloring agents.

[0245] The composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned above. Sterile injectable formulations can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol, or polyethylene glycol can also be used. Preservatives such as phenol or benzyl alcohol can be used.

[0246] In addition, sterile, fixed oils are generally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injections.

[0247] Topical, dermal and subdermal formulations may include lotions, creams, ointments, gels or pastes.

[0248] Organic solvents that can be used include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butylene glycol, 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 glycol, 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.

[0249] As a vehicle or diluent, the composition of the present disclosure may include vegetable oils, such as but not limited to soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils, such as but not limited to petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons, or medium chain (such as C8-C 12 ) triglycerides.

[0250] Dosage forms may contain from about 0.5 mg to about 5 g of active agent.

[0251] In one embodiment of the present disclosure, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight / volume.

[0252] The compounds of formula (I), formula (a) and formula (IVb) can be used as such or in combination in the form of their preparations or formulations.

[0253] Compounds of Formula (I), (Ia), and (Ib) according to the present disclosure may be combined with one or more agents having the same spectrum of activity, for example, to increase activity, or with agents having another spectrum of activity, for example, to broaden the spectrum of activity. For example, combinations of compounds of Formula (I) (or (Ia) and (Ib)) with one or more additional JAK inhibitors or JAK / signal transducer and activator of transcription (JAK / STAT) modulators may provide therapeutic advantages. Examples of JAK inhibitors that can be used as combination agents include baricitinib, ruxolitinib, filgotinib, CYT387, upadacitinib, fidartinib, peftinib, lestaurtinib, paritinib, oclacitinib, seletinib, and tofacitinib.

[0254] The compounds of Formula (I), (Ia), and (Ib) according to the present disclosure may be combined with one or more additional pharmaceutical or veterinary active agents. Other active agents that can be used in combination with the compounds of Formula (I), (Ia), or (Ib) in the methods provided herein include, but are not limited to, disease-modifying antirheumatic drugs (DMARDs, such as cyclosporine A and methotrexate), anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, mycophenolate mofetil, biologics, TNF-α inhibitors (such as etanercept), Cox-2 inhibitors (such as firocoxib), and analgesics. These agents may include, but are not limited to, cyclosporine A such as Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate mofetil such as Cellcept®, azathioprine such as Imuran®, daclizumab such as Zenapax®, OKT3 such as Orthocolone®, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids such as prednisolone or dexamethasone.

[0255] In some embodiments, the second active agent may include, but is not limited to, an anti-inflammatory drug, such as an NSAID, including but not limited to diclofenac (e.g., ARTHROTEC®), diflunisal (e.g., DOLOBID®), and ® ), etodolac (e.g., LODINE®), fenoprofen (e.g., NALPON®), ibuprofen (e.g., ADVIL®, ADVIL / MOTRIN® for children, MEDIPREN®, MOTRIN®, or PEDIACARE FEVER®), indomethacin (e.g., ARTHREXIN®), ketoprofen (e.g., ORUVAIL®), ketorolac (e.g., TORADOL®), fosfomycin tromethamine (e.g., MONURAL®), meclofenamic acid (e.g., MECLOMEN®), and fenamic acid. ® ), nabumetone (e.g., RELAFEN®), naproxen (e.g., ANAPROX ® ANAPROX ® DS, EC-NAPROSYN®, NAPRELAN ® or NAPROSYN®), oxaprozin (such as DAY PRO®), piroxicam (such as FELDENE®), sulindac (such as CLINORIL®), and tolmetin (such as TOLECTIN® DS or TOLECTIN®).

[0256] In other embodiments, the second active agent may include, but is not limited to, disease-modifying antirheumatic drugs (e.g., DMARDs) or immunosuppressants such as, but not limited to, methotrexate (e.g., RHEUMATREX®), sulfasalazine (e.g., AZULFIDINE®), and cyclosporine (e.g., SANDIMMUNE®). ® or NEROAL®; and includes cyclosporine A).

[0257] In other embodiments, the second active agent may include, but is not limited to, mycophenolate mofetil (e.g., CellCept®), an immunosuppressant widely used in organ transplantation and increasingly popular for the treatment of autoimmune and inflammatory skin disorders.

[0258] In other embodiments, the second active agent can include, but is not limited to, biologics such as etanercept (e.g., ENBREL®), infliximab (e.g., REMICADE®), and adalimumab (e.g., HUMIRA®).

[0259] In other embodiments of interest, the second active agent can include, but is not limited to, Cox-2 inhibitors such as celecoxib (e.g., CELEBREX®), filoxib (e.g., PREVICOX®), valdecoxib (e.g., BEXTRA®), and meloxicam (e.g., MOBIC®, METACAM®).

[0260] In other embodiments, the second active agent may include a veterinary therapeutic agent known in the art (see, for example, Plumb's Veterinary Drug Handbook, 5th edition, Donald C. Plumb, ed., Blackwell Publishing, (2005) or The Merck Veterinary Manual). Veterinary Manual, 9th Edition, (January 2005), including but not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetylhydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, salbutamol sulfate, alfentanil, allopurinol, alprazolam, nalprogesterone, amantadine, amikacin sulfate, aminocaproic acid, aminovaleramide bisulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, clavulanate potassium, amphotericin B deoxycholate, Lipid-based amphotericin B, ampicillin, amprolium, antacids (oral), antivenom, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth salicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budesonide, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, tricalcitonin Alcohol, calcium salt, captopril, carbenicillin indane sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, ceftriaxone sodium, cefotetan disodium, cefxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporin, cefapirin, charcoal (active), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide, clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisplatin Priligy, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, adrenocorticotropic hormone (ACTH), teicosin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deserelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone,Dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium, edetate calcium, edrophonium chloride, enalapril / enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin Ding, ethacryl, erythromycin, esmolol, estradiol cypionate, ethacrynic acid / ethacrynic acid sodium, ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasia drugs containing pentobarbital, famotidine, fatty acids (essential / omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / cartilage sulfate glutamine, glyburide, glycerol (oral), glycopyrrolate, gonadorelin, griseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin, hydroxyethyl starch, sodium hyaluronate, hydralazine, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imipenem-cilastatin sodium, imipramine, amrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium / potassium), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, Ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), chlorfenuron, lysine, magnesium, mannitol, marbofloxacin, nitrogen mustard, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelic acid / hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole,Mexiletine, mibolone, midazolam-milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mannolone decanoate, naproxen, narcotic (opioid) agonist analgesics, neomycin sulfate, neostigmine, nicotinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, opioid antidiarrheals drugs, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancrelipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine, general information penicillin, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphates, phytonadione Quinone / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, patozuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic gel, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampicin, s-adenosine methylphenidate Methionine (SAMe), saline / hyperosmolar laxatives, silamectin, selegiline / l-propenylamine, sertraline, sevelamer, sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozotocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyrifos sodium, sulfadiazine / trimethoprim, sulfamethoxazole, Trimethoprim / sulfamethoxazole, sulfadimethoxine, sulfadimethoxine / ormeprim, sulfasalazine, taurine, tepoxaline, terbinafine, terbutaline sulfate, testosterone, tetracycline, sodium thiothiazide, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, tylosin, ticarcillin disodium, tiletamine / zolazepam, tilmicosin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid, topiramate, Tramadol, triamcinolone acetonide acetate, trientine, trilostane, alimamazine tartrate (with prednisolone), tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / sulfate, and zonisamide, and mixtures thereof.

[0261] These one or more other active agents can be administered as part of the same or separate dosage forms, by the same or different routes of administration, and on the same or different administration schedules, according to standard pharmaceutical practice known to those skilled in the art.

[0262] Pharmaceutical formulations comprising compounds of Formula (Ia), (Ib) and (I) for delivery to humans or other mammals are preferably in unit dosage form, wherein the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form can be a capsule, tablet, or lozenge per se, or any of these in a suitable number of packaged forms.

[0263] The amount of active ingredient in a unit dose formulation can be varied or adjusted between about 0.1 mg and about 1000 mg, depending on the specific application and the efficacy of the active ingredient. If desired, the composition may also contain other compatible therapeutic agents. In therapeutic applications for treating or alleviating inflammation, autoimmune diseases, and cancer in humans or other mammals, the compound used in the method of treatment is administered at an initial dose of about 0.1 mg / kg to about 100 mg / kg per interval, about 0.1 mg / kg to about 50.0 mg / kg per interval, about 0.1 mg / kg to about 10.0 mg / kg per interval, about 0.1 mg / kg to about 5.0 mg / kg per interval, about 0.1 mg / kg to about 2.5 mg / kg per interval, about 0.1 mg / kg to about 2.0 mg / kg per interval, about 0.1 mg / kg to about 1.0 mg / kg per interval, about 0.4 mg / kg to about 1.0 mg / kg per interval, or about 0.4 mg / kg to about 0.6 mg / kg per interval. Preferred intervals may be daily, weekly, monthly, quarterly, semi-annually or annually.

[0264] The dosage can be varied according to the patient's requirements, such as the size of the person or mammal being treated, the severity of the disease being treated, the route of administration, and the effectiveness of the compound being administered. It is within the practitioner's skill to determine the dosage and route of administration suitable for the specific circumstances. Typically, treatment will begin with a smaller dose that is less than the optimal dose of the compound, which can be increased in small increments until the best effect is achieved in a particular case. For convenience, the total daily dose can be divided into multiple portions and administered in divided doses throughout the day, if desired.

[0265] In therapeutic use, compounds of Formula (Ia), (Ib) and (I) can be used to prepare a medicament for use in a method for treating any indication requiring inhibition of JAK, including but not limited to cancer, neuroinflammation, inflammatory airway disease, ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and atopic dermatitis. In one or more embodiments, one or more compounds of Formula (Ia), (Ib) and (I) can be used to treat one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behçet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous 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, secondary eosinophilic syndrome (HES), allergies, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis and cancer. One route of administration can be oral. One route of administration can be topical.

[0266] In one aspect, the present disclosure provides a method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, comprising administering to a subject in need thereof an effective amount of a compound that is an embodiment of Formula (I), (Ia), or (Ib) herein.

[0267] In one embodiment, the present disclosure provides a method for treating atopic dermatitis, flea allergy dermatitis, psoriasis, or rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound that is an embodiment of Formula (I), (Ia), or (Ib). In one embodiment, the compound is administered orally; in one embodiment, the compound is administered parenterally; in one embodiment, the compound is administered topically.

[0268] In one embodiment, the present disclosure provides a method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, comprising administering to a subject in need thereof an effective amount of a compound according to any embodiment of Formula (I), (Ia), or (Ib) herein, wherein the subject is a mammal.

[0269] In one embodiment, the present disclosure provides a method for treating one or more diseases or disorders in inflammation, autoimmune dysfunction and cancer, comprising administering an effective amount of a compound according to any embodiment of Formula (I), (Ia) or (Ib) herein to a subject in need thereof, wherein the subject is selected from one or more of livestock mammals, domesticated mammals and companion animals. In one embodiment, the mammal is one or more of humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs and cats. In one embodiment, the mammal is humans, dogs or cats.

[0270] In one aspect, the present disclosure provides a compound for use in a medicine, wherein the compound is an embodiment of formula (I), (Ia) or (Ib) herein. In another aspect, the present disclosure provides the use of a compound according to any embodiment of any one of formula (I), (Ia) and (Ib) herein for the preparation of a medicine for treating one or more diseases or disorders in inflammation, autoimmune dysfunction and cancer. In one embodiment, the present disclosure provides the use of a compound according to any embodiment of formula (I), (Ia) or (Ib) herein for the preparation of a medicine for treating a disease or disorder that can be improved by selective inhibition of Janus kinase JAK 1 relative to JAK 2. In one embodiment, the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis or rheumatoid arthritis. In one aspect, the present disclosure provides the use of a compound according to an embodiment of formula (I), (Ia) or (Ib) herein and a second active agent for the preparation of a medicine for treating a disease or disorder that can be improved by selective inhibition of Janus kinase JAK 1 relative to JAK 2. In one aspect, the present disclosure provides the use of a compound according to an embodiment of Formula (I), (Ia) or (Ib) herein for treating one or more diseases or disorders selected from the group consisting of inflammation, autoimmune dysfunction and cancer. In one embodiment, the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis or rheumatoid arthritis.

[0271] The present disclosure explicitly encompasses the compounds described herein, including their salt forms. The present disclosure also encompasses those compounds presented herein, including their stereoisomers. In some embodiments, the compounds encompassed by the present disclosure include compounds selected from Table 1 and Table 2 described herein.

[0272] Compositions comprising a therapeutically acceptable amount of any compound described herein are within the scope of the present disclosure. The composition may further comprise a pharmaceutically or veterinarily acceptable excipient, diluent, carrier, or mixtures thereof. Such compositions may be administered to a subject in need thereof to treat or control a disease or disorder mediated, directly or indirectly, in whole or in part, by a JAK. As described herein, the composition may further comprise an additional active agent.

[0273] Example

[0274] Experimental procedure:

[0275] The following examples provide a more detailed description of the process conditions for preparing the compounds of the present disclosure. It should be understood, however, that the present disclosure is not intended to be limited to the details of the following schemes or modes of preparation, as fully described herein and set forth in the claims.

[0276] Certain abbreviations may be used in describing embodiments of the present disclosure. The abbreviations are considered to be consistently applied within the scope of commonly accepted usage by those skilled in the art.

[0277] Chemical Examples

[0278] In the following schemes, common substituents are represented with designations that may not be consistent with the disclosed formulae. The following schemes provide symbolic illustrations of such substituents, which should follow the schemes and do not apply to the disclosed formulae.

[0279] The following abbreviations are used in the chemical example schemes herein.

[0280] Abbreviations:

[0281]

[0282]

[0283] Common intermediate synthesis

[0284] Preparation of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile

[0285]

[0286] Preparation of 6-(p-Toluenesulfonyl)-6-azabicyclo[3.1.0]hexane

[0287]

[0288] Two reaction mixtures were run in parallel. To a mixture of cyclopentene (50 g, 734 mmol, 64.9 mL, 1 eq) and sodium [chloro(p-toluenesulfonyl)amino] (184 g, 807 mmol, 1.1 eq) in MeCN (2.5 L) at 25°C under N₂ was added phenyltrimethylammonium tribromide (27.6 g, 73.4 mmol, 0.1 eq) portionwise. The mixture was stirred at 25°C for 48 h. TLC indicated the reaction was complete. The combined reactions were combined and concentrated under vacuum to give a residue. The residue was quenched with H₂O (2 L) and extracted with EtOAc (1 L x 2). The combined organic phases were washed with brine (1 L), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to give 6-(p-toluenesulfonyl)-6-azabicyclo[3.1.0]hexane (125 g, 35.8% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz): 1.36 - 1.45 (m, 1 H) 1.57 - 1.69 (m, 3 H) 1.89 -2.00 (m, 2 H) 2.44 (s, 3 H) 3.33 (s, 2 H) 7.29 - 7.38 (m, 2 H) 7.81 (d, J=8.25 Hz, 2H).

[0289] Preparation of N-(trans)-2-cyanocyclopentyl)-4-methylbenzenesulfonamide

[0290]

[0291] Two reactions were performed in parallel. For each reaction, TMSCN (34.4 g, 347 mmol, 43.5 mL, 1.5 eq) and TBAF (1 M in THF, 46.3 mL, 0.2 eq) were added dropwise to a solution of 6-(p-toluenesulfonyl)-6-azabicyclo[3.1.0]hexane (55 g, 231 mmol, 1 eq) in THF (550 mL) at 20°C under N2. After the addition, the mixture was heated and stirred at 45°C for 16 h. TLC indicated the reaction was complete. The two reaction mixtures were combined, poured into H2O (1 L), and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 300 g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient @ 200 mL / min) to give N-(trans)-(2-cyanocyclopentyl)-4-methyl-benzenesulfonamide (100 g, 81.8% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz): δ = 7.82 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 5.64 (d, J=5.9 Hz, 1H), 3.76 (m, 1H), 2.84 (dt, J=8.5, 6.0 Hz, 1H), 2.45(s, 3H), 2.04-2.16 (m, 1H), 1.82-2.02 (m, 2H), 1.66-1.80 (m, 2H), 1.40-1.55ppm (m, 1H).

[0292] Preparation of tert-butyl ((trans)-2-cyanocyclopentyl)(toluenesulfonyl)carbamate

[0293]

[0294] To a solution of N-(trans)-(2-cyanocyclopentyl)-4-methyl-benzenesulfonamide (95 g, 359 mmol, 1 eq) in MeCN (1520 mL) at 20°C under N2 was added Boc2O (117 g, 539 mmol, 124 mL, 1.5 eq) and DMAP (13.1 g, 108 mmol, 0.3 eq). Following the addition, the mixture was heated at 45°C and stirred for 2 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient at 200 mL / min), affording tert-butyl ((trans)-2-cyanocyclopentyl)(tosyl)carbamate (130 g, 99.2% yield) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ= 7.87 (d, J=8.3 Hz, 2H), 7.33(d, J=8.1 Hz, 2H), 5.13 (m, 1H), 3.49-3.58 (m, 1H), 2.45 (s, 3H), 2.23-2.33(m, 1H), 2.11-2.20 (m, 2H), 1.89-2.00 (m, 2H), 1.76-1.87 (m, 1H), 1.36 ppm (s, 9H).

[0295] Preparation of tert-butyl ((trans)-2-cyanocyclopentyl)carbamate

[0296]

[0297] Three reactions were performed in parallel. To each solution of tert-butyl ((trans)-2-cyanocyclopentyl)-N-(p-toluenesulfonyl)carbamate (32 g, 87.8 mmol, 1 eq) in MeOH (480 mL) was carefully added Mg (14.9 g, 612 mmol, 7 eq) over 0.5 h at 20°C under N2. Following the addition, the reaction was stirred at 20°C for an additional 0.5 h. TLC indicated the reaction was complete. The three reaction mixtures were combined, diluted with DCM (500 mL), and poured into 1N aq. HCl (500 mL). The pH of the mixture was adjusted to 5 with 2N aq. HCl at 0°C and extracted with DCM (300 mL x 3). The organic phase was then washed with saturated aq. NaHCO₃ (100 mL x 3), and the combined organic layers were washed with brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl ((trans)-2-cyanocyclopentyl)carbamate (49 g, 88.4% yield) as a white solid. 1 HNMR (CDCl3, 400 MHz): δ = 4.12 (m, 1H), 2.82 (s, 1H), 2.06-2.20 (m, 2H), 1.88-2.00 (m, 1H), 1.81 (m, 2H), 1.38-1.50 ppm (m, 10H).

[0298] Preparation of (trans)-2-aminocyclopentanecarbonitrile hydrochloride

[0299]

[0300] To a mixture of tert-butyl ((trans)-2-cyanocyclopentyl)carbamate (62 g, 294 mmol, 1 eq) in EtOAc (900 mL) at 0°C was added HCl / EtOAc (4 M, 221 mL, 3 eq). The mixture was stirred at 20°C for 1 hour. A white solid formed after 30 minutes of reaction. TLC indicated the reaction was complete. The reaction mixture was filtered and the filter cake was concentrated in vacuo to afford (trans)-2-aminocyclopentanecarbonitrile hydrochloride (36 g, 66% yield) as a white solid. 1 H NMR (D2O-d6, 400 MHz) δ = 3.90 (m, 1H), 3.06 (m, 1H), 2.16-2.30 (m, 2H), 1.90-1.99(m, 1H), 1.80 (m, 2H), 1.62-1.73 ppm (m, 1H).

[0301] Preparation of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile

[0302]

[0303] To a mixture of 2,4-dichloro-5-methyl-pyrimidine (22.4 g, 136 mmol, 1 eq) and (trans)-2-aminocyclopentanecarbonitrile hydrochloride (20 g, 136.4 mmol, 1 eq) in DMA (200 mL) at 20°C was added DIEA (105 mmol, 818 mL, 6 eq). The mixture was heated at 140°C and stirred for 8 h. TLC indicated the reaction was complete. The reaction mixture was poured into H2O (1 L), whereupon a precipitate formed. The precipitate was filtered to afford (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (26 g, 80% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ = 7.84(s, 1H), 5.13 (m, 1H), 4.64-4.72 (m, 1H), 2.87-3.02 (m, 1H), 2.14-2.36 (m,2H), 1.96-2.06 (m, 4H), 1.88-1.93 (m, 2H), 1.61-1.72 (m, 1H).

[0304] Preparation of (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0305]

[0306] Preparation of 7-tosyl-7-azabicyclo[4.1.0]heptane

[0307]

[0308] Two reactions were performed in parallel. For each reaction, sodium [chloro(p-toluenesulfonyl)amino] (86.6 g, 380 mmol, 1.25 eq) and phenyltrimethylammonium tribromide (11.4 g, 30.4 mmol, 0.1 eq) were added to a mixture of cyclohexene (25 g, 304 mmol, 30.8 mL, 1 eq) in MeCN (500 mL) at 0°C. The mixture was then heated and stirred at 25°C for 16 h. TLC indicated the reaction was complete. The two parallel reactions were combined and the reaction mixture was quenched by adding water (200 mL) at 0°C, followed by extraction with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give 7-tosyl-7-azabicyclo[4.1.0]heptane (66 g, 43.1% yield) as a colorless oil. 1 H NMR (CDCl3-d 6, 400 MHz) δ 7.82 (d, J=8.3 Hz,2H), 7.33 (d, J=8.2 Hz, 2H), 2.98 (d, J=1.1 Hz, 2H), 2.45 (s, 3H), 1.79 (m,4H), 1.48 - 1.35 (m, 2H), 1.25 - 1.17 (m, 2H).

[0309] Preparation of N-((trans)-2-cyanocyclohexyl)-4-methylbenzenesulfonamide

[0310]

[0311] To a mixture of 7-(p-toluenesulfonyl)-7-azabicyclo[4,1,0]heptane (60 g, 238 mmol, 1 eq) in THF (600 mL) at 25°C was added TMSCN (35.5 g, 358 mmol, 1.5 eq) and TBAF (1 M in THF, 47.7 mL, 0.2 eq), and the mixture was stirred at 25°C for 2 hours. TLC indicated the reaction was complete. The reaction mixture was quenched by adding water (300 mL) at 0°C and then extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-((trans)-2-cyanocyclohexyl)-4-methylbenzenesulfonamide (70 g, crude) as a brown solid. 1H NMR (CDCl3-d 6, 400 MHz) δ 7.82 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.43-5.27 (m, 1H), 5.34 (br d, J =8.0 Hz, 1H), 3.39-3.35 (m, 1H), 2.67-2.65 (1H), 2.44 (s, 3H), 2.05-2.00 (m,1H), 1.98-1.87 (m, 1H), 1.69-1.62 (m, 2H), 1.37-1.29 (m, 2H).

[0312] Preparation of tert-butyl ((trans)-2-cyanocyclohexyl)-N-(p-toluenesulfonyl)carbamate

[0313]

[0314] Two reactions were performed in parallel. For each reaction, a mixture of N-((trans)-2-cyanocyclohexyl)-4-methyl-benzenesulfonamide (30 g, 107 mmol, 1 eq) in MeCN (300 mL) was added with Boc2O (35.2 g, 161 mmol, 1.5 eq) and DMAP (3.95 g, 32.3 mmol, 0.3 eq) at 20°C, and the mixture was then stirred at 40°C for 2 hr. TLC indicated the reaction was complete. The two parallel reactions were combined and quenched by adding water (300 mL) at 0°C, followed by extraction with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give tert-butyl ((trans)-2-cyanocyclohexyl)-N-(p-toluenesulfonyl)carbamate (72 g, 88% yield) as a white solid. 1 H NMR (CDCl3-d 6,400 MHz) δ 7.93 (d, J = 8.4 Hz, 2H), 7.32 (d,J = 8.0 Hz, 2H), 4.55-4.48 (m, 1H), 3.66-3.59 (m, 1H), 2.43 (s, 3H), 2.27-2.23 (m, 2H), 2.05-1.97 (m, 1H), 1.80-1.68 (m, 3H), 1.53-1.48 (m, 1H), 1.34(s, 9H), 1.33-1.22 (m, 1H).

[0315] Preparation of tert-butyl ((trans)-2-cyanocyclohexyl)carbamate

[0316]

[0317] Two reactions were performed in parallel. For each reaction, Mg (16.7 g, 687 mmol, 10 eq) was carefully added to a mixture of tert-butyl ((trans)-2-cyanocyclohexyl)-N-(p-toluenesulfonyl)carbamate (26 g, 68.7 mmol, 1 eq) in MeOH (300 mL) at 20°C. The mixture was then stirred at 20°C under N₂ for 0.5 h. TLC indicated the reaction was complete. The two parallel reactions were combined, and the mixture was diluted with DCM (500 mL) and poured into aq. HCl (1N, 500 mL). The pH was then adjusted to 5 with aq. HCl (2N) at 0°C, and the mixture was extracted with DCM (300 mL x 3). The organic phase was then washed with saturated aq. NaHCO₃. The combined organic layers were washed with brine (200 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give tert-butyl (trans)-2-cyanocyclohexyl)carbamate (28 g, 90% yield) as a white solid. 1 HNMR (CDCl3-d 6, 400 MHz) δ 4.64 (s, 1H), 3.69 (d, J = 6.0 Hz, 1H), 2.60 (s,1H), 2.15-1.96 (m, 2H), 1.81-1.61 (m, 3H), 1.47 (s, 9H), 1.42-1.22 (m, 3H).

[0318] Preparation of (trans)-2-aminocyclohexanecarbonitrile hydrochloride

[0319]

[0320] To a mixture of tert-butyl (trans)-2-cyanocyclohexyl)carbamate (38 g, 169 mmol, 1 eq) in EtOAc (100 mL) at 20°C was added HCl / EtOAc (4 M, 300 mL), and the mixture was stirred at 20°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give (trans)-2-aminocyclohexanecarbonitrile hydrochloride (27 g, 99.2% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.62 (s, 2H), 3.34 (s, 1H), 3.12-3.01 (m, 1H), 2.52 (d, J = 2.0 Hz, 1H), 2.13-2.00 (m, 2H), 1.74-1.55 (m, 3H), 1.50-1.22 (m, 3H).

[0321] Preparation of (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0322]

[0323] Two reactions were performed in parallel. For each reaction, 2,4-dichloro-5-methyl-pyrimidine (13.2 g, 80.9 mmol, 1 eq) and DIPEA (62.7 g, 485 mmol, 6 eq) were added to a mixture of (trans)-2-aminocyclohexanecarbonitrile hydrochloride (13 g, 80.9 mmol, 1 eq) in DMA (150 mL) at 20°C, and the mixture was then stirred at 140°C for 12 h. TLC indicated the reaction was complete. The two parallel reactions were combined and quenched by adding water (100 mL) at 0°C, followed by extraction with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (30 g, 73.9% yield) as a colorless oil. 1 H NMR (CDCl3-d 6,400 MHz) δ 7.87 (s, 1H), 4.86 (d, J = 8.0Hz, 1H), 4.44-4.30 (m, 1H), 2.85-2.75 (m, 1H), 2.17-2.15 (m, 2H), 2.02 (s,3H), 1.88-1.73 (m, 3H), 1.61-1.49 (m, 1H), 1.46-1.30 (m, 2H).

[0324] Preparation of (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0325]

[0326] Preparation of 7-Tosyl-3-oxa-7-azabicyclo[4,1,0]heptane

[0327]

[0328] Two reactions were performed in parallel. To a mixture of 3,6-dihydro-2H-pyran (100 g, 1.18 mol, 1 eq) in MeCN (2 L) under N₂ were added phenyltrimethylammonium tribromide (67 g, 179 mmol, 0.15 eq) and chloramine-T (406 g, 1.78 mol, 1.5 eq) portionwise. The mixture was then stirred at 25°C under N₂ for 12 hours. TLC indicated the reaction was complete. The combined reaction mixture was quenched by the addition of water (1 L) at 25°C and extracted with MTBE (2 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (1 L) at 25 °C for 2 h, then filtered, and the filtrate was concentrated under reduced pressure to give 7-tosyl-3-oxa-7-azabicyclo[4,1,0]heptane (750 g, crude) as a yellow oil.

[0329] Preparation of N-(trans)-(4-cyanotetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

[0330]

[0331] Six reactions were performed in parallel. To each solution of 7-tosyl-3-oxa-7-azabicyclo[4,1,0]heptane (100 g crude, 395 mmol, 1 eq) in THF (1 L) under N₂ was added portionwise TBAF (1 M in THF, 178 mL, 0.45 eq) and TMSCN (137 g, 1.4 mol, 173 mL, 3.5 eq). The mixture was then stirred at 70°C under N₂ for 3 hours. TLC indicated the reaction was complete. The six reaction mixtures were combined, quenched by the addition of H₂O (3 L) at 25°C, and extracted with EtOAc (3 L x 3). The combined organic layers were washed with brine (3 L x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give a crude product, which was triturated with MTBE (1 L) at 25 °C for 2 h and filtered to give N-(trans)-(4-cyanotetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide (320 g) as a yellow solid. 1 H NMR (CDCl 3, 400 MHz) δ=7.78 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 5.33 (d, J = 8.0 Hz, 1H), 3.85 (dd, J = 2.4, 12.0 Hz, 1H), 3.77 - 3.74 (m, 2H), 3.47 - 3.42 (m,1H), 3.36 - 3.32 (m, 1H), 3.06 - 3.03 (m, 1H), 2.45 (s, 3H), 2.23 - 2.16 (m,1H), 1.82 - 1.76 (m, 1H).

[0332] Preparation of tert-butyl ((trans)-(4-cyanotetrahydro-2H-pyran-3-yl)(tosyl)carbamate

[0333]

[0334] Four reactions were performed in parallel. To each solution of N-(trans)-(4-cyanotetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide (80 g, 285 mmol, 1 eq) in MeCN (600 mL) was added portionwise BocO (93 g, 428 mmol, 98 mL, 1.5 eq) and DMAP (10.5 g, 86 mmol, 0.3 eq) under N₂. The mixture was stirred at 40°C for 2 hours. TLC indicated the reaction was complete. The four reaction mixtures were combined, quenched by the addition of H₂O (2 L) at 25°C, and concentrated under reduced pressure to remove the MeCN. The mixture was then extracted with EtOAc (2 L x 3). The combined organic layers were washed with brine (2 L x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give tert-butyl ((trans)-(4-cyanotetrahydro-2H-pyran-3-yl)(tosyl)carbamate (300 g, 69.1% yield) as a yellow solid. 1 H NMR (CDCl 3, 400 MHz) δ = 7.91(d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.74 - 4.68 (m, 1H), 4.05 -3.89 (m, 4H), 3.41 - 3.34 (m, 1H), 2.45 (s, 3H), 2.17 - 2.08 (m, 2H), 1.36 (s, 9H).

[0335] Preparation of tert-butyl ((trans)-4-cyanotetrahydro-2H-pyran-3-yl)carbamate

[0336]

[0337] Six reactions were performed in parallel. To each solution of tert-butyl ((trans)(4-cyanotetrahydro-2H-pyran-3-yl)(tosyl)carbamate (50 g, 131 mmol, 1 eq) in MeOH (800 mL) was carefully added portionwise Mg (26 g, 1.1 mol, 8.2 eq) at 25°C. The resulting suspension was stirred at 25°C for 1 h with heat generation (exotherm) and bubbling. TLC showed the reaction was complete. The six reactions were combined and poured into ice water (2.5 L), then the pH was adjusted to 5 with aq. HCl (2N) and extracted with EtOAc (1.5 L x 3). The combined organic layers were washed with brine (3 L x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl ((trans)-4-cyanotetrahydro-2H-pyran-3-yl)carbamate (170 g, 95.5% yield). 1 H NMR (DMSO-d 6, 400 MHz) δ = 7.18 (d, J = 9.2 Hz,1H), 3.78 (m, 1H), 3.71 (dd, J = 4.4, 11.2 Hz, 1H), 3.57 - 3.54 (m, 1H), 3.23- 3.17 (m, 1H), 2.96 (t, J = 10.8 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.06 - 2.01(m, 1H), 1.83 - 1.72 (m, 1H), 1.39 (s, 9H).

[0338] Preparation of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (hydrochloride)

[0339]

[0340] To tert-butyl ((trans)-4-cyanotetrahydro-2H-pyran-3-yl)carbamate (170 g, 751 mmol, 1 eq) was slowly added HCl / EtOAc (4 M, 1.7 L) at 25°C. Following the addition, the reaction was stirred at 25°C for 1 hour. After a 30-minute reaction time, a solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to afford (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (91 g, 74.5% yield, HCl salt) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ = 8.74 (s, 3H), 3.89 (dd, J = 2.8, 12.0 Hz, 1H), 3.75-3.65 (m, 1H), 3.62-3.42 (m, 4H), 2.25 - 2.15 (m, 1H), 1.85 - 1.75 (m,1H).

[0341] Preparation of (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0342]

[0343] To a solution of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (82 g, 504 mmol, 1 eq, HCl) in DMA (1 L) was added DIPEA (391 g, 3.02 mol, 525 mL, 6 eq) and 2,4-dichloro-5-methyl-pyrimidine (82.5 g, 504 mmol, 1 eq), and the mixture was stirred at 135°C for 12 hours. TLC indicated the reaction was complete. The reaction mixture was quenched by adding H2O (4 L) at 20°C and then extracted with EtOAc (2 L x 3). The combined organic layers were washed with brine (2 L x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc (500 mL) at 20 °C for 12 hr to give (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (75 g, 58.9% yield) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ = 7.92 (s, 1H),7.27 (d, J = 8.4 Hz, 1H), 4.38 - 4.29 (m, 1H), 3.89 - 3.81 (m, 2H), 3.28-3.27(m, 1H), 3.23 - 3.16 (m, 1H), 3.10 (t, J = 10.8 Hz, 1H), 2.15 - 2.11 (m, 1H), 2.00 (s, 3H), 1.96 - 1.86 (m, 1H). The material (20 g) was separated by SFC (column: DAICELCHIRALPAK IC (250 mm x 50 mm, 10 um); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 60%-60%, 8.5 min) to give (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (8.95 g, 94.5% purity, 97.56% ee, first peak, Rt = 2.160 min) stereoisomer 1 (int-B05-P1) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ = 7.91 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.35 -4.33 (m, 1H), 3.89 - 3.81 (m, 2H), 3.33 - 3.08 (m, 3H), 2.15 - 2.11 (m, 1H),2.00 (s, 3H), 1.96 - 1.86 (m, 1H), and (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile as a white solid (9.05 g, 99.19% purity, 98.9% ee, second peak, Rt = 3.141 min) stereoisomer 2 (int-B05-P2), 1 H NMR (DMSO-d 6, 400 MHz) δ = 7.92 (s, 1H), 7.27(d, J = 8.8 Hz, 1H), 4.35 - 4.33 (m, 1H), 3.89 - 3.81 (m, 2H), 3.33 - 3.08(m, 3H), 2.15 - 2.11 (m, 1H), 2.00 (s, 3H), 1.96 - 1.86 (m, 1H).

[0344] Preparation of (trans)-3-((2,5-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0345]

[0346] A mixture of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (2 g, 15.8 mmol, 1 eq, HCl salt), 2,4,5-trichloropyrimidine (2.91 g, 15.8 mmol, 1 eq), and DIEA (4.10 g, 31.7 mmol, 5.52 mL, 2 eq) in DMA (20 mL) was degassed and purged with N₂ three times, then stirred at 100°C under an N₂ atmosphere for 12 h. TLC indicated the reaction was complete. The reaction mixture was diluted with H₂O (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-65% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford (trans)-3-((2,5-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (1.2 g, 27.7% yield) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ= 8.29 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 4.40 - 4.28 (m, 1H), 3.90 - 3.83(m, 2H), 3.29 - 3.11 (m, 3H), 2.18 - 2.08 (m, 1H), 1.93 - 1.85 (m, 1H).

[0347] Preparation of (trans)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0348]

[0349] To a solution of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (500 mg, 3.07 mmol, 1 eq, HCl salt) in DMA (5 mL) was added DIEA (1.6 g, 12.3 mmol, 2 mL, 4 eq) and 2,4-dichloro-5-fluoro-pyrimidine (513 mg, 3.07 mmol, 1 eq) at 25°C, and the mixture was stirred at 100°C for 12 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of H2O (20 mL) at 25°C, then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-25% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give (trans)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (310 mg, 39% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ =8.37 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 3.2 Hz, 1H), 4.27 - 4.24 (m, 1H), 3.88- 3.84 (m, 2H), 3.31 - 3.07 (m, 3H), 2.14 - 2.10 (m, 1H), 1.98 - 1.87 (m, 1H).

[0350] Preparation of (trans)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanecarbonitrile

[0351]

[0352] To a mixture of (trans)-2-aminocyclohexanecarbonitrile (1 g, 6.22 mmol, 1 eq, HCl salt) in DMA (10 mL) was added DIEA (4.83 g, 37.3 mmol, 6.5 mL, 6 eq) and 2,4-dichloro-5-fluoro-pyrimidine (1.04 g, 6.22 mmol, 1 eq) at 25°C, and the mixture was stirred at 140°C for 12 h. TLC indicated the reaction was complete. The reaction mixture was quenched by adding H2O (40 mL) at 25°C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was triturated with MTBE (10 mL) at 25 °C for 30 min to afford (trans)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (1.2 g, 75.8% yield) as a brown solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.34 (d, J =8.8 Hz, 1H), 8.15 (d, J = 3.2 Hz, 1H), 4.21-4.14 (m, 1H), 2.86-2.79 (m, 1H), 2.13-2.09 (m, 1H), 1.89-1.85 (m, 1H), 1.72-1.64 (m, 3H), 1.36-1.25 (m, 2H), 1.21-1.10 (m, 1H).

[0353] Preparation of (trans)-2-((2,5-dichloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0354]

[0355] A mixture of (trans)-2-aminocyclohexanecarbonitrile (2.00 g, 12.4 mmol, 1 eq, HCl salt), 2,4,5-trichloropyrimidine (2.28 g, 12.4 mmol, 1 eq), and DIEA (9.65 g, 74.7 mmol, 13.0 mL, 6 eq) in DMA (20 mL) was degassed and purged with N2 three times, then stirred at 140°C under N2 for 12 h. TLC indicated the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-35% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford (trans)-2-((2,5-dichloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (2 g, 59.2% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.98 (d, J =9.2 Hz, 1H), 4.30 - 4.17 (m, 1H), 2.99 (m, 1H), 2.16 - 2.05 (m, 1H), 1.88 -1.78 (m, 1H), 1.73 - 1.58 (m, 3H), 1.44 - 1.30 (m, 2H), 1.21 - 1.06 (m, 1H).

[0356] Preparation of 3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0357]

[0358] To a solution of 2-aminotetrahydropyran-4-carbonitrile (2 g, 12.3 mmol, 1 eq, HCl) in THF (20 mL) was added DIEA (4.77 g, 36.9 mmol, 6.4 mL, 3 eq) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.20 g, 14.7 mmol, 1.2 eq) at 25 ° C. The mixture was stirred at 25 ° C for 16 hours. LCMS showed that the reaction was complete and two peaks with the desired MS were observed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 10u 250mm 80 mm; mobile phase: [water (NH4HCO3) -ACN]; B%: 20%-55%, 30 min), gave (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (800 mg, 21.2% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.56 - 8.44 (m, 1H), 7.85 (d,J = 8.4 Hz, 1H), 4.60 - 4.43 (m, 1H), 3.91 - 3.78 (m, 2H), 3.45 - 3.40 (m,1H), 3.28 - 3.17 (m, 2H), 2.18 - 2.07 (m, 1H), 1.96 - 1.86 (m, 1H).

[0359] Preparation of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0360]

[0361] To a solution of (trans)-2-aminocyclohexanecarbonitrile (2 g, 12.4 mmol, 1 eq, HCl) in THF (20 mL) was added DIEA (4.83 g, 37.3 mmol, 3 eq) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.24 g, 14.9 mmol, 1.2 eq) at 25°C. The mixture was stirred at 25°C for 16 hours. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 10u 250mm 80 mm; mobile phase: [water (NH4HCO3) -ACN]; B%: 35%-75%, 35 min), gave (trans)-2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (900 mg, 23.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 7.86 (d, J = 8.8 Hz,1H), 4.47 - 4.34 (m, 1H), 3.08 (m, 1H), 2.17 - 2.06 (m, 1H), 1.85 - 1.75 (m,1H), 1.75 - 1.57 (m, 3H), 1.51 - 1.28 (m, 2H), 1.21 - 1.06 (m, 1H).

[0362] Preparation of (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0363]

[0364] To a solution of (trans)-2-aminocyclopentanecarbonitrile (2 g, 13.6 mmol, 1 eq, HCl) in THF (20 mL) was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.96 g, 13.6 mmol, 1 eq) and DIEA (5.29 g, 40.9 mmol, 7.13 mL, 3 eq) at 25°C. The mixture was stirred at 25°C for 16 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Agela DuraShell C18250 70 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 20 min), to give (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (1.37 g, 34.5% yield) as a white solid. 1 HNMR (CDCl 3, 400 MHz) δ 8.34 (s, 1H), 5.35 (s, 1H), 4.85-4.75 (m, 1H), 2.92-2.83 (m, 1H), 2.42-2.31 (m, 1H), 2.27-2.17 (m, 1H), 2.14-2.03 (m, 1H), 2.01-1.88 (m, 2H), 1.71-1.61 (m, 1H).

[0365] Synthesis Examples (Compounds in Tables 1 and 2)

[0366] 1. Preparation of (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0367]

[0368] 1.1 Preparation of methyl 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate

[0369]

[0370] (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (2.00 g, 8.45 mmol, 1 eq), 5-amino-2-bromo-benzoic acid methyl ester (2.14 g, 9.29 mmol, 1.1 eq) and TsOH.H2O (3.21 g, 16.9 mmol, 2 eq) were reacted in a 2% ethanol solution. The mixture was heated at 80°C and stirred in oxane (60 mL) for 12 h. TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue. The residue was quenched with saturated aq. Na2CO3 (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was triturated with a mixed solvent of MTBE (50 mL) and EtOAc (10 mL) to give methyl 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (1.50 g, 41% yield) as a gray solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.05 (s, 1H), 7.80 (s, 1H), 7.76-7.73 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.68-4.62 (m, 1H),4.50-4.48 (m, 1H), 3.94 (s, 3H), 2.88-2.84 (m, 1H), 2.36-2.34 (m, 1H), 2.15-2.08 (m, 2H), 1.97 (s, 3H), 1.93-1.91 (m, 1H), 1.64-1.62 (m, 1H).

[0371] 1.2 Preparation of methyl 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzoate

[0372]

[0373] Methyl 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (500 mg, 1.16 mmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dimethyl ... The mixture was heated at 120°C and stirred for 3 h in 20 mL of oxane (20 mL). TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was then concentrated in vacuo to give a residue. The residue was triturated with a mixed solvent of MTBE (50 mL), EtOAc (5 mL), and petroleum ether (10 mL) to give methyl 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (300 mg, crude) as a gray solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.14 (s, 1H), 7.82-7.80 (m, 2H), 7.51-7.49 (m, 1H), 7.15 (s, 1H), 4.68-4.65 (m, 1H), 4.46-4.45 (m, 1H), 3.92 (s, 3H), 3.79 (s, 4H), 3.61-3.60 (m, 6H), 2.92-2.87 (m, 1H), 2.36-2.35 (m, 1H), 2.15-2.13 (m, 1H), 2.13-2.05 (m, 1H), 1.96 (s, 3H), 1.93-1.92 (m, 2H), 1.63-1.62 (m, 1H), 1.10 (s, 6H).

[0374] 1.3 Preparation of (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0375]

[0376] To a solution of methyl 5-[[4-[((trans)-2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (500 mg, 1.08 mmol, 1 eq) in THF (10 mL) and MeOH (2 mL) was added NaBH₄ (204 mg, 5.40 mmol, 5 eq) portionwise at 0°C. Following the addition, the reaction was allowed to warm to 25°C and stirred at 25°C for 1 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was carefully quenched with aq. HCl (1 N, 5 mL) and diluted with H₂O (10 mL). The mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a residue. The residue was triturated with a mixed solvent of MeCN (5 mL) and H2O (2 mL) to give (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (48.3 mg, 11.6% yield) as a white solid. 1 HNMR (DMSO-d 6, 400 MHz) δ 12.27 (s, 1H),10.63 (s, 1H), 9.14 (s, 1H), 8.43 (s, 1H), 7.84 (s, 1H), 7.75-7.73 (m, 2H),7.48-7.46 (m, 1H), 5.00 (s, 2H), 4.76-4.74 (m, 1H), 3.26-3.24 (m, 1H), 2.18-2.17 (m, 1H), 2.12-2.09 (m, 1H), 2.04 (s, 3H), 1.86-1.71 (m, 4H). MS (ESI): Calculated mass for C18H21BClN5O2: 349.17, m / z found: 350.1 [M+H] + . HPLC: 94.26% (220 nm), 92.97% (254 nm).

[0377] 2. Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0378]

[0379] 2.1 Preparation of methyl 2-bromo-5-[[4-[(trans)-(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate

[0380]

[0381] At 20 ° C under N2, (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (1.40 g, 5.91 mmol, 1 eq) and 5-amino-2-bromo-3-methyl-benzoic acid methyl ester (1.59 g, 6.51 mmol, 1.1 eq) were reacted in distilled water. To this mixture in oxane (15 mL) was added TsOH·H₂O (2.25 g, 11.8 mmol, 2 eq) in one step. The mixture was heated at 80°C and stirred for 12 h. TLC indicated the reaction was complete. The reaction mixture was filtered, and the white filter cake was washed with EtOAc (10 mL) to afford methyl 2-bromo-5-[[4-[(trans)-(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (1.2 g, 45.6% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ 10.41(s, 1H), 8.36 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 4.76-4.68(m, 1H), 3.86 (s, 3H), 3.21-3.19 (m, 1H), 2.42 (s, 3H), 2.20-2.18 (m, 1H), 2.06-2.03 (m, 4H), 1.85-1.69 (m, 4H).

[0382] 2.2 Preparation of 5-[[4-[(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-3-methyl-benzoic acid methyl ester

[0383]

[0384] To the reaction mixture of 2-bromo-5-[[4-[((trans)-2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoic acid methyl ester (600 mg, 1.35 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (762 mg, 3.38 mmol, 2.5 eq) in dioxaborinane was added ... To this mixture in 2,4-dioxane (6 mL) was added KOAc (331 mg, 3.38 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (94 mg, 135 umol, 0.1 eq) in one step. The mixture was stirred at 120°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (20 mL) at 20°C for 10 min, yielding methyl 5-[[4-[((trans)-2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate (900 mg, crude) as an off-white solid.

[0385] 2.3 Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0386]

[0387] To a mixture of 5-[[4-[((trans)-2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoic acid methyl ester (900 mg, 1.89 mmol, 1 eq) in THF (10 mL) and MeOH (1 mL) at 0°C was added NaBH4 (178 mg, 4.71 mmol, 2.5 eq) portionwise. After the addition, the reaction was allowed to warm to 20°C and stirred at 20°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was adjusted to pH = 6 with aq. HCl (2N). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 80 40mm 3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%-35%, 7 min), to give (trans) 2-[[2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (30 mg) as a white solid. 1 HNMR (DMSO-d6, 400 MHz) δ 12.62 (s, 1H), 10.47 (s, 1H), 8.88 (s, 1H), 8.42 (d,J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 4.96 (s, 2H), 4.80-4.72 (m, 1H), 3.27-3.22 (m, 1H), 2.44 (s, 3H), 2.23-2.19 (m, 1H), 2.12-2.10 (m, 1H), 2.03 (s, 3H), 1.88-1.70 (m, 4H). MS (ESI): Calculated mass for 19H23BClN5O2: 363.11, m / z found: 364.2 [M+H] + . HPLC: 96.69% (220 nm), 96.77% (254 nm).

[0388] 3. Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0389]

[0390] 3.1 Preparation of methyl 2-amino-3-chloro-5-nitrobenzoate

[0391]

[0392] Three reactions were performed in parallel. For each reaction, NCS (8.85 g, 66.2 mmol, 1.3 eq) was added to a solution of 2-amino-5-nitro-benzoic acid methyl ester (10 g, 51.0 mmol, 1 eq) in DMF (100 mL) at 25°C. The mixture was stirred at 25°C for 14 h. TLC indicated the reaction was complete. The contents of the three parallel reactions were combined and the mixture was poured into water (300 mL) at 0°C, after which a yellow precipitate formed and was collected. The yellow precipitate was washed with H2O (80 mL x 2) and petroleum ether (50 mL x 2) to give 2-amino-3-chloro-5-nitro-benzoic acid methyl ester (34.1 g, 96.7% yield) as a yellow solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.58 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H).

[0393] 3.2 Preparation of methyl 2-bromo-3-chloro-5-nitrobenzoate

[0394]

[0395] Three reactions were performed in parallel. For each reaction, methyl 2-amino-3-chloro-5-nitro-benzoate (10 g, 43.3 mmol, 1 eq) was added portionwise to a mixture of t-BuONO (8.94 g, 86.7 mmol, 10.3 mL, 2 eq) and CuBr2 (14.5 g, 65.1 mmol, 3.1 mL, 1.5 eq) in MeCN (100 mL) at 65°C. The mixture was stirred at 65°C for 30 min. TLC indicated the reaction was complete. The three parallel reactions were combined, poured into H2O (350 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aq. Na2SO3 (100 mL x 3). The combined organic layers were then washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-bromo-3-chloro-5-nitro-benzoic acid methyl ester (33 g, 86.1% yield) as a yellow solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.44-8.42 (m, 2H), 4.02 (s, 3H).

[0396] 3.3 Preparation of 5-amino-2-bromo-3-chloro-benzoic acid methyl ester

[0397]

[0398] Three reactions were performed in parallel. For each reaction, Fe (6.26 g, 112 mmol, 3 eq) and NHCl (3.00 g, 56.0 mmol, 1.5 eq) were added in one step to a mixture of 2-bromo-3-chloro-5-nitro-benzoic acid methyl ester (11 g, 37.3 mmol, 1 eq) in EtOH (120 mL) and H₂O (40 mL) at 25°C. The mixture was heated to 80°C and stirred at 80°C for 2 h. TLC indicated the reaction was complete. The three parallel reactions were combined, filtered, and then concentrated under reduced pressure to give a residue. The residue was quenched with water (500 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (250 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-amino-2-bromo-3-chloro-benzoic acid methyl ester (28 g, 94.5% yield) as a yellow oil. 1 H NMR (CDCl 3, 400 MHz) δ 6.90 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.90-3.80 (m, 2H).

[0399] 3.4 Preparation of (5-amino-2-bromo-3-chlorophenyl)methanol

[0400]

[0401] To a solution of 5-amino-2-bromo-3-chloro-benzoic acid methyl ester (10 g, 37.8 mmol, 1 eq) in THF (150 mL) at -60°C was added DIBAL-H (1 M, 113 mL, 3 eq) dropwise. The mixture was stirred at -60°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of aqueous potassium sodium tartrate (500 mL) at 0°C and then extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (30 mL) at 25°C for 5 min to give (5-amino-2-bromo-3-chloro-phenyl)methanol (8.2 g, 91.7% yield) as a yellow solid. 1 H NMR (CDCl 3,400 MHz) δ 6.76 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 5.54 (s, 2H), 5.39 (t, J = 5.6Hz, 1H), 4.37 (d, J = 5.6 Hz, 2H).

[0402] 3.5 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0403]

[0404] Five reactions were performed in parallel. For each reaction, (5-amino-2-bromo-3-chloro-phenyl)methanol (0.5 g, 2.11 mmol, 1 eq) and (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (525 mg, 2.22 mmol, 1.05 eq) were added to distilled water at 25°C. To a solution of 1,000 tantalum (1,000 tantalum) in 2,000 tantalum (1,000 tantalum) in 1,000 tantalum (1,000 tantalum) was added TsOH·H₂O (603 mg, 3.17 mmol, 1.5 eq). The mixture was heated to 90°C and stirred at 90°C for 5 h. TLC indicated the reaction was complete. Five parallel reactions were combined, quenched by the addition of saturated aq. NaHCO₃ (80 mL) at 0°C, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (15 mL) at 25°C for 10 min, affording (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (2.8 g, 60.6% yield) as a white solid. 1 HNMR (DMSO-d 6,400 MHz) δ 9.29 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.50 (t, J = 5.6 Hz, 1H), 4.87-4.78(m, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.15-3.08 (m, 1H), 2.24-2.12 (m, 2H), 1.94(s, 3H), 1.89-1.83 (m, 1H), 1.82-1.74 (m, 2H), 1.57-1.47 (m, 1H).

[0405] 3.6 Preparation of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0406]

[0407] To a solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (2.8 g, 6.41 mmol, 1 eq) and 2,6-lutidine (2.08 g, 19.2 mmol, 2.3 mL, 3 eq) in THF (60 mL) at 0°C was added TBSOTf (2.54 g, 9.62 mmol, 2.2 mL, 1.5 eq). The mixture was stirred at 25°C for 3 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NH4Cl (80 mL) at 0°C, followed by extraction with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc (30 mL) at 25 °C for 20 min to give (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (2.5 g, 70.7% yield) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ 9.39 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.78 (m, 1H), 4.66 (s,2H), 3.13 (q, J = 8.4 Hz, 1H), 2.25-2.09 (m, 2H), 1.95 (s, 3H), 1.87-1.73 (m,3H), 1.60-1.51 (m, 1H), 0.92 (s, 9H), 0.10 (s, 6H).

[0408] 3.7 Preparation of [2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-6-chloro-4-[[4-[(trans)-(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]phenyl]boronic acid

[0409]

[0410] Six reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (0.4 g, 726 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dimethyl-1,3,2-dioxaborinan-3-yl) ... The mixture in oxane (6 mL) was degassed and purged with N2 three times. The mixture was then heated to 120°C under N2 and stirred at 120°C for 40 min. LCMS indicated the reaction was complete, and the desired MS was observed. Six parallel reactions were cooled to room temperature, combined, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250 50mm 10 μm; mobile phase: [water (NH4HCO3) -ACN]; B%: 50%-90%, 10 min), to give [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-4-[[4-[(trans)-(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]phenyl]boronic acid and 2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (1.2 g, mixture) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.11(s, 1H), 8.04 (s, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 6.78 (d, J =8.0 Hz, 1H), 4.80-4.70 (m, 1H), 4.63 (s, 2H), 3.20-3.10 (m, 1H), 2.25-2.09(m, 2H), 1.95 (s, 3H), 1.87-1.73 (m, 3H), 1.60-1.51 (m, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

[0411] 3.8 Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0412]

[0413] To a solution of [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-4-[[4-[(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]phenyl]boronic acid and 2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (a mixture, 1.2 g, 1.16 mmol, 1 eq) in THF (10 mL) at 0°C was added HCl (6 M, 775 μL, 4 eq). The mixture was heated to 40°C and stirred at 40°C for 1 h. LCMS indicated the reaction was complete, with a major peak of the desired mass detected. The reaction was concentrated under reduced pressure to afford a residue. The residue was triturated with MeCN (15 mL) at 25° C. for 10 min to give the racemic product (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (880 mg). The racemic product (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (880 mg) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 40%-40%, 6 min), affording (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (stereoisomer 1) as a white solid (335.9 mg, 97.10% purity, 98.96% ee, first peak, Rt = 3.898 min). 1 HNMR (DMSO-d 6,400 MHz) δ 9.39 (s, 1H), 8.84 (s, 1H), 7.81 (s, 1H), 7.78 (s,1H), 7.76 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.85-4.75 (m, 1H), 3.13 (q, J = 8.4 Hz, 1H), 2.25-2.10 (m, 2H), 1.96 (s, 3H), 1.90-1.73 (m, 3H), 1.62-1.53 ​​(m, 1H). MS (ESI):C 18 H 19 The calculated mass of BClN5O2 is 383.13, and the found m / z is 384.1 [M+H] + HPLC: 97.10% (220 nm), 98.17% (254 nm); and 370 mg of stereoisomer 2 (contains isopropanol residues), which was further purified by pre-HPLC (column: Phenomenex Luna 80 30mm 3 μm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 8 min) to remove isopropanol residues to give (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (stereoisomer 2) as a white solid (332.9 mg, 97.31% purity, 97.80% ee, second peak, Rt = 4.470 min). 1 H NMR (DMSO-d 6, 400 MHz) δ 10.40 (br s, 1H), 9.05 (br s, 1H), 8.10 (brs, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 4.99 (s, 2H), 4.80-4.70 (m,1H), 3.26-3.19 (m, 1H), 2.26-2.19 (m, 1H), 2.15-2.09 (m, 1H), 2.03 (s, 3H), 1.90-1.75 (m, 3H), 1.71-1.63 (m, 1H). MS (ESI): C 18 H 19 The calculated mass of BClN5O2 is 383.13, and the found m / z is 384.1 [M+H]+ . HPLC: 97.31% (220 nm), 97.90% (254 nm).

[0414] 4. Preparation of (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0415]

[0416] 4.1 Preparation of methyl 2-amino-3-methoxybenzoate

[0417]

[0418] To a solution of 2-amino-3-methoxy-benzoic acid (40.0 g, 239 mmol, 1 eq) in MeOH (500 mL) was added a 0°C H2SO4 solution (1.32 mol, 70 mL, 5.5 eq) dropwise over 5 minutes under N2 at 0°C. Following the addition, the reaction mixture was heated and stirred at 95°C for 16 hours. TLC indicated the reaction was complete. The pH of the reaction mixture was adjusted to 7 with saturated aq. Na2CO3 (1 L) at 0°C and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford 2-amino-3-methoxy-benzoic acid methyl ester (43 g, 99% yield) as a white solid. 1 H NMR (CDCl 3, 400 MHz) δ 7.40 (d, J = 8.4Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 6.50 (t, J = 8.0 Hz, 1H), 5.94 (s, 2H), 3.79 (s, 6H).

[0419] 4.2 Preparation of 2-amino-5-iodo-3-methoxy-benzoic acid methyl ester

[0420]

[0421] To a mixture of methyl 2-amino-3-methoxybenzoate (43.0 g, 237 mmol, 1 eq) in EtOH (500 mL) at 20°C was added AgSO (77.6 g, 249 mmol, 1.05 eq) and I (63.2 g, 249 mmol, 1.05 eq) in one step. The mixture was stirred at 20°C for 5 h. TLC indicated the reaction was complete. The mixture was poured into ice water (1 L) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (600 mL x 3). The combined organic phases were washed with saturated aq. NaSO (400 mL x 2) and brine (150 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 2-amino-5-iodo-3-methoxy-benzoic acid methyl ester (45.0 g, 61% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 7.61 (s, 1H), 7.15 (s, 1H), 6.45 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H).

[0422] 4.3 Preparation of methyl 2-bromo-5-iodo-3-methoxybenzoate

[0423]

[0424] To a solution of methyl 2-amino-5-iodo-3-methoxybenzoate (45.0 g, 146 mmol, 1 eq) in MeCN (600 mL) at 25°C was added CuBr2 (66.4 g, 297 mmol, 2.03 eq). The mixture was stirred at 25°C for 20 minutes, then tert-butyl nitrite (264 mmol, 31 mL, 1.8 eq) was added dropwise at 10°C over 10 minutes. The reaction mixture was stirred at 10°C for an additional 30 minutes, after which the mixture was heated and stirred at 60°C for 12 hours. The residue was poured into ice water (1 L) and saturated aqueous Na2CO3 (600 mL). The aqueous phase was extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated aq. Na2SO3 (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 2-bromo-5-iodo-3-methoxy-benzoic acid methyl ester (33 g, 60% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 7.47 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H).

[0425] 4.4 Preparation of methyl 2,5-dibromo-3-hydroxybenzoate

[0426]

[0427] To a solution of methyl 2-bromo-5-iodo-3-methoxy-benzoate (33.0 g, 88.9 mmol, 1 eq) in DCM (400 mL) at 0°C under N2 was slowly added BBr3 (267 mmol, 25.7 mL, 3 eq). After the addition, the reaction was allowed to warm to 20°C and stirred for 1 h. TLC indicated the reaction was complete. MeOH (2.67 mol, 108 mL, 30 eq) was slowly added to the reaction mixture, and the resulting mixture was stirred at 20°C for 30 min. The mixture was poured into ice water (600 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (350 mL x 3). The combined organic phases were washed with brine (400 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 2,5-dibromo-3-hydroxy-benzoic acid methyl ester (17.0 g, 62% yield) as a white solid. 1 H NMR (DMSO-d 6,, 400 MHz) δ 11.16 (s, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H).

[0428] 4.5 Preparation of methyl 2,5-dibromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate

[0429]

[0430] To a mixture of methyl 2,5-dibromo-3-hydroxybenzoate (8.0 g, 25.8 mmol, 1 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (9.26 g, 38.7 mmol, 1.5 eq) in DMF (80 mL) at 20°C under N2 was added K2CO3 (7.13 g, 51.6 mmol, 2 eq) and NaI (774 mg, 5.16 mmol, 0.2 eq) in one step. The mixture was heated to 60°C and stirred for 16 h. TLC indicated the reaction was complete. The mixture was poured into ice water (150 mL) and stirred for 10 min. The aqueous phase was then extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give methyl 2,5-dibromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate (12.0 g, 99% yield) as a yellow oil. 1 H NMR (CDCl 3, 400 MHz) δ 7.41(d, J = 2.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.14 (t, J = 4.8 Hz, 2H), 4.02(t, J = 5.2 Hz, 2H), 3.94 (s, 3H), 0.91 (s, 9H), 0.11 (s, 6H).

[0431] 4.6 Preparation of methyl 2-bromo-5-(tert-butoxycarbonylamino)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate

[0432]

[0433] At 20 ° C under N2, 2,5-dibromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoic acid methyl ester (5.0 g, 10.6 mmol, 1 eq) and NH2Boc (1.38 g, 11.7 mmol, 1.1 eq) were added to distilled water. To a mixture of 2,000 tantalum (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (80 mL) was added Pd(OAc)2 (239 mg, 1.07 mmol, 0.1 eq), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (617 mg, 1.07 mmol, 0.1 eq), and Cs2CO3 (6.96 g, 21.36 mmol, 2 eq) in one step. The mixture was heated to 100°C and stirred for 16 h. TLC indicated the reaction was complete. The reaction mixture was filtered and concentrated in vacuo to afford a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford methyl 2-bromo-5-(tert-butoxycarbonylamino)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate (3.3 g, 61% yield) as a white solid. 1 H NMR (CDCl 3, 400 MHz) δ 7.40 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.53 (s, 1H), 4.13 (t, J = 4.8 Hz, 2H), 4.02 (t, J = 5.2Hz, 2H), 3.92 (s, 3H), 1.52 (s, 9H), 0.91 (s, 9H), 0.12 (s, 6H).

[0434] 4.7 Preparation of tert-butyl N-[4-bromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-(hydroxymethyl)phenyl]carbamate

[0435]

[0436] To a mixture of methyl 2-bromo-5-(tert-butoxycarbonylamino)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate (4.0 g, 7.93 mmol, 1 eq) in THF (40 mL) at 0°C under N₂ was added MeOH (49.4 mmol, 2.00 mL, 6.23 eq) and LiBH₄ (2 M in THF, 15 mL, 3.78 eq) dropwise. Following the addition, the reaction was allowed to warm to 20°C and stirred for 4 h. TLC indicated the reaction was complete. The mixture was poured into ice water (100 mL), and the pH of the aqueous phase was adjusted to 7-8 with aq. HCl (2N). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give tert-butyl N-[4-bromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-(hydroxymethyl)phenyl]carbamate (4 g, crude) as a white solid. 1 H NMR (CDCl 3, 400 MHz) δ 7.26 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.56 (s, 1H), 4.70 (s, 2H), 4.12 (t, J = 4.8 Hz, 2H), 4.01 (t, J = 4.8 Hz, 2H), 1.52 (s, 9H), 0.92 (s, 9H), 0.12 (s, 6H).

[0437] 4.8 Preparation of tert-butyl N-[7-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-1-hydroxy-3H-2,1-benzoxaborol-5-yl]carbamate

[0438]

[0439] At 25 °C under N2, tert-butyl N-[4-bromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-(hydroxymethyl)phenyl]carbamate (4.0 g, 8.39 mmol, 1 eq) was added to distilled water. To this mixture in 2% dextrose (120 mL) was added KOAc (2.47 g, 25.2 mmol, 3 eq), Pd(dppf)Cl2 (614 mg, 840 umol, 0.1 eq), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (4.74 g, 20.9 mmol, 2.5 eq) in one step. The mixture was then heated to 100°C and stirred for 16 h. TLC indicated the reaction was complete. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to give tert-butyl N-[7-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-1-hydroxy-3H-2,1-benzoxaborol-5-yl]carbamate (2.5 g, crude) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 7.04 (s, 1H), 6.90 (s, 1H), 6.60 (s, 1H), 5.85 (s, 1H), 5.31 (s, 1H), 5.00 (s, 2H), 4.14 (t, J = 4.4 Hz, 2H), 3.98 (t, J = 4.8 Hz, 2H), 1.53 (s, 9H), 0.93 (s, 9H), 0.13 (s, 6H).

[0440] 4.9 Preparation of tert-butyl (7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-yl)carbamate

[0441]

[0442] To a mixture of tert-butyl N-[7-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-1-hydroxy-3H-2,1-benzoxaborol-5-yl]carbamate (250 mg, 590 umol, 1 eq) in THF (10 mL) at 0°C was added aq. HCl (3 M, 1.18 mL, 6 eq) dropwise. After the addition, the reaction was heated and stirred at 40°C for 30 min. TLC indicated the reaction was complete. The mixture was poured into ice water (6 mL). The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 2:1) and further purified by prep-HPLC (column: Waters Xbridge BEH C18 100 30mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 10 min), to give tert-butyl (7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulen-4-yl)carbamate (43.2 mg, 99.58% purity) as an off-white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ9.57 (s, 1H), 7.22 (s, 1H), 6.95 (s, 1H), 5.05 (s, 2H), 4.63-4.59 (m, 1H), 4.30-4.29 (m, 1H), 4.26-4.12 (m, 2H), 1.47 (s, 9H). MS (ESI): C 14 H 18 The calculated mass of BNO5 is 291.13, and the measured m / z is 290.2 [MH] - . HPLC: 99.58% (220 nm), 99.68% (254 nm).

[0443] 4.10 Preparation of 7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-amine hydrochloride

[0444]

[0445] To a mixture of tert-butyl (7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-yl)carbamate (1.0 g, 3.44 mmol, 1 eq) in EtOAc (10 mL) was added dropwise HCl / EtOAc (4 M, 40 mL, 46.58 eq) at 20°C. Following the addition, the reaction was heated and stirred at 40°C for 2 h. The mixture was then cooled to 10°C and stirred, causing a solid to precipitate. The solid was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2) and dried in vacuo to give the crude product. The crude product was triturated with acetonitrile (10 mL) at 20 °C for 10 min to give 7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-amine hydrochloride (550 mg, 96.86% purity) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.60 (s, 3H), 6.63 (s, 1H), 6.43 (s, 1H), 5.04 (s, 2H), 4.63-4.60 (m, 1H), 4.30-4.25 (m, 1H), 4.21-4.15 (m, 2H). MS(ESI):C9H 11 The calculated mass of BClNO3 is 227.05, and the found m / z is 192.2 [M+H] + . HPLC: 96.86% (220 nm), 98.77% (254 nm).

[0446] 4.11 Preparation of (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile

[0447]

[0448] To a mixture of 7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-amine hydrochloride (50 mg, 219 umol, 1 eq, HCl salt) and (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (57.2 mg, 241 umol, 1.1 eq) in 2-methylbutan-2-ol (2 mL) at 20°C under N2 was added BrettPhos Pd G3 (19.9 mg, 21.9 umol, 0.1 eq), Brettphos (11.8 mg, 21.9 umol, 0.1 eq), and Cs2CO3 (214 mg, 659 umol, 3 eq) in one step. The mixture was heated to 100°C and stirred for 16 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 30mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 10 min), to give (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (63 mg, 99.18% purity) as a white solid. 1 HNMR (DMSO-d 6, 400 MHz) δ 9.19-9.16 (m, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.53 (d,J = 46 Hz, 1H) 7.29 (d, J = 25.2 Hz, 1H), 6.85-6.75 (m, 1H), 5.09 (s, 2H),4.79-4.47 (m, 2H), 4.30-4.25 (m, 2H), 4.16-4.12 (m, 1H), 3.63-3.10 (m, 1H),2.17-2.05 (m, 2H), 2.01-1.84 (m, 5H), 1.64-1.61 (m, 2H). MS (ESI): C 20 H 22 The calculated mass of BN5O3 is 391.18, and the found m / z is 392.0 [M+H] + . HPLC: 99.18% (220 nm), 98.79% (254 nm).

[0449] 5. Preparation of (trans)-2-[[5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclopentane-1-carbonitrile

[0450]

[0451] 5.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-[(trans)(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]benzoate

[0452]

[0453] (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclopentane-1-carbonitrile (2.20 g, 8.56 mmol, 1 eq), 5-amino-2-bromo-benzoic acid methyl ester (2.17 g, 9.41 mmol, 1.1 eq) and TsOH.H2O (3.26 g, 17.1 mmol, 2 eq) were reacted in a 2% ethanol solution. The mixture was heated at 80°C and stirred in oxane (60 mL) for 12 h. TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue. The residue was triturated with a mixed solvent of EtOAc (50 mL) and saturated aq. Na2CO3 (50 mL), and the resulting suspension was filtered. The filter cake was dried in vacuo to give methyl 2-bromo-5-[[5-chloro-4-[(trans)-(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]benzoate (2.05 g, 64.8% yield) as a gray solid.

[0454] 5.2 Preparation of methyl 5-[[5-chloro-4-[(trans)-(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzoate

[0455]

[0456] Methyl 2-bromo-5-[[5-chloro-4-[(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]benzoate (2.00 g, 4.44 mmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl (2.51 g, 11.0 mmol, 2.5 eq), Pd(PPh3)2Cl2 (311 mg, 443 umol, 0.1 eq) and KOAc (1.09 g, 11.0 mmol, 2.5 eq) were reacted in distilled water. The mixture was heated at 120°C in 2% paraffin (60 mL) and stirred for 3 h. TLC showed that the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with a mixed solvent of MTBE (50 mL), EtOAc (5 mL), and petroleum ether (10 mL) to give methyl 5-[[5-chloro-4-[(trans)-(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (2.0 g, crude) as a brown solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.16 (s, 1H), 8.08(s, 1H), 7.89 (s, 1H), 7.71 (d, J=7.6 Hz, 2H), 7.50-7.48 (m, 1H), 5.26-5.24(m, 1H), 4.73-4.66 (m, 1H), 3.90 (s, 3H), 3.77 (s, 4H), 3.57-3.56 (m, 1H), 2.88-2.84 (m, 1H), 2.33-2.31 (m, 1H), 2.15-2.13 (m, 1H), 2.05-2.04 (m, 1H),1.92-1.86 (m, 2H), 1.65-1.61 (m, 1H), 1.08 (s, 6H).

[0457] 5.3 Preparation of (trans)-2-[[5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0458]

[0459] To a solution of methyl 5-[[5-chloro-4-[(trans)-2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (5.00 g, 10.3 mmol, 1 eq) in THF (100 mL) and MeOH (5 mL) was added NaBH₄ (1.96 g, 51.6 mmol, 5 eq) portionwise at 0°C. Following the addition, the reaction was allowed to warm to 25°C and stirred at 25°C for 1 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was carefully quenched with aq. HCl (1 N, 5 mL) and diluted with H₂O (20 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a residue. The residue was triturated with a mixed solvent of MeCN (10 mL) and H2O (3 mL) to give (trans)-2-[[5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclopentanecarbonitrile (118.6 mg) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.57 (s, 1H), 9.07 (s, 1H), 8.06 (s,1H), 7.92 (s, 1H), 7.62-7.54 (m, 2H), 7.48-7.46 (m, 1H), 4.95 (s, 2H), 4.83-4.75 (m, 1H), 3.26-3.20 (m, 1H), 2.19-2.09 (m, 2H), 1.89-1.80 (m, 3H), 1.64-1.54 (m, 1H). MS (ESI): Calculated mass for C17H17BClN5O2: 369.11, m / z found: 370.1 [M+H] + . HPLC: 92.18% (220 nm), 93.35% (254 nm).

[0460] 6. Preparation of (trans)2-[[2-[[1-hydroxy-7-(trifluoromethyl)-3H-2,1-benzoxaborol-5-yl]amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0461]

[0462] 6.1 Preparation of methyl 2-bromo-5-[[4-[(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate

[0463]

[0464] To 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (2.00 g, 8.45 mmol, 1 eq) and methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (2.77 g, 9.29 mmol, 1.1 eq) in distilled water was added at 20 °C. To the mixture in oxane (20 mL) was added TsOH·H₂O (3.21 g, 16.9 mmol, 2 eq) in one step. The mixture was heated at 80°C and stirred for 12 h. TLC indicated the reaction was complete. The reaction mixture was adjusted to pH 9 with saturated aq. Na₂CO₃. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (30 mL) at 20°C for 20 min to give methyl 2-bromo-5-[[4-[(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate (1.1 g, 26.1% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.62-8.60(m, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 4.75-4.67 (m, 1H), 3.91(s, 3H), 3.30-3.26 (m, 1H), 2.27-2.23 (m, 1H), 2.06-2.03 (m, 4H), 1.80-1.79(m, 2H), 1.72-1.68 (m, 2H).

[0465] 6.2 Preparation of 2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0466]

[0467] To a mixture of methyl 2-bromo-5-[[4-[(2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate (0.65 g, 1.30 mmol, 1 eq) in THF (15 mL) at 0°C was added LiBH₄ (4M in THF, 1.63 mL, 5 eq) dropwise. The mixture was heated at 50°C and stirred for 8 h. TLC indicated the reaction was complete. The reaction was quenched with ice water (30 mL) and adjusted to pH = 2 with aq. HCl (2N). A white solid precipitated and was filtered. The filter cake was washed with H₂O (10 mL) to afford 2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (0.45 g, crude) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ8.54 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.75-7.73 (m, 1H),5.68-5.65 (m, 1H), 4.81-4.72 (m, 1H), 4.60-4.54 (m, 2H), 3.32 (s, 3H), 3.13-3.08 (m, 1H), 2.19-2.14 (m, 2H), 2.00 (s, 3H), 1.73-1.72 (m, 1H), 1.71-1.65(m, 2H), 1.58-1.55 (m, 1H).

[0468] 6.3 Preparation of (trans)-2-[[2-[[1-hydroxy-7-(trifluoromethyl)-3H-2,1-benzoxaborol-5-yl]amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0469]

[0470] Five reactions were performed in parallel. For each reaction, 2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (60 mg, 127 umol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (72 mg, 318 umol, 2.5 eq) were added to distilled water at 20°C under N2. To this mixture in 2 mL of oxane (2 mL) was added KOAc (31 mg, 318 umol, 2.5 eq) and Pd(PPh3)2Cl2 (8.95 mg, 12.7 umol, 0.1 eq) in one step. The mixture was heated at 120°C and stirred for 10 h. LCMS indicated the reaction was complete, and the desired MS was observed. Five parallel reactions were combined, and the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 100 25mm 3 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%-30%, 8 min), giving 2-[[2-[[1-hydroxy-7-(trifluoromethyl)-3H-2,1-benzoxaborol-5-yl]amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (77.1 mg, 30.2% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.61 (s, 1H),9.09 (s, 1H), 8.10 (m, 2H), 7.86 (s, 1H), 5.06 (s, 2H), 4.79-4.75 (m, 1H),3.25-3.13 (m, 1H), 2.22-2.21 (m, 1H), 2.05-2.03 (m, 4H), 1.82-1.65 (m, 4H). MS(ESI):C 15 H 15 The calculated mass of BO4 is 417.16, and the found m / z is 418.2 [M+H] + . HPLC: 99.09% (220 nm), 99.29 (254 nm).

[0471] 7. Preparation of (trans)-2-((2-((2-hydroxy-2H-benzo[e][1,2]oxaborolan-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0472]

[0473] To (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (100 mg, 422 umol, 1 eq) and 2-hydroxy-1,2-benzoxaborin-6-amine (83.4 mg, 422 umol, 1 eq, HCl) was added dichloromethane at 20 °C. To the mixture in 2% dextrose (5 mL) was added TsOH·H2O (121 mg, 634 umol, 1.5 eq), and the mixture was stirred at 80°C for 12 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 30mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-45%, 10 min), to give (trans)-2-((2-((2-hydroxy-2H-benzo[e][1,2]oxaborin-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (17 mg, 95.13% purity) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.03 (s, 1H), 8.83 (s, 1H), 7.88 (s,1H), 7.76-7.68 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.94-6.70 (m, 1H), 6.11 (d, J = 11.6 Hz, 1H), 4.79-4.72 (m, 1H), 3.19-3.09(m, 1H), 2.20-2.15 (m, 1H), 2.12-2.07 (m, 1H), 1.94 (s, 3H), 1.85-1.77 (m, 2H), 1.73-1.66 (m, 1H), 1.62-1.57 (m, 1H). MS (ESI): C 19 H 20 The calculated mass of BN5O2 is 361.17, and the found m / z is 362.2 [M+H] + . HPLC: 95.13% (220 nm), 97.25% (254 nm).

[0474] 8. Preparation of (trans)2-[[2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0475]

[0476] 8.1 Preparation of methyl 2-bromo-5-[[4-[(trans)-(2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]benzoate

[0477]

[0478] To (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (1.30 g, 5.18 mmol, 1 eq) and 5-amino-2-bromo-benzoic acid methyl ester (1.43 g, 6.22 mmol, 1.2 eq) was added dichloromethane (100 mL) at 20 °C. To this mixture in oxane (20 mL) was added TsOH·H₂O (1.97 g, 10.3 mmol, 2 eq) in one step. The mixture was heated at 80°C and stirred for 12 h. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (10 mL) at 20°C for 10 min, affording methyl 2-bromo-5-[[4-[(2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]benzoate (0.8 g, 34% yield) as an off-white solid. 1 H NMR (DMSO-d6,400 MHz) δ 9.29 (s, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.76-7.73 (m, 2H), 7.55(d, J = 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.27 (br d, J = 5.2 Hz, 1H), 3.85 (s, 3H), 3.31 (s, 3H), 2.93 (dt, J=3.6, 11.6 Hz, 1H), 2.21 - 2.10 (m,1H), 1.97 - 1.84 (m, 4H), 1.80 - 1.52 (m, 3H), 1.38 - 1.13 (m, 4H).

[0479] 8.2 Preparation of methyl 5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzoate

[0480]

[0481] To a solution of methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]benzoate (800 mg, 1.80 mmol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.02 g, 4.50 mmol, 2.5 eq) in dioxaborinane was added at 20 °C under N2. To this mixture in 2-nitropropane (10 mL) was added KOAc (442 mg, 4.50 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (253 mg, 360 umol, 0.2 eq) in one step. The mixture was heated at 120°C and stirred for 1 h. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (10 mL) at 20°C for 15 min to give methyl 5-[[4-[((trans)2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (0.8 g, crude) as an off-white solid.

[0482] 8.3 Preparation of (trans)-2-[[2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0483]

[0484] To a mixture of methyl 5-[[4-[((trans)2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (800 mg, 1.68 mmol, 1 eq) in THF (10 mL) and MeOH (1 mL) at 0°C was added NaBH4 (159 mg, 4.19 mmol, 2.5 eq) portionwise. After the addition, the reaction was allowed to warm to 20°C and stirred at 20°C for 2 h. The reaction mixture was adjusted to pH = 6 with aq. HCl (2N). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 80 40mm 3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 18%-43%, 7 min), gave (trans)-2-[[2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (80 mg, 13% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ12.37 (s, 1H), 10.76 (s, 1H), 9.17 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.87(s, 1H), 7.76-7.72 (m, 2H), 7.48 (dd, J = 1.6, 8.0 Hz, 1H), 5.05-4.96 (m,2H), 4.32-4.23 (m, 1H), 3.08 (m, 1H), 2.19 (d, J = 12.8 Hz, 1H), 2.05 (s,3H), 1.96-1.94 (m, 1H), 1.80-1.71 (m, 2H), 1.66-1.56 (m, 1H), 1.46-1.37 (m, 1H), 1.33-1.15 (m, 2H). MS (ESI): C 19 H 23 The calculated mass of BClN5O2 is 363.19, and the found m / z is 364.2 [M+H] + . HPLC: 96.51% (220 nm), 99.68 (254 nm).

[0485] 9. Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0486]

[0487] 9.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid

[0488]

[0489] To a mixture of 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 eq) in H2SO4 (70 mL, 98% purity) at 0°C was added a solution of KNO3 (4.70 g, 46.5 mmol, 1 eq) in H2SO4 (30 mL, 98% purity) over 0.5 h, and the mixture was stirred at 0°C for 2.5 h. TLC indicated the reaction was complete. The reaction mixture was poured into ice H2O (200 mL), the resulting solid was filtered, and the filter cake was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-bromo-3-methyl-5-nitro-benzoic acid (10.5 g, 86% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 8.58 (d, J = 2.4Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 2.63 (s, 3H).

[0490] 9.2 Preparation of methyl 2-bromo-3-methyl-5-nitrobenzoate

[0491]

[0492] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.00 g, 30.8 mmol, 1 eq) in MeOH (80 mL) at 0°C was added SOCl₂ (61.5 mmol, 4.46 mL, 2 eq). Following the addition, the reaction was heated at 80°C and stirred for 12 h. TLC indicated the reaction was complete. The reaction was concentrated under reduced pressure to give a residue. The residue was dissolved in H₂O (80 mL), the pH adjusted to 7 with saturated aq. NaHCO₃, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0-15% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give methyl 2-bromo-3-methyl-5-nitro-benzoate (6 g, 71% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) 8.35 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H) 2.59 (s, 3H).

[0493] 9.3 Preparation of 5-amino-2-bromo-3-methyl-benzoic acid methyl ester

[0494]

[0495] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid methyl ester (6 g, 21.9 mmol, 1 eq) in EtOH (80 mL) and H₂O (20 mL) at 25°C under N₂ was added NH₄Cl (4.68 g, 87.6 mmol, 4 eq) and Fe (4.89 g, 87.6 mmol, 4 eq). The mixture was stirred at 80°C for 1 h. TLC indicated the reaction was complete. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 5-amino-2-bromo-3-methyl-benzoic acid methyl ester (5 g, 93% yield) as a yellow oil. 1 H NMR (CDCl3, 400 MHz) δ 6.80 (d, J = 2.8 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 2.36 (s, 3H).

[0496] 9.4 Preparation of 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoic acid methyl ester

[0497]

[0498] At 20 ° C under N2, (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (2.00 g, 7.98 mmol, 1 eq) and 5-amino-2-bromo-3-methyl-benzoic acid methyl ester (2.14 g, 8.77 mmol, 1.1 eq) were reacted in distilled water. To the mixture in oxane (40 mL), 4-methylbenzenesulfonic acid monohydrate (3.03 g, 16.0 mmol, 2 eq) was added in one step. The mixture was heated to 80°C and stirred for 16 h. TLC indicated the reaction was complete. The mixture was poured into ice water (80 mL), and the pH of the aqueous phase was adjusted to 5-6 with saturated aqueous Na2CO3. The resulting mixture was diluted with EtOAc (30 mL x 3), and the suspension was filtered. The filter cake was washed with water (30 mL x 2) and dried in vacuo to give a residue. The residue was purified by trituration with MTBE (30 mL) at 20°C for 0.5 h, giving methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (1.5 g, 41% yield) as an off-white solid.

[0499] 9.5 Preparation of methyl 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-3-methylbenzoate

[0500]

[0501] Three reactions were performed in parallel. For each reaction, 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoic acid methyl ester (200 mg, 436 umol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (246 mg, 1.09 mmol, 2.5 eq) were added to distilled water at 20°C under N2. To this mixture in 2,000 mL of 4,000 mL of ethanol (6 mL) was added AcOK (107 mg, 1.09 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (15.3 mg, 21.8 umol, 0.05 eq) in one step. The mixture was heated at 120°C and stirred for 1 h. TLC indicated the reaction was complete. The three parallel reactions were combined, and the reaction mixture was filtered and concentrated in vacuo to give a residue. The crude product was triturated with MTBE (20 mL) at 20°C for 0.5 h, affording methyl 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylbenzoate (300 mg, 46% yield) as a gray solid. 1 H NMR (CDCl3, 400 MHz) δ7.97 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 4.59-4.48 (m, 1H), 4.44-4.37 (m,1H), 3.94 (s, 3H), 3.82 (s, 4H), 2.86-2.76 (m, 1H), 2.48 (s, 3H), 2.21-2.18(m, 1H), 1.99 (s, 3H), 1.84-1.71 (m, 4H), 1.60-1.49 (m, 2H), 1.42-1.36 (m,2H), 1.15 (s, 6H).

[0502] 9.6 Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0503]

[0504] To a solution of methyl 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylbenzoate (150 mg, 305 umol, 1 eq) and MeOH (0.5 mL) in THF (6 mL) was added NaBH4 (57.7 mg, 1.53 mmol, 5 eq) at 0°C. After the addition, the reaction was allowed to warm to 25°C and stirred for 1 h. The reaction was quenched with H2O (10 mL) and the pH was adjusted to 5 with aq. HCl (2N). EtOAc (10 mL) was added to the reaction mixture, and a precipitate formed. The precipitate was filtered to give (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile as an off-white solid (28 mg, 95.47% purity). 1 H NMR (DMSO-d6, 400MHz) δ 9.03 (s, 1H), 8.57 (s, 1H), 7.74 (s, 1H), 7.71 (s, 1H), 7.37 (s, 1H), 6.68 (d, J = 8.8 Hz,, 1H), 4.94-4.85 (m, 2H), 4.38-4.25 (m, 1H), 2.99-2.91(m, 1H), 2.38 (s, 3H), 2.18 (d, J = 12.4 Hz, 1H), 1.98-1.96 (m, 1H), 1.94 (s,3H), 1.81-1.70 (m, 2H), 1.65-1.56 (m, 1H), 1.37-1.30 (m, 2H), 1.24-1.15 (m,1H). MS (ESI): C 20 H 24 The calculated mass of BN5O2 is 377.20, and the found m / z is 378.2 [M+H] + . HPLC: 95.47% (220 nm), 94.36% (254 nm).

[0505] 10. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0506]

[0507] 10.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0508]

[0509] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (3 g, 12.6 mmol, 1 eq) in i-PrOH (30 mL) at 20°C was added TFA (2.89 g, 25.37 mmol, 1.90 mL, 2 eq) and 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (3.50 g, 13.95 mmol, 1.1 eq). The mixture was heated to 90°C and stirred at 90°C for 16 hours. After a reaction time of 3 hours, a solid precipitated. TLC indicated that the reaction was complete. The reaction was filtered to give a crude product. The crude product was triturated with aqueous NaHCO3 (40 mL) at 20°C for 30 minutes and then filtered. The filter cake was washed with THF (100 mL) to give (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (5 g, 87% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 - 7.89(m, 2H), 7.85 (s, 1H), 7.73 (s, 1H), 5.69 (s, 1H), 4.52 (s, 2H), 4.41 - 4.28(m, 1H), 3.84 - 3.72 (m, 1H), 3.00 (dt, J = 2.4, 12.0 Hz, 1H), 2.16 (d, J =12.4 Hz, 1H), 2.02 (s, 3H), 1.90 - 1.80 (m, 1H), 1.77 - 1.52 (m, 3H), 1.50 -1.30 (m, 2H), 1.27 - 1.10 (m, 1H).

[0510] 10.2 Preparation of 2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0511]

[0512] To a solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (6 g, 13.3 mmol, 1 eq) and 2,6-lutidine (5.76 g, 53.2 mmol, 4 eq) in THF (60 mL) at 0°C was added TBSOTf (7.04 g, 26.6 mmol, 6.12 mL, 2 eq) dropwise. The mixture was stirred at 25°C for 3 h. LCMS indicated the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NH4Cl (100 mL) at 0°C and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with a solution of petroleum ether (15 mL) and ethyl acetate (15 mL) at 20 °C for 30 min to give (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (5.2 g, 69.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 1H), 8.32 (s, 1H), 7.75 (s,1H), 7.66 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 4.43 - 4.21 (m,1H), 2.95 - 2.85 (m, 1H), 2.27 - 2.08 (m, 1H), 2.03 - 1.85 (m, 4H), 1.83 -1.67 (m, 2H), 1.65 - 1.52 (m, 1H), 1.47 - 1.12 (m, 3H), 0.94 (s, 9H), 0.13(s, 6H).

[0513] 10.3 Preparation of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0514]

[0515] Five reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (0.4 g, 708 umol, 1 eq) was added to distilled water at 20°C. To a solution of 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl in 1,2-dioxaborinane (800 mg, 3.54 mmol, 5 eq), KOAC (208 mg, 2.12 mmol, 3 eq), and Pd(PPh3)2Cl2 (50 mg, 70.8 umol, 0.1 eq) were added. The mixture was then stirred at 120°C under a N2 atmosphere for 40 min. LCMS showed the reaction was complete. The reaction was cooled to room temperature, and five parallel reactions were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250 70mm#10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 45%-75%, 20min), giving 2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (1 g, 47.2% yield, 95% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 7.98 (s, 1H),7.74 (s, 1H), 7.43 (s, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.63 (s, 2H), 4.42 -4.26 (m, 1H), 3.70 (s, 4H), 2.95 - 2.90 (m, 1H), 2.18 (d, J = 11.6 Hz, 1H), 1.98 - 1.87 (m, 4H), 1.80 - 1.67 (m, 2H), 1.68 - 1.53 (m, 1H), 1.46 - 1.27(m, 2H), 1.47 - 1.12 (m, 1H), 1.04 (s, 6H), 0.92 - 0.87 (m, 9H), 0.06 (s, 6H).

[0516] 10.4 Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0517]

[0518] To a solution of (trans)2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (1.8 g, 3.40 mmol, 1 eq) in THF (20 mL) was added HCl (6 M, 2.26 mL, 4 eq) at 20°C. The mixture was stirred at 40°C for 1 hour. LCMS showed that the reaction was complete, and a major peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was triturated with MeCN (15 mL) at 25°C for 10 min to give a racemic product (1.5 g). The racemic product (1.5 g) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm 30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 42%-42%, 8 min), affording (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (90.5 mg, 95.79% purity, 98.80% ee, first peak, Rt = 1.280 min) stereoisomer 1 as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.84 (s, 1H), 7.84 (s, 1H), 7.77 (s,1H), 7.71 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.00 - 4.85 (m, 2H), 4.40 - 4.26(m, 1H), 2.93 (dt, J = 3.2, 11.2 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.00 -1.90 (m, 4H), 1.90 - 1.76 (m, 2H), 1.75 - 1.62 (m, 1H), 1.53 - 1.33 (m, 2H),1.33 - 1.19 (m, 1H). MS(ESI):C19H21 The calculated mass of BClN5O2 is 397.15, and the found m / z is 398.0 [M+H] + HPLC: 95.79% (220 nm), 95.88% (254 nm). (Trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (206 mg, 96.14% purity, 98.78% ee, second peak, Rt = 1.841 min) stereoisomer 2 was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.84 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.07 - 4.78 (m, 2H), 4.46 - 4.13 (m,1H), 2.93 (dt, J = 3.6, 12.0 Hz, 1H), 2.18 (d, J = 11.2 Hz, 1H), 2.00 - 1.90(s, 4H), 1.83 - 1.69 (m, 2H), 1.68 - 1.56 (m, 1H), 1.46 - 1.27 (m, 2H), 1.26- 1.13 (m, 1H). MS(ESI):C19H 21 The calculated mass of BClN5O2 is 397.15, and the found m / z is 398.1 [M+H] + . HPLC: 96.14% (220 nm), 99.69% (254 nm).

[0519] 11. Preparation of (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0520]

[0521] 11.1 Preparation of (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0522]

[0523] To a mixture of [5-amino-2-bromo-3-(trifluoromethyl)phenyl]methanol (3.6 g, 13.3 mmol, 1 eq) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (3.34 g, 13.3 mmol, 1 eq) in i-PrOH (40 mL) at 25°C was added TFA (2.28 g, 20.0 mmol, 1.5 mL, 1.5 eq) in one step. The mixture was stirred at 90°C for 5 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was cooled to room temperature, whereupon a large amount of precipitate formed. The mixture was filtered, and the filter cake was triturated with saturated aq. NaHCO 3 to afford 2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (5.2 g, 80.5% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.43 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.18 (d, J= 2.4 Hz, 1H), 7.77 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.57 (t, J = 5.2 Hz,1H), 4.54 (d, J = 5.2 Hz, 2H), 4.42-4.32 (m, 1H), 2.95-2.88 (m, 1H), 2.18-2.12 (m, 1H), 1.95 (s, 3H), 1.90-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.66-1.56 (m, 1H), 1.37-1.29 (m, 2H), 1.20-1.10 (m, 1H).

[0524] 11.2 Preparation of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0525]

[0526] To a solution of (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (3.5 g, 7.23 mmol, 1 eq) and 2,6-lutidine (2.34 g, 21.7 mmol, 2.6 mL, 3 eq) in THF (100 mL) at 0°C was added TBSOTf (2.87 g, 10.8 mmol, 2.5 mL, 1.5 eq). Following the addition, the reaction was allowed to warm to 25°C and stirred for 3 h. TLC indicated the reaction was complete. The reaction mixture was quenched with saturated aq. NH4Cl (80 mL) at 0°C and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (40 mL) at 25 °C for 30 min to give (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (4.1 g, 94.8% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.55 (s, 1H), 8.45 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 6.74 (d, J = 9.2 Hz, 1H), 4.72 (s, 2H), 4.37-4.28(m, 1H), 2.97-2.89 (m, 1H), 2.20-2.14 (m, 1H), 1.95 (s, 3H), 1.88-1.80 (m,1H), 1.76-1.68 (m, 2H), 1.60-1.50 (m, 1H), 1.39-1.14 (m, 4H), 0.95 (s, 9H), 0.14 (s, 6H).

[0527] 11.3 Preparation of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0528]

[0529] Four reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (1 g, 1.67 mmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-3 ... The mixture in 20 mL of 4-nitropropane (20 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C under N2 atmosphere for 40 min. LCMS showed that the reaction was complete and the desired MS was observed. The four parallel reactions were combined, filtered, and the filter cake was washed with EtOAc (90 mL x 2). The filtrate was concentrated under reduced pressure to give a residue (6 g, crude product). The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 75 mL / min) to give the crude product, which was purified by prep-HPLC (column: C18 (250 50mm 10 μm); mobile phase: [water (NH4HCO3)-ACN]; B%: 75%-95%, 10 min), to give 2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (2.4 g) as a colorless oil. 1 H NMR (DMSO-d 6,400 MHz) δ 9.34 (s, 1H), 8.27 (s,1H), 7.79 (s, 1H), 7.75 (s, 1H), 6.69 (d, J = 9.2 Hz, 1H), 4.73 (s, 2H),4.37-4.30 (m, 1H), 3.70 (s, 4H), 2.92 (m, 1H), 2.20-2.15 (m, 1H), 1.95 (s,3H), 1.90-1.85 (m, 1H), 1.76-1.68 (m, 2H), 1.60-1.50 (m, 1H), 1.36-1.26 (m,2H), 1.24-1.13 (m, 1H), 1.03 (s, 6H), 0.90 (s, 9H), 0.07 (s, 6H).

[0530] 11.4 Preparation of (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0531]

[0532] To a mixture of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (2 g, 3.17 mmol, 1 eq) in THF (20 mL) at 0°C was added HCl (6 M, 2.64 mL, 5 eq) dropwise. The mixture was stirred at 40°C for 0.5 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was cooled to room temperature, and a large precipitate formed. The reaction was filtered. The filter cake was washed with deionized water to give the crude product. The crude product was triturated with MeCN (20 mL) at 25 °C for 20 min to give (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (1.2 g) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ 10.91 (s, 1H), 9.17 (s, 1H), 8.44(d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 5.13-5.04 (m,2H), 4.32-4.22 (m, 1H), 3.04 (m, 1H), 2.18 (d, J = 11.2 Hz, 1H), 2.06 (s,3H), 1.88 (d, J = 12.8 Hz, 1H), 1.78-1.72 (m, 2H), 1.60-1.38 (m, 2H), 1.27-1.16 (m, 2H). The materials were separated by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm 50 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 40%-40%, 5 min), affording (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (557 mg, 99.90% ee, first peak, Rt = 1.246 min) stereoisomer 1 as an off-white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.51 (s, 1H), 8.89 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.06-4.97 (m, 2H),4.37-4.28 (m, 1H), 2.93 (m, 1H), 2.18 (d, J = 11.6 Hz, 1H), 1.96 (s, 3H),1.95-1.90 (m, 1H), 1.78-1.70 (m, 2H), 1.65-1.54 (m, 1H), 1.39-1.28 (m, 2H), 1.25-1.14 (m, 1H). MS (ESI): C 20 H 21 The calculated mass of BF3N5O2 is 431.17, and the found m / z is 432.3 [M+H] +HPLC: 99.25% (220 nm), 99.33% (254 nm). (Trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (551.7 mg, 99.34% ee, second peak, Rt = 1.443 min) stereoisomer 2 was obtained as an off-white solid. 1 HNMR (DMSO-d 6, 400 MHz) δ 9.54 (s, 1H), 8.90 (s, 1H), 8.13 (s, 1H), 8.03 (s,1H), 7.79 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.06-4.97 (m, 2H), 4.37-4.28 (m,1H), 2.94 (m, 1H), 2.20-2.15 (m, 1H), 1.97 (s, 3H), 1.95-1.90 (m, 1H), 1.78-1.69 (m, 2H), 1.65-1.54 (m, 1H), 1.39-1.29 (m, 2H), 1.26-1.15 (m, 1H). MS (ESI): C 20 H 21 The calculated mass of BF3N5O2 is 431.17, and the found m / z is 432.3 [M+H] + . HPLC: 97.52% (220nm), 98.26% (254nm).

[0533] 12. Preparation of 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile

[0534]

[0535] 12.1 Preparation of Methyl 2-Amino-3-Bromo-5-Nitrobenzoate

[0536]

[0537] To a solution of 2-amino-5-nitro-benzoic acid methyl ester (60 g, 305 mmol, 1 eq) in DMF (700 mL) at 35°C was added NBS (70.7 g, 397 mmol, 1.3 eq). The mixture was stirred at 35°C for 12 h. After 3 h of reaction, a solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to give the crude product (filter cake). The crude product was triturated with MTBE (50 mL) at 25°C for 1 h to afford 2-amino-3-bromo-5-nitro-benzoic acid methyl ester (70 g, 83.2% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.61 (d, J = 2.8 Hz, 1H), 8.47 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H).

[0538] 12.2 Preparation of Methyl 2-Amino-3-cyano-5-nitrobenzoate

[0539]

[0540] A mixture of methyl 2-amino-3-bromo-5-nitrobenzoate (70 g, 254 mmol, 1 eq), Zn (3.50 g, 53.5 mmol, 0.21 eq), Zn(CN)2 (59.7 g, 508 mmol, 2 eq), Pd2(dba)3 (6.99 g, 7.63 mmol, 0.03 eq), and 1,1-bis(diphenylphosphino)ferrocene (DPPF, 8.47 g, 15.2 mmol, 0.06 eq) in DMA (600 mL) was degassed and purged with N2 three times. The mixture was then stirred at 110°C under N2 atmosphere for 1 h. TLC indicated the reaction was complete. The reaction mixture was diluted with H2O (3 L) and extracted with EtOAc (1 L × 3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with DCM (60 mL) at 25°C for 1 h to afford 2-amino-3-cyano-5-nitro-benzoic acid methyl ester (30 g, 55.3% yield) as a gray solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.74 - 8.67 (m, 2H), 8.20 (s, 2H), 3.90 (s, 3H).

[0541] 12.3 Preparation of Methyl 2-Bromo-3-cyano-5-nitrobenzoate

[0542]

[0543] To a mixture of tert-butyl nitrite (27.9 g, 271 mmol, 32.2 mL, 2 eq) and CuBr2 (45.4 g, 203 mmol, 1.5 eq) in MeCN (100 mL) was added methyl 2-amino-3-cyano-5-nitro-benzoate (30 g, 135 mmol, 1 eq) portionwise at 65°C. The mixture was stirred at 65°C for 1 h. LCMS indicated the reaction was complete, and the desired mass was detected. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent: 0-25% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford methyl 2-bromo-3-cyano-5-nitro-benzoate (32 g, 82.7% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 3.94 (s, 3H).

[0544] 12.4 Preparation of Methyl 5-Amino-2-Bromo-3-cyanobenzoate

[0545]

[0546] To a solution of 2-bromo-3-cyano-5-nitro-benzoic acid methyl ester (30 g, 105 mmol, 1 eq) in EtOH (200 mL) and H₂O (100 mL) were added Fe (13.5 g, 242 mmol, 2.3 eq) and NHCl (12.9 g, 242 mmol, 2.3 eq). The mixture was stirred at 70°C for 2 h. LCMS indicated the reaction was complete, and the desired mass was detected. The reaction mixture was diluted with H₂O (500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (80 mL) at 25°C for 1 h to afford 5-amino-2-bromo-3-cyano-benzoic acid methyl ester (22 g, 81.9% yield) as a gray solid. 1HNMR (400 MHz, DMSO-d6) δ = 7.27 - 7.00 (m, 2H), 6.05 (s, 2H), 3.84 (s, 3H).

[0547] 12.5 Preparation of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile

[0548]

[0549] To a solution of 5-amino-2-bromo-3-cyano-benzoic acid methyl ester (22 g, 86.2 mmol, 1 eq) in THF (200 mL) at 25°C was added LiBH₄ (4 M in THF, 64.7 mL, 259 mmol, 3 eq). The mixture was stirred at 35°C for 12 h. LCMS indicated the reaction was complete, with the desired mass detected. The reaction mixture was quenched by the addition of H₂O (300 mL) at 0°C, and the pH was adjusted to 2 with aq. HCl (2 M). The resulting solution was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford a residue. The residue was triturated with MTBE (50 mL) at 25 °C for 1 h to afford 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile (10 g, 51.0% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.07 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 5.79 (s, 2H), 5.52 (t, J = 5.6 Hz, 1H), 4.39(d, J = 5.6 Hz, 2H).

[0550] 12.6 Preparation of 2-bromo-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile

[0551]

[0552] A mixture of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile (4.12 g, 18.1 mmol, 1.3 eq), 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexanecarbonitrile (3.5 g, 13.9 mmol, 1 eq), and TFA (2.39 g, 20.9 mmol, 1.55 mL, 1.5 eq) in i-PrOH (40 mL) was degassed and purged with N2 three times. The mixture was then stirred at 85°C under N2 for 12 h. LCMS indicated the reaction was complete, and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with saturated aq. NaHCO3 (20 mL) at 25°C for 2 h to afford 2-bromo-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile (2.3 g, 37.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.63 (s, 1H), 4.50 (s, 2H), 4.41 - 4.26 (m, 1H), 2.95 - 2.85 (m, 1H), 2.16 (d, J = 11.2 Hz, 1H), 1.99 - 1.86 (m, 4H), 1.79 - 1.59 (m, 3H), 1.50 -1.27 (m, 2H), 1.25 - 1.10 (m, 1H).

[0553] 12.7 Preparation of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile

[0554]

[0555] To a solution of 2-bromo-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile (2.3 g, 5.21 mmol, 1 eq) in THF (50 mL) at 25°C was added 2,6-lutidine (1.78 g, 16.6 mmol, 1.94 mL, 3 eq) and [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (2.20 g, 8.33 mmol, 1.91 mL, 1.5 eq). The mixture was stirred at 35°C for 2 h. LCMS showed complete consumption of the reaction, and a major peak with the desired mass was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (50 mL) at 25°C for 30 min to afford 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-((2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (3 g, 97.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.67 (s,1H), 8.51 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 6.90(d, J = 8.4 Hz, 1H), 4.67 (s, 2H), 4.38 - 4.22 (m, 1H), 3.00 - 2.95 (m, 1H), 2.17 (d, J = 13.6 Hz, 1H), 1.96 (s, 3H), 1.92 - 1.84 (m, 1H), 1.80 - 1.54 (m,3H), 1.43 - 1.29 (m, 2H), 1.26 - 1.08 (m, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

[0556] 12.9 Preparation of (2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-cyano-4-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)boronic acid

[0557]

[0558] Six reactions were performed in parallel. For each reaction, 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (500 mg, 899 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl (1.42 g, 6.30 mmol, 7 eq), KOAc (264 mg, 2.70 mmol, 3 eq), Pd(PPh3)2Cl2 (63.1 mg, 90.0 umol, 0.1 eq) were added to a 1% ethanol solution in a 1% ethanol solution. The mixture in 10 mL of oxane (10 mL) was degassed and purged with N2 three times, then stirred at 120°C under N2 for 1 h. LCMS showed complete consumption of the reaction and detection of the desired compound. Six parallel reactions were combined, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by prep-HPLC (neutral conditions; column: Waters Xbridge BEH C18 250 50mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 10 min), to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyano-4-((4-(((trans)2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)boronic acid (400 mg, 12.5% ​​yield) as a white solid.

[0559] 12.10 Preparation of 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile

[0560]

[0561] To a solution of (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyano-4-((4-((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)boronic acid (400 mg, 679 μmol, 1 eq) in THF (10 mL) was added aq. HCl (6 M, 640 μL, 4 eq) at 25°C. The mixture was stirred at 25°C for 2 h. A solid then precipitated. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was filtered to afford 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile (360 mg, 95% yield, 99% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 11.11 (s, 1H), 9.49 - 9.35 (m, 1H), 8.65 - 8.55 (m, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 5.06 (s, 2H), 4.33 - 4.21 (m, 1H), 3.64- 3.56 (m, 1H), 3.12 - 2.98 (m, 1H), 2.20 - 2.14 (m, 1H), 2.06 (s, 3H), 1.95- 1.87 (m, 1H), 1.74 - 1.57 (m, 2H), 1.50 - 1.30 (m, 2H), 1.27 - 1.13 (m, 1H). The racemic material was separated by SFC (column: DAICEL CHIRALPAK AD (250mm 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 36%-36%, 6 min), to afford 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile (80.8 mg, 99.62% purity, 99.42% ee, first peak, Rt = 1.108 min) stereoisomer 1 as a white solid; 1H NMR(400 MHz, DMSO-d6) δ = 9.55 (s, 1H), 9.17 (s, 1H), 8.23 ​​(s, 1H), 8.02 (s,1H), 7.80 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.05 - 4.95 (m, 2H), 4.37 - 4.25(m, 1H), 3.00 - 2.90 (m, 1H), 2.22 - 2.11 (m, 1H), 2.00 - 1.95 (s, 4H), 1.81- 1.57 (m, 3H), 1.45 - 1.27 (m, 2H), 1.26 - 1.12 (m, 1H). MS (ESI): C 20 H 21 The calculated mass of BN6O2 is 388.18, and the measured m / z is 389.2 [M+H] + HPLC: 99.62% (220 nm), 99.60% (254 nm). Stereoisomers 2 of 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile (72.0 mg, 99.62% purity, 98.64% ee, second peak, Rt = 1.499 min) were obtained as white solids. 1 H NMR (400 MHz, DMSO-d6) δ = 9.58 (s, 1H),9.19 (s, 1H), 8.23 ​​(s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 6.84 (d, J = 8.8 Hz,1H), 5.05 - 4.95 (m, 2H), 4.38 - 4.25 (m, 1H), 2.98 - 2.86 (m, 1H), 2.22 -2.13 (m, 1H), 2.00 - 1.95 (s, 4H), 1.82 - 1.57 (m, 3H), 1.44 - 1.27 (m, 2H),1.25 - 1.12 (m, 1H). MS (ESI): C 20 H 21 The calculated mass of BN6O2 is 388.18, and the measured m / z is 387.1 [MH] - . HPLC: 99.62% (220 nm), 100.0% (254 nm).

[0562] 13. Preparation of (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0563]

[0564] To a mixture of 7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulene-4-amine (50 mg, 219 umol, 1 eq, HCl) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (60.6 mg, 241 umol, 1.1 eq) in 2-methylbutan-2-ol (3 mL) at 20°C under N2 was added BrettPhos Pd G3 (19.9 mg, 21.9 umol, 0.1 eq), BRETTPHOS (11.8 mg, 21.9 umol, 0.1 eq), and Cs2CO3 (214 mg, 659 umol, 3 eq) in one step. The mixture was heated to 100°C and stirred for 16 h. LCMS indicated the reaction was complete, with the desired MS observed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 30mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 10 min), to give 2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-boronobenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (24 mg, 95.34% purity) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ 9.23 (s, 1H), 7.77 (s, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 6.65 (d, J = 6.4 Hz, 1H), 5.06 (s, 2H), 4.66-4.57 (m, 1H), 4.35-4.24 (m, 2H),4.22-4.12 (m, 1H), 4.03-3.98 (m, 1H), 3.76-3.74 (m, 1H), 2.03-1.99 (m, 1H),1.98 (s, 3H), 1.88-1.77 (m, 3H), 1.74-1.65 (m, 2H), 1.45-1.39 (m, 2H). MS (ESI): C 21 H 24 The calculated mass of BN5O3 is 405.20, and the measured m / z is 404.3 [MH] - . HPLC: 95.34% (220nm), 90.93% (254nm).

[0565] 14. Preparation of (trans)-2-[[2-[(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile hydrochloride

[0566]

[0567] 14.1 Preparation of methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate

[0568]

[0569] To a mixture of 5-amino-2-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol, 1 eq) in MeOH (35 mL) at 20°C was added Boc2O (10.4 g, 47.8 mmol, 2.2 eq) and Na2CO3 (6.91 g, 65.2 mmol, 3 eq). The mixture was stirred at 20°C for 24 h. TLC indicated the reaction was complete. Methanol was removed from the reaction under reduced pressure, and the resulting residue was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-13% ethyl acetate / petroleum ether gradient @ 75 mL / min) to give methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate (6.00 g, 83.6% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 7.84 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz,1H), 7.40 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.69 (br s, 1H), 3.91 (s, 3H), 1.51(s, 9H).

[0570] 14.2 Preparation of 2-(5-amino-2-bromo-phenyl)propan-2-ol

[0571]

[0572] To a solution of MeMgBr (3 M in diethyl ether, 48.5 mL, 12 eq) in THF (40 mL) was added methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate (4.00 g, 12.1 mmol, 1 eq) at 0°C over 0.5 h. Following the addition, the reaction was warmed to 35°C and stirred for 5.5 h. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aq. NH4Cl (100 mL), the pH adjusted to 6 with 2N HCl at 0°C, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient @ 75 mL / min) to give 2-(5-amino-2-bromo-phenyl)propan-2-ol as a yellow solid (2.3 g, 82% yield). 1 H NMR (CDCl3, 400 MHz) δ 7.31 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.4 Hz, 2.8Hz, 1H), 1.72 (s, 6H).

[0573] 14.3 Preparation of 2-[[2-[4-Bromo-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0574]

[0575] At 25 ° C under N2, 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (700 mg, 2.79 mmol, 1 eq) was added to dichloromethane. To a solution of 2-(5-amino-2-bromo-phenyl)propan-2-ol (697 mg, 3.03 mmol, 1.09 eq) and TsOH·H₂O (797 mg, 4.19 mmol, 1.5 eq) in 2% dextrose (20 mL) was added, and the mixture was heated at 80°C and stirred for 12 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with H₂O (20 mL), the pH adjusted to 7 with saturated aqueous NaHCO₃ at 0°C, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (20 mL) at 25 °C to give 2-[[2-[4-bromo-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (700 mg, 56.4% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.64 (dd,J = 8.8 Hz, 2.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H),5.13 (s, 1H), 4.39-4.31 (m, 1H), 2.97-2.90 (m, 1H),2.16-2.11 (m, 1H), 1.93(s, 3H), 1.92-1.88 (m, 1H), 1.75-1.66 (m, 3H), 1.61 (s, 6H), 1.45-1.23 (m, 3H).

[0576] 14.4 Preparation of (trans)-2-[[2-[(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile hydrochloride

[0577]

[0578] Five reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 225 umol, 1 eq) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 225 umol, 1 eq) were added to the mixture at 25°C under N2. To a solution of 1% ethyl acetate (44.2 mg, 450 μmol, 2 eq) and Pd(PPh3)2Cl2 (15.8 mg, 22.5 μmol, 0.1 eq) in 1% dextrose (5 mL) was added. The mixture was heated at 120°C and stirred for 0.5 h. TLC indicated the reaction was complete. Five parallel reactions were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 80 40mm 3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 18%-32%, 7 min), gave (trans)-2-[[2-[(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile hydrochloride (163.3 mg, 35.2% yield, 95.81% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 12.17 (s, 1H),10.42 (s, 1H), 9.03 (s, 1H), 8.36 (s, 1H), 7.84 (s, 1H), 7.68 (d, J = 7.6 Hz,1H), 7.59 (s, 1H), 7.47 (dd, J = 9.6 Hz, 8.0 Hz 1H), 4.34-4.25 (m, 1H), 3.08-2.99 (m, 1H), 2.24-2.17 (m, 1H), 2.04 (s, 3H), 1.93-1.85 (m, 1H), 1.78-1.69(m, 2H), 1.61-1.51 (m, 1H), 1.48 (d, J = 10.4 Hz, 6H), 1.44-1.37 (m, 1H), 1.28-1.14 (m, 2H). MS (ESI): C 21 H 27The calculated mass of BClN5O2 is 391.22, and the found m / z is 392.3 [M+H] + . HPLC: 95.81% (220 nm), 96.45% (254 nm).

[0579] 15. Preparation of (trans)-2-[[2-[(2-hydroxy-1,2-benzoxaborol-6-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0580]

[0581] 15.1 Preparation of 2-[[2-[(4-methoxyphenyl)methylamino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0582]

[0583] A mixture of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (600 mg, 2.39 mmol, 1 eq) and PMBNH2 (6.36 g, 46 mmol, 6 mL, 19 eq) was stirred at 100°C for 4 h. TLC indicated the reaction was complete. The reaction was poured into saturated aq. NH4Cl (20 mL) and the pH was adjusted to 5 with aq. HCl (2N). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give (trans)-2-[[2-[(4-methoxyphenyl)methylamino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (370 mg, 44% yield) as a white solid. 1 H NMR (CDCl 3,400 MHz) δ 12.16 (s, 1H),8.45 (s, 1H), 8.23 ​​(q, J = 8.4 Hz, 1H), 7.65 (s, 1H), 8.28 (q, J = 8.8 Hz,2H), 6.89 (q, J = 8.4 Hz, 2H), 4.55-4.25 (m, 2H), 4.40-4.20 (m, 1H), 3.72 (s,3H), 3.10-2.90 (m, 1H), 2.20-2.10 (m, 1H), 1.95 (s, 3H), 1.75-1.65 (m, 2H),1.63-1.50 (m. 1H), 1.40-1.20 (m, 2H), 1.20-1.00 (m, 1H).

[0584] 15.2 Preparation of 2-[(2-amino-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile

[0585]

[0586] A mixture of (trans)-2-[[2-[(4-methoxyphenyl)methylamino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (300 mg, 853 umol, 1 eq) in TFA (3 mL) was stirred at 20°C under an N2 atmosphere for 3 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The aqueous layer was lyophilized to give (trans)-2-[(2-amino-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (200 mg, 96% yield) as a white solid.

[0587] 15.3 Preparation of (trans)-2-[[2-[(2-hydroxy-1,2-benzoxaborol-6-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0588]

[0589] A mixture of 6-bromo-2-hydroxy-1,2-benzoxaborinane (100 mg, 444 umol, 1 eq), (trans)-2-[(2-amino-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (103 mg, 444 umol, 1 eq), KCO (123 mg, 889 umol, 2 eq), Pd(dba) (20 mg, 22 umol, 0.05 eq), and t-BuXphos (19 mg, 44 umol, 0.1 eq) in i-PrOH (6 mL) was degassed and purged with N three times. The mixture was then stirred at 80°C under a N atmosphere for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NHCl (10 mL) at 20°C and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters XbridgeBEH C18 100 30mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-50%, 10 min), gave (trans)-2-[[2-[(2-hydroxy-1,2-benzoxaborin-6-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (31.8 mg, 19% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.85(s, 1H), 8.80 (s, 1H), 7.89 (s, 1H), 7.80-7.65 (m, 2H), 7.60 (d, J = 8.8 Hz,1H), 7.11 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.11 (d, J = 12.0Hz, 1H), 4.35-4.25 (m, 1H), 3.00-2.90 (m, 1H), 2.18 (d, J = 11.6 Hz, 1H), 2.00-1.90 (m, 4H), 1.85-1.70 (m, 2H), 1.65-1.50 (m, 1H), 1.40-1.25 (m, 2H), 1.25-1.10 (m, 1H). MS (ESI): C 20 H 22The calculated mass of BN5O2 is 375.19, and the found m / z is 374.3 [MH] - . HPLC: 98.55% (220 nm), 99.53% (254 nm).

[0590] 16. Preparation of (trans)-2-((2-((2-hydroxy-3-methyl-2H-benzo[e][1,2]oxaborolan-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0591]

[0592] 16.1 Preparation of tert-Butyl N-(2-hydroxy-3-methyl-1,2-benzoxaborin-6-yl)carbamate

[0593]

[0594] Three reactions were performed in parallel. For each reaction, 6-bromo-2-hydroxy-3-methyl-1,2-benzoxaborinane (200 mg, 837 umol, 1 eq) and tert-butyl carbamate (118 mg, 1.0 mmol, 1.2 eq) were added to the mixture at 25 °C under N2. To a mixture of 2,4-dioxane (3 mL) was added t-BuXphos (36 mg, 83.7 umol, 0.1 eq), K3PO4 (355 mg, 1.67 mmol, 2 eq), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (t-BuXphosPdG3, 66 mg, 83.7 umol, 0.1 eq) in one step. The mixture was heated at 100°C and stirred for 10 h. TLC indicated the reaction was complete. The three parallel reactions were combined, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 70-80% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl N-(2-hydroxy-3-methyl-1,2-benzoxaborin-6-yl)carbamate (600 mg, 60% yield, 70% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.26 (s, 1H), 8.81 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz,1H), 2.00 (s, 3H), 1.48 (s, 9H).

[0595] 16.2 Preparation of 2-Hydroxy-3-methyl-1,2-benzoxaborin-6-amine Hydrochloride

[0596]

[0597] To a mixture of tert-butyl N-(2-hydroxy-3-methyl-1,2-benzoxaborinan-6-yl)carbamate (500 mg, 1.27 mmol, 70% purity, 1 eq) in EtOAc (3 mL) was added HCl / EtOAc (4N, 6.36 mL, 20 eq) in one step at 25°C under N2. The mixture was stirred at 25°C for 2 h. TLC indicated the reaction was complete. The mixture was concentrated to give a residue. The residue was triturated with EtOAc (2 mL) to give 2-hydroxy-3-methyl-1,2-benzoxaborinan-6-amine hydrochloride (150 mg, 55% yield, HCl salt) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.12(s, 3H), 9.09 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.32-7.27 (m, 2H), 2.03(s, 3H).

[0598] 16.3 Preparation of (trans)-2-((2-((2-hydroxy-3-methyl-2H-benzo[e][1,2]oxaborolan-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0599]

[0600] Two reactions were performed in parallel. For each reaction, 2-hydroxy-3-methyl-1,2-benzoxaborin-6-amine hydrochloride (100 mg, 472 umol, 1 eq, HCl salt) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (119 mg, 472 umol, 1 eq) were added to the mixture at 25°C under N2. To the mixture in oxane (5 mL), TsOH·H₂O (81 mg, 472 umol, 1 eq) was added in one step. The mixture was heated at 80°C and stirred for 15 h. TLC indicated the reaction was complete. The two parallel reactions were combined and concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (10 mL) and washed with saturated aq. NaHCO₃ (5 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with a mixed solvent of MeCN (5 mL) and H₂O (5 mL) to give 2-((2-((2-hydroxy-3-methyl-2H-benzo[e][1,2]oxaborolan-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (102 mg, 27% yield, 99.68% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.79 (s, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.03 (d, J =8.0 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.31-4.28 (m, 1H), 2.98-2.91 (m, 1H), 2.19-2.16 (m, 1H), 1.99 (s, 3H), 1.93 (s, 3H), 1.82-1.90 (m, 1H), 1.76-1.69(m, 2H), 1.59-1.56 (m, 1H), 1.32-1.24 (m, 2H), 1.21-1.14 (m, 1H). MS (ESI): C 21 H 24 The calculated mass of BN5O2 is 389.20, and the found m / z is 390.3 [M+H] + . HPLC: 99.68% (220 nm), 99.75% (254 nm).

[0601] 17. Preparation of (trans)-2-((5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0602]

[0603] 17.1 Preparation of methyl 2-bromo-5-((5-chloro-4-((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)benzoate

[0604]

[0605] (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (2.30 g, 8.48 mmol, 1 eq), 5-amino-2-bromo-benzoic acid methyl ester (2.15 g, 9.33 mmol, 1.1 eq) and TsOH·H2O (3.23 g, 16.9 mmol, 2 eq) were reacted in a 2% ethanol solution. The mixture was heated at 80°C and stirred in oxane (60 mL) for 12 h. TLC indicated the reaction was complete. The reaction mixture was cooled and concentrated in vacuo to afford a residue. The residue was triturated with a mixed solvent of EtOAc (50 mL) and saturated aq. Na2CO3 (50 mL) to afford methyl 2-bromo-5-[[5-chloro-4-[(2-cyanocyclohexyl)amino]pyrimidin-2-yl]amino]benzoate (2.1 g, 53% yield) as a gray solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.02(s, 1H), 7.95 (s, 1H), 7.59-7.54 (m, 2H), 7.15 (s, 1H), 5.27-5.25 (m, 1H), 4.38-4.32 (m, 1H), 3.92 (s, 3H), 2.76-2.73 (m, 1H), 2.12-2.10 (m, 2H), 1.80-1.77 (m, 3H), 1.62-1.58 (m, 1H), 1.47-1.43 (m, 2H).

[0606] 17.2 Preparation of methyl 5-((5-chloro-4-(((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzoate

[0607]

[0608] To methyl 2-bromo-5-((5-chloro-4-(((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)benzoate (500 mg, 1.08 mmol, 1 eq) in dichloromethane was added at 25°C under N2. To this mixture in 2% dextrin (15 mL) was added KOAc (264 mg, 2.69 mmol, 2.5 eq), Pd(PPh3)2Cl2 (75.5 mg, 107 umol, 0.1 eq), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (608 mg, 2.69 mmol, 2.5 eq) in one step. The mixture was then heated to 120°C and stirred for 3 hours. TLC indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (20 mL) at 20 °C for 30 min to give methyl 5-((5-chloro-4-(((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (500 mg, crude) as an off-white solid which was used directly in the next step.

[0609] 17.3 Preparation of (trans)-2-((5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0610]

[0611] To a mixture of methyl 5-((5-chloro-4-(((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (500 mg, 1.00 mmol, 1 eq) in THF (10 mL) at 0°C under N2 was added MeOH (12.3 mmol, 0.5 mL, 12.3 eq) and NaBH4 (95.0 mg, 2.51 mmol, 2.5 eq) portionwise. The mixture was stirred at 0°C for 1 h. TLC indicated the reaction was complete. The mixture was poured into ice water (20 mL), and the pH of the aqueous phase was adjusted to 5-6 with aq. HCl (2N). The resulting mixture was diluted with ethyl acetate (20 mL), and the suspension was filtered. The filter cake was washed with water (10 mL x 3) and dried in vacuo to give the crude product. The crude product was purified by trituration with THF (10 mL) at 20°C for 0.5 h to give (trans)-2-((5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile as an off-white solid (132.4 mg, 32% yield, 95.1% purity). 1H NMR (DMSO-d 6, 400 MHz) δ 9.52 (s,1H), 8.94 (br s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.57 (q, J = 8.0 Hz, 2H),7.35 (d, J = 8.8 Hz, 1H), 4.99-4.90 (m, 2H), 4.33-4.27 (m, 1H), 3.05-3.04 (m,1H), 2.20-2.17 (m, 1H), 1.95-1.91 (m, 1H), 1.80-1.79 (m, 1H), 1.76-1.71 (m,1H), 1.63-1.59 (m, 1H), 1.37-1.35 (m, 1H), 1.34-1.20 (m, 2H). MS (ESI): C 18 H 19 The calculated mass of BClN5O2 is 383.64, and the found m / z is 384.0 [M+H] + . HPLC: 95.1% (220 nm), 93.88% (254 nm).

[0612] 18. Preparation of 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile

[0613]

[0614] 18.1 Preparation of 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile

[0615]

[0616] To a solution of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile (3 g, 13.2 mmol, 1 eq) in i-PrOH (25 mL) at 25°C was added TFA (2.26 g, 19.8 mmol, 1.47 mL, 1.5 eq) and 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (3.13 g, 13.3 mmol, 1 eq). The mixture was stirred at 80°C for 12 h. After 3 h of reaction, a solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to give a filter cake. The filter cake was triturated with saturated aq. NaHCO3 (20 mL) at 25°C for 30 min to give 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile (3.6 g, 63.7% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ = 9.51 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J =2.4 Hz, 1H), 7.80 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.63 (s, 1H), 4.90 -4.80 (m, 1H), 4.51 (s, 2H), 3.13 (q, J = 8.8 Hz, 1H), 2.26 - 2.10 (m, 2H), 1.98 (s, 3H), 1.94 - 1.74 (m, 3H), 1.63 - 1.50 (m, 1H).

[0617] 18.2 Preparation of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile

[0618]

[0619] To a solution of 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile (3.6 g, 8.43 mmol, 1 eq) in THF (35 mL) at 25°C was added 2,6-lutidine (2.71 g, 25.2 mmol, 2.94 mL, 3 eq) and [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (3.34 g, 12.6 mmol, 2.90 mL, 1.5 eq). The mixture was stirred at 25°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NHCl (80 mL) at 0°C and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (10 mL) at 25°C for 30 min to give the compound 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (3 g, 65.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.60 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 6.86 (d, J= 8.0 Hz, 1H), 4.85 - 4.75 (m, 1H), 4.67 (s, 2H), 3.11 (q, J = 8.4 Hz, 1H), 2.26 - 2.06 (m, 2H), 1.96 (s, 3H), 1.89 - 1.73 (m, 3H), 1.63 - 1.52 (m, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

[0620] 18.3 Preparation of 3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzonitrile

[0621]

[0622] Six reactions were performed in parallel. For each reaction, 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (500 mg, 923 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dimethylpyrimidin ... The mixture in 20% dextrose (10 mL) was degassed and purged with N2 three times, then stirred at 120°C under N2 atmosphere for 1 h. LCMS indicated the reaction was complete, and the desired MS was observed. The six parallel reactions were combined, diluted with H2O (150 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral conditions; column: Waters Xbridge BEH C18 250 50mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 10 min), giving 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (900 mg, 28.2% yield) as a white solid.

[0623] 18.4 Preparation of 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile

[0624]

[0625] To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (900 mg, 1.57 mmol, 1 eq) in THF (5 mL) was added HCl (6 M, 2 mL, 7.66 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete, and a major peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid (FA) conditions; column: Phenomenexluna C18 (250 70 mm, 15 um); mobile phase: [water (FA)-ACN]; B%: 15%-45%, 20 min), affording 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-7-carbonitrile (160.5 mg, 28.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ = 9.55 (s, 1H), 9.17 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.09 (s, 1H), 7.80(s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H), 4.84 - 4.75 (m, 1H), 3.32 -3.07 (m, 1H), 2.25 - 2.08 (m, 2H), 1.97 (s, 3H), 1.92 - 1.72 (m, 3H), 1.66 -1.51 (m, 1H). MS (ESI): C 19 H 19 The calculated mass of BN6O2 is 374.17, and the found m / z is 375.1 [M+H] + . HPLC: 96.77% (220 nm), 95.94% (254 nm).

[0626] 19. Preparation of (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0627]

[0628] 19.1 Preparation of 2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0629]

[0630] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (800 mg, 3.38 mmol, 1 eq) in i-PrOH (10 mL) at 25°C was added TFA (578 mg, 5.07 mmol, 375 μL, 1.5 eq) and (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (917 mg, 3.38 mmol, 1 eq). The mixture was stirred at 80°C for 5 h. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to afford a filter cake. The filter cake was triturated with saturated aq. NaHCO₃ (10 mL) to afford (trans)-2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (1 g, 62.7% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.65(s, 1H), 8.09 - 8.03 (m, 1H), 7.83 (s, 1H), 7.36 (d, J = 9.2 Hz, 1H), 5.56(s, 1H), 4.49 (s, 2H), 4.41 - 4.29 (m, 1H), 3.60 (t, J = 6.4 Hz, 1H), 3.08 -2.96 (m, 1H), 2.20 - - 2.10 (m, 1H), 1.95 - 1.85 (s, 1H), 1.75 - 1.58 (m,3H), 1.46 - 1.31 (m, 2H), 1.24 - 1.09 (m, 1H).

[0631] 19.2 Preparation of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0632]

[0633] To a solution of (trans)-2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (900 mg, 1.91 mmol, 1 eq) in THF (20 mL) was added 2,6-lutidine (818 mg, 7.64 mmol, 4 eq) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (757 mg, 2.87 mmol, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 3 h. TLC showed the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NH4Cl (30 mL) at 0°C and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (10 mL) to give (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (600 mg, 53.6% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ = 9.78 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.03 (s,1H), 7.62 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.66 (s, 2H), 4.36 - 4.25 (m,1H), 3.02 (t, J = 2.8, 12.4 Hz, 1H), 2.22 - 2.13 (m, 1H), 1.95 - 1.85 (m,1H), 1.79 - 1.67 (m, 2H), 1.64 - 1.50 (m, 1H), 1.48 - 1.28 (m, 2H), 1.24 -1.10 (m, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

[0634] 19.3 Preparation of (trans)-2-((2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0635]

[0636] Two reactions were performed in parallel. For each reaction, (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (200 mg, 341 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-3-yl)-2-methyl-4-oxadiazole (540 mg, 2.39 mmol, 7 eq), KOAc (100 mg, 1.02 mmol, 3 eq), Pd(PPh3)2Cl2 (24 mg, 34.1 umol, 0.1 eq) were added to a 1% ethanol solution in a 1% ethanol solution. The mixture in 1% dextrose (3 mL) was degassed and purged with N₂ three times, then stirred at 120°C under N₂ for 1 h. LCMS indicated the reaction was complete, with the desired MS observed. The two parallel reactions were combined and filtered, and the residue was purified by prep-HPLC (neutral conditions; column: Waters Xbridge PrepOBD C₁₈ 150 40mm 10 μm; mobile phase: [water (NH4HCO3) -ACN]; B%: 50%-90%, 8 min), gave (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (60 mg, 15% yield) as a white solid.

[0637] 19.4 Preparation of (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0638]

[0639] To a solution of (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (60 mg, 109 umol, 1 eq) in THF (5 mL) at 25°C was added aq. HCl (6 M, 0.2 mL). The mixture was stirred at 25°C for 1 h. LCMS showed the reaction was complete, and the desired MS was observed. The reaction was concentrated under reduced pressure to give a residue. The residue was triturated with n-pentane (1 mL) to give (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile as a white solid (18.9 mg, 41.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 8.91 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.05 -4.95 (m, 2H), 4.36 - 4.24 (m, 1H), 3.03 (t, J = 2.8, 12.0 Hz, 1H), 2.20 -2.15 (d, J = 12.4 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.81 - 1.68 (m, 2H), 1.67 -1.55 (m, 1H), 1.44 - 1.29 (m, 2H), 1.24 - 1.13 (m, 1H). MS (ESI): C 18 H 18 The calculated mass of BCl2N5O2 is 417.09, and the found m / z is 418.0 [M+H] + . HPLC: 97.31% (220 nm), 98.50% (254nm).

[0640] 20. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0641]

[0642] 20.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0643]

[0644] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (1 g, 4.22 mmol, 1 eq) and (trans)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (1.07 g, 4.22 mmol, 1 eq) in i-PrOH (10 mL) at 25°C was added TFA (1.44 g, 12.7 mmol, 3 eq) dropwise. The resulting mixture was stirred at 80°C for 12 h. After a 3-hour reaction time, a solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to afford a residue. The residue was triturated with saturated aq. NaHCO₃ (20 mL) and filtered to afford (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (1 g, 52% yield) as a white solid. 1 H NMR (DMSO-d6,400 MHz) δ 10.37 (s, 1 H), 8.76 (s, 1 H), 8.20 (d, J = 4.4 Hz, 1 H), 7.97 (d,J = 2.8 Hz, 1 H), 7.79 (d, J = 2.8 Hz, 1 H), 4.52 (s, 2 H), 4.32-4.20 (m, 1H), 2.93-2.75 (m, 1 H), 2.20-2.10 (m, 1 H), 2.02-1.93 (m, 1 H), 1.78-1.61 (m,3 H), 1.41-1.35 (m, 2 H), 1.34-1.23 (m, 1 H).

[0645] 20.2 Preparation of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-fluoropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0646]

[0647] To a solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (803 mg, 1.77 mmol, 1 eq) in THF (10 mL) at 25°C was added 2,6-lutidine (757 mg, 7.07 mmol, 820 μL, 4 eq) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (700 mg, 2.65 mmol, 600 μL, 1.5 eq). The mixture was stirred at 25°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of H₂O (20 mL) at 0°C and extracted with EtOAc (20 mL x 3). 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. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-fluoropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (0.8 g, 79.6% yield) as a white solid.

[0648] 20.3 Preparation of (trans)-2-((2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0649]

[0650] Five reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 175 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dimethyl-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-3-yl)-1,3,2-dioxaborinan-3-yl)-1,3,2-dimethyl ... The mixture was degassed in 1,2-dioxaborinane (5 mL) and purged with N2 three times, then stirred at 120°C under an N2 atmosphere for 40 min. TLC indicated the reaction was complete. Five parallel reactions were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (0.5 g, crude) as a white solid.

[0651] 20.4 Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0652]

[0653] To a solution of (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (0.5 g, 830 umol, 1 eq) in THF (10 mL) at 25° C. was added aq. HCl (4 M, 2.0 mL, 9.6 eq). The mixture was stirred at 25° C. for 1 h. A solid precipitated. The reaction mixture was filtered to give a residue. The residue was triturated with MeCN (5 mL) and filtered to give 2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (81 mg, 24.3% yield, 98.07% purity) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1 H), 8.89 (s, 1 H), 8.01 (d, J = 3.6Hz, 1 H), 7.85-7.75 (m, 2 H), 7.69 (s, 1 H), 5.00 - 4.90 (m, 2 H), 4.32-4.20(m, 1 H), 2.92-2.63 (m, 1 H), 2.38-2.30 (m, 1 H), 1.86-1.77 (m, 1 H), 1.76-1.75 (m, 2 H), 1.74-1.70 (m, 1 H), 1.41-1.35 (m, 2 H), 1.34-1.30 (m, 1 H). MS(ESI):C 18 H 18 The calculated mass of BClFN5O2 is 401.12, and the found m / z is 402.2 [M+H] + . HPLC: 98.07% (220nm), 98.08% (254nm).

[0654] 21. Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0655]

[0656] 21.1 Preparation of (trans)-2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0657]

[0658] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (500 mg, 2.11 mmol, 1 eq) in i-PrOH (5 mL) at 25°C was added TFA (361 mg, 3.17 mmol, 1.5 eq) and (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (643 mg, 2.11 mmol, 1 eq). The mixture was stirred at 80°C for 4 hours. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was triturated with saturated aq. NaHCO₃ (30 mL) and filtered, affording (trans)-2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile (800 mg, 75.1% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.36 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.51 (d, J =6.0 Hz, 1H), 4.51 (s, 2H), 4.50 - 4.40 (m, 1H), 3.20 - 3.10 (m, 1H), 2.20 -2.09 (m, 1H), 1.90 - 1.79 (m, 1H), 1.78 - 1.54 (m, 3H), 1.52 - 1.28 (m, 2H),1.21 - 1.05 (m, 1H).

[0659] 21.2 Preparation of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0660]

[0661] To a solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (500 mg, 990 umol, 1 eq) in THF (20 mL) at 25°C was added 2,6-lutidine (424 mg, 3.96 mmol, 4 eq) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (393 mg, 1.49 mmol, 1.5 eq). The mixture was stirred at 25°C for 2 hours. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of H2O (20 mL) at 0°C and extracted with EtOAc (20 mL x 3). 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. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile (500 mg, 81.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.14 (s, 1H), 8.28(s, 2H), 7.62 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H), 4.54 - 4.38(m, 1H), 3.19 - 3.04 (m, 1H), 2.22 - 2.09 (m, 1H), 1.90 - 1.80 (m, 1H), 1.79- 1.65 (m, 2H), 1.65 - 1.51 (m, 1H), 1.51 - 1.40 (m, 1H), 1.40 - 1.29 (m,1H), 1.22 - 1.08 (m, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

[0662] 21.3 Preparation of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0663]

[0664] To (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile (400 mg, 646 umol, 1 eq) was added dichloromethane at 25 °C. To a solution of 1,4-dioxaborin-2-yl (45.3 mg, 64.6 umol, 0.1 eq) in 1,2-dioxaborinane (8 mL) was added Pd(PPh3)2Cl2 (45.3 mg, 64.6 umol, 0.1 eq), KOAc (190 mg, 1.94 mmol, 3 eq), and 2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (729 mg, 3.23 mmol, 5 eq). The mixture was stirred at 120°C for 10 min. TLC indicated the reaction was complete. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 40mm 3 um; mobile phase: [water (FA formic acid) -ACN]; B%: 30%-80%, 8 min), gave 2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (110 mg, 26.1% yield) as a white solid.

[0665] 21.4 Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0666]

[0667] To a solution of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (110 mg, 168 μmol, 1 eq) in THF (2 mL) at 25°C was added aq. HCl (6 M, 2 mL). The mixture was stirred at 25°C for 1 hour. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was triturated with THF (5 mL) to give (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile as a white solid (13.6 mg, 17.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.09 (s, 1H), 8.31 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.03 - 4.89 (m, 2H), 4.52 - 4.40 (m,1H), 3.19 - 3.05 (m, 1H), 2.25 - 2.15 (m, 1H), 1.91 - 1.84 (m, 1H), 1.81 -1.67 (m, 2H), 1.67 - 1.54 (m, 1H), 1.52 - 1.29 (m, 2H), 1.27 - 1.06 (m, 1H). MS (ESI): C 19 H 18 The calculated mass of BClF3N5O2 is 451.12, and the found m / z is 449.9 [MH] - . HPLC: 98.10% (220 nm), 100% (254 nm).

[0668] 22. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0669]

[0670] 22.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0671]

[0672] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (500 mg, 2.11 mmol, 1 eq) in i-PrOH (10 mL) at 25°C was added (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (614 mg, 1.83 mmol, 1 eq) and TFA (360 mg, 3.17 mmol, 1.5 eq). The mixture was stirred at 80°C for 12 h. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to give the crude product (filter cake). The crude product was triturated with saturated aq. NaHCO3 (30 mL) and filtered to give (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (820 mg, 79.1% yield) as a white solid. 1 H NMR(DMSO-d6, 400 MHz) δ 10.16 (s, 1 H), 8.33 (s, 1 H), 8.02 (s, 1 H), 7.94 (s, 1H), 7.42 (d, J = 8.0 Hz, 1 H), 5.02-4.91 (m, 1 H), 4.51 (s, 2 H), 3.35 - 3.20 (m, 1 H), 2.23-2.07 (m, 2 H), 1.93-1.71 (m, 3 H), 1.64-1.52 (m, 1 H).

[0673] 22.2 Preparation of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0674]

[0675] To a solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (820 mg, 1.67 mmol, 1 eq) in THF (20 mL) at 25°C was added 2,6-lutidine (716 mg, 6.68 mmol, 780 μL, 4 eq) and [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (662 mg, 2.51 mmol, 580 μL, 1.5 eq). The mixture was stirred at 25°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of H₂O (20 mL) at 0°C and extracted with EtOAc (10 mL x 3). 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. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (840 mg, 83.0% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.14(s, 1 H), 8.29 (s, 2 H), 7.66 (s, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 4.98-4.86(m, 1 H), 4.68 (s, 2 H), 3.31-3.24 (m, 1 H), 2.26-2.05 (m, 2 H), 1.90-1.70 (m, 3 H), 1.67-1.54 (m, 1 H), 0.94 (s, 9 H), 0.13 (s, 6 H).

[0676] 22.3 Preparation of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0677]

[0678] Two reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (400 mg, 661 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-2-yl)-1,3,2-dimethyl-2,3 ... The mixture in 1% methyl parathione (10 mL) was degassed and purged with N₂ three times, then stirred at 120°C under an N₂ atmosphere for 40 min. TLC indicated the reaction was complete. The two parallel reactions were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (0.5 g, 59.2% yield) as a yellow solid.

[0679] 22.4 Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0680]

[0681] To a solution of (trans)-2-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (0.5 g, 783 umol, 1 eq) in THF (5 mL) at 25°C was added aq. HCl (4 M, 2 mL, 10 eq). The mixture was stirred at 25°C for 1 h. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to give the crude product (filter cake). The crude product was triturated with THF (5 mL) and filtered to give (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (157.5 mg, 45.9% yield, 97.36% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.10 (s, 1H), 8.33 (s, 1 H), 7.83 (s, 1 H), 7.72 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H),5.00-4.87 (m, 3 H), 3.35 - 3.25 (m, 1 H), 2.26-2.04 (m, 2 H), 1.92-1.70 (m, 3H), 1.68-1.55 (m, 1 H). MS (ESI): C 18 H 16 The calculated mass of BClF3N5O2 is 437.10, and the found m / z is 435.9 [MH] - . HPLC: 97.36% (220 nm), 97.17% (254 nm).

[0682] 23. Preparation of (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0683]

[0684] 23.1 Preparation of (trans)-2-((2-((4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0685]

[0686] To a solution of (5-amino-2-bromo-3-fluoro-phenyl)methanol (500 mg, 2.27 mmol, 1 eq) in i-PrOH (10 mL) at 25°C was added TFA (388 mg, 3.41 mmol, 1.5 eq) and (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (616 mg, 2.27 mmol, 1 eq). The mixture was stirred at 80°C for 5 h. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to obtain a filter cake. The filter cake was triturated with saturated aq. NaHCO3 (10 mL) at 25°C for 30 min to give (trans)-2-[[2-[4-bromo-3-fluoro-5-(hydroxymethyl)anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (850 mg, 82.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ = 9.67 (s, 1H), 8.05 (s, 1H), 7.80 (dd, J = 2.4, 12.0 Hz, 1H), 7.71 (s,1H), 7.38 (d, J = 9.2 Hz, 1H), 5.52 (s, 1H), 4.50 (s, 2H), 4.40 - 4.24 (m,1H), 3.08 - 2.96 (m 1H), 2.16 (d, J = 12.0 Hz, 1H), 1.94 - 1.86(m, 1H), 1.76- 1.56 (m, 3H), 1.40 - 1.35 (m, 2H), 1.24 - 1.09 (m, 1H).

[0687] 23.2 Preparation of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0688]

[0689] To a solution of (trans)-2-[[2-[4-bromo-3-fluoro-5-(hydroxymethyl)anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (850 mg, 1.87 mmol, 1 eq) and 2,6-lutidine (801 mg, 7.48 mmol, 870 uL, 4 eq) in THF (10 mL) at 25°C was added TBSOTf (741 mg, 2.80 mmol, 640 uL, 1.5 eq). The mixture was then stirred at 25°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of saturated aq. NH4Cl (20 mL) at 0°C, followed by extraction with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (20 mL) at 25 °C for 30 min to give 2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-fluoro-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (570 mg, 53.5% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.81 (s, 1H), 8.03 (s, 1H), 7.99 (dd, J = 2.8, 12.4 Hz,1H), 7.52 (s, 1H), 7.42 (d, J = 9.2 Hz, 1H), 4.67 (s, 2H), 4.36 - 4.20 (m,1H), 3.09 - 2.97 (m, 1H), 2.21 - 2.15(m, 1H), 1.94 - 1.87 (m, 1H), 1.81 -1.67 (m, 2H), 1.62 - 1.49 (m, 1H), 1.44 - 1.25 (m, 2H), 1.25 - 1.11 (m, 1H), 0.93 (s, 9H), 0.13 (s, 6H).

[0690] 23.3 Preparation of (trans)-2-((2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5-fluorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0691]

[0692] Five reactions were performed in parallel. For each reaction, (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-fluoro-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 175 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-3-yl)-1,277 mg, 1.23 mmol, 7 eq), KOAc (51.7 mg, 527 umol, 3 eq), Pd(PPh3)2Cl2 (12.3 mg, 17.5 umol, 0.1 eq) were added in distilled water. The mixture in 1,2-dioxane (5 mL) was degassed and purged with N₂ three times, then stirred at 120°C under N₂ for 1 h. LCMS indicated the reaction was complete, and the desired MS was observed. Five parallel reactions were combined, filtered, and concentrated under reduced pressure to afford a residue. The residue was then purified by prep-HPLC (Phenomenex Luna C₁₈ 75 HPLC column). 30mm 3um; mobile phase: [water (formic acid FA)-ACN]; B%: 40%-70%, 8 min), gave (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (200 mg, 42.6% yield) as a white solid.

[0693] 23.4 Preparation of (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0694]

[0695] To a solution of (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-((2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)-6-fluorophenyl)boronic acid (200 mg, 374 umol, 1 eq) in THF (3 mL) was added aq. HCl (6 M, 0.3 mL, 5 eq) at 25°C. The mixture was stirred at 25°C for 1 h. A solid precipitated out. LCMS showed that the reaction was complete and the desired MS was observed. The reaction mixture was filtered to give a residue. The residue was washed with THF (2 mL). 1 mL) and filtered to give (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (65.5 mg, 43.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.91 (s, 1H), 8.11 (s, 1H), 7.66(d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 11.2 Hz, 1H), 5.00 - 4.95 (m,2H), 4.34 - 4.22 (m, 1H), 3.10 - 2.99 (m, 1H), 2.19 (d, J = 11.6 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.82 - 1.68 (m, 2H), 1.65 - 1.52 (m, 1H), 1.46 - 1.26(m, 2H), 1.25 - 1.12 (m, 1H). MS (ESI): C 18 H 18 The calculated mass of BClFN5O2 is 401.12, and the found m / z is 402.1 [M+H] + . HPLC: 99.09% (220 nm), 99.70% (254 nm).

[0696] 24. Preparation of 2-[[5-chloro-2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0697]

[0698] 24.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid

[0699]

[0700] Dissolve 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 eq) in concentrated H₂SO₄ (70 mL). Add KNO₃ (4.61 g, 45.5 mmol, 0.98 eq) dissolved in H₂SO₄ (30 mL) dropwise to the solution at 0°C. Stir the mixture at 0°C for 3 h. TLC indicates the reaction is complete. Pour the reaction mixture into ice water (200 mL) and filter to yield 2-bromo-3-methyl-5-nitro-benzoic acid (10.6 g, crude) as a brown solid. 1 H NMR (CDCl 3, 400MHz) δ 8.55 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 2.63 (s, 3H).

[0701] 24.2 Preparation of methyl 2-bromo-3-methyl-5-nitrobenzoate

[0702]

[0703] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.5 g, 32.7 mmol, 1 eq) in MeOH (100 mL) at 0°C was added thionyl chloride (65.3 mmol, 4.7 mL, 2 eq) dropwise. The mixture was heated to 80°C and stirred for 15 h. TLC indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give methyl 2-bromo-3-methyl-5-nitro-benzoate (8.5 g, 94.9% yield) as an off-white solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.35 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H), 2.59 (s, 3H).

[0704] 24.3 Preparation of 5-amino-2-bromo-3-methyl-benzoic acid methyl ester

[0705]

[0706] To a solution of 2-bromo-3-methyl-5-nitro-benzoic acid methyl ester (7.5 g, 27.3 mmol, 1 eq) in EtOH (100 mL) and H₂O (20 mL) at 25°C was added NHCl (5.86 g, 109 mmol, 4 eq) and Fe powder (6.11 g, 109 mmol, 4 eq). The mixture was stirred at 80°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 5-amino-2-bromo-3-methyl-benzoic acid methyl ester (5.5 g, 82.3% yield) as a brown oil. 1 H NMR (CDCl3, 400 MHz)δ 6.80 (s, 1 H), 6.68 (s, 1 H), 3.91 (s, 3 H), 3.72 (s, 2 H), 2.36 (s, 3 H).

[0707] 24.4 Preparation of (5-amino-2-bromo-3-methyl-phenyl)methanol

[0708]

[0709] To a solution of 5-amino-2-bromo-3-methyl-benzoic acid methyl ester (5.5 g, 22.5 mmol, 1 eq) in THF (50 mL) at 0°C was added DIBAL-H (1 M in THF, 90.1 mL, 4 eq) dropwise. The mixture was stirred at 0°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aq. potassium sodium tartrate (100 mL) at 0°C and stirred at room temperature for 1 h, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (30 mL) and filtered to give (5-amino-2-bromo-3-methyl-phenyl)methanol (1.5 g, 30.8% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 6.67 (d, J = 2.8 Hz, 1 H), 6.54 (d, J = 2.8 Hz, 1 H), 4.66 (s, 2 H), 3.58 (s, 2 H), 2.33 (s, 3 H).

[0710] 24.5 Preparation of (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0711]

[0712] To a solution of (5-amino-2-bromo-3-methyl-phenyl)methanol (500 mg, 2.31 mmol, 1 eq) in i-PrOH (5 mL) at 25°C was added (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (627 mg, 2.31 mmol, 1 eq) and TFA (395 mg, 3.47 mmol, 256 μL, 1.5 eq). The mixture was stirred at 80°C for 12 h. A solid precipitated. TLC indicated the reaction was complete. The reaction mixture was filtered to give a residue. The residue was triturated with saturated aq. NaHCO3 (30 mL) and filtered to give (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (875 mg, 83.8% yield) as a yellow solid. 1 H NMR(CDCl3, 400 MHz) δ 7.95 (s, 1 H), 7.67 (d, J = 2.8 Hz, 1 H), 7.34 (d, J = 2.4Hz, 1 H), 7.02 (s, 1 H), 5.25 (d, J = 8.4 Hz, 1 H), 4.76 (s, 2 H), 4.49-4.40(m, 1 H), 2.84-2.74 (m, 1 H), 2.43 (s, 3 H), 2.19-2.06 (m, 2 H), 1.85-1.69(m, 3 H), 1.62-1.35 (m, 3 H).

[0713] 24.6 Preparation of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0714]

[0715] To a solution of (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (460 mg, 1.02 mmol, 1 eq) in THF (5 mL) at 25°C was added 2,6-lutidine (437 mg, 4.08 mmol, 4 eq) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (404 mg, 1.53 mmol, 1.5 eq). The mixture was stirred at 25°C for 2 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of H2O (20 mL) at 0°C and extracted with EtOAc (20 mL x 3). 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. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (500 mg, 86.7% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1 H), 7.98 (s, 1H), 7.78 (s, 1 H), 7.58 (s, 1 H), 7.27 (d, J = 9.2 Hz, 1 H), 4.66 (s, 2 H),4.35-4.24 (m, 1 H), 3.10 - 3.00 (m, 1 H), 2.35 (s, 3 H), 2.22-2.13 (m, 1 H), 1.92-1.83 (m, 1 H), 1.79-1.66 (m, 2 H), 1.62-1.49 (m, 1 H), 1.37-1.10 (m, 3H), 0.94 (s, 9H), 0.12 (s, 6 H).

[0716] 24.7 Preparation of (trans)-2-((2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0717]

[0718] (trans)-2-[[2-[4-Bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (500 mg, 884 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinane (999 mg, 4.42 mmol, 5 eq), Pd(PPh3)2Cl2 (93 mg, 132 umol, 0.15 eq) and KOAc (191 mg, 1.95 mmol, 2.2 eq) were reacted in distilled water. The mixture was degassed in 1% paraffin (10 mL) and purged with N2 three times, then stirred at 120°C under an N2 atmosphere for 40 min. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (0.4 g, 75.5% yield) as a yellow solid.

[0719] 24.8 Preparation of (trans)-2-[[5-chloro-2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0720]

[0721] To a solution of (trans)-2-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (0.4 g, 668 umol, 1 eq) in THF (5 mL) at 25°C was added aq. HCl (4 M, 1.67 mL, 10 eq). The mixture was stirred at 25°C for 1 h. A solid precipitated. TLC showed the reaction was complete. The reaction mixture was filtered to give a residue. The residue was triturated with THF (5 mL) and filtered to give (trans)-2-[[5-chloro-2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclohexanecarbonitrile (99.0 mg, 37.2% yield, 98.68% purity) as a white solid.1 H NMR (DMSO-d6, 400 MHz) δ 9.98 (s, 1 H), 8.16(s, 1 H), 8.01 (d, J = 4.4 Hz, 1 H), 7.55 (s, 1 H), 7.34 (s, 1 H), 4.99-4.88(m, 2 H), 4.32-4.21 (m, 1 H), 3.10 - 3.00 (m, 1 H), 2.42 (s, 3 H), 2.23-2.14(m, 1 H), 1.95-1.86 (m, 1 H), 1.82-1.67 (m, 2 H), 1.64-1.51 (m, 1 H), 1.48-1.36 (m, 1 H), 1.34-1.10 (m, 2H). MS (ESI): C 19 H 21 The calculated mass of BClN5O2 is 397.15, and the found m / z is 398.2 [M+H] + . HPLC: 98.68% (220 nm), 98.78% (254 nm).

[0722] 25. Preparation of 3-[[2-[(7-cyclopropyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0723]

[0724] 25.1 Preparation of 2-Hydroxy-3-methyl-benzoic acid methyl ester

[0725]

[0726] Four reactions were performed in parallel. For each reaction, cyclopropylboronic acid (13.0 g, 151 mmol, 4 eq), tricyclohexylphosphane (4.25 g, 15.1 mmol, 4.91 mL, 0.4 eq), K₃PO₄ (16.0 g, 75.7 mmol, 2 eq), and Pd(OAc)₂ (850 mg, 3.79 mmol, 0.1 eq) were added to a solution of methyl 3-bromo-2-hydroxybenzoate (8.75 g, 37.8 mmol, 1 eq) in toluene (360 mL) and water (36 mL) at 20°C. The mixture was stirred at 100°C for 12 h. TLC indicated the reaction was complete. The four parallel reactions were combined, poured into H₂O (150 mL), and extracted with MTBE (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 99 / 1 to 3 / 1) to give 2-hydroxy-3-methyl-benzoic acid methyl ester (11.5 g, 45.6% yield) as a yellow oil. 1 H NMR (CDCl3, 400 MHz)δ 11.17 (s, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.78(t, J = 8.0 Hz, 1 H), 3.95 (s, 3 H), 2.25-2.18 (m, 1 H), 1.00-0.95 (m, 2 H), 0.70-0.65 (m, 2 H).

[0727] 25.2 Preparation of methyl 3-cyclopropyl-2-hydroxy-5-nitrobenzoate

[0728]

[0729] Two reactions were performed in parallel. For each reaction, a solution of methyl 3-cyclopropyl-2-hydroxybenzoate (8.4 g, 43.7 mmol, 1 eq) in DCM (35 mL) was cooled to -10°C, followed by the dropwise addition of a mixture of HNO₃ (6.35 g, 65.5 mmol, 4.5 mL, 65% purity, 1.5 eq) and H₂SO₄ (15.4 g, 157 mmol, 8.4 mL, 3.61 eq) at -10°C. Following the addition, the reaction was allowed to warm to 0°C and stirred at 0°C for 2 hours. TLC indicated the reaction was complete. The two parallel reactions were combined, poured into H₂O (100 mL), and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give 3-cyclopropyl-2-hydroxy-5-nitro-benzoic acid methyl ester (10.6 g, 51.1% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 11.85 (s, 1H), 8.62 (s, 1 H), 7.91 (s, 1 H), 4.04 (s, 3 H), 2.28-2.20 (m, 1 H), 1.15-1.01 (m, 2 H), 0.81-0.74 (m, 2 H).

[0730] 25.3 Preparation of 5-amino-3-cyclopropyl-2-hydroxy-benzoic acid methyl ester

[0731]

[0732] To a solution of methyl 3-cyclopropyl-2-hydroxy-5-nitro-benzoate (3.5 g, 14.7 mmol, 1 eq) in EtOH (53 mL) and water (17 mL) at 25°C was added Fe powder (2.47 g, 44.2 mmol, 3 eq) and NH4Cl (1.18 g, 22.1 mmol, 1.5 eq). The mixture was stirred at 80°C for 2 hours. TLC indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 3 / 1) to give 5-amino-3-cyclopropyl-2-hydroxy-benzoic acid methyl ester (2.7 g, 87.2% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 10.62 (s, 1H), 7.00 (s, 1 H), 6.48 (s, 1 H), 3.93 (s, 3 H), 3.41 (s, 2 H), 2.24-2.15 (m,1 H), 1.01-0.90 (m, 2 H), 0.70-0.60 (m, 2 H).

[0733] 25.4 Preparation of methyl 5-((4-(((trans)-4-cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-cyclopropyl-2-hydroxybenzoate

[0734]

[0735] To a solution of 5-amino-3-cyclopropyl-2-hydroxy-benzoic acid methyl ester (0.85 g, 4.10 mmol, 1 eq) and (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (1.04 g, 4.10 mmol, 1 eq) in i-PrOH (34 mL) was added TFA (935 mg, 8.20 mmol, 2 eq) at 20°C. The mixture was stirred at 90°C for 12 h. TLC indicated the reaction was complete. The residue was poured into H2O (35 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give methyl 5-((4-(((trans)-4-cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-cyclopropyl-2-hydroxybenzoate (1.25 g, 71.9% yield) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 11.49 (br s, 1 H),11.11 (s, 1 H), 7.86 (s, 1 H), 7.49 (s, 1 H), 7.05 (s, 1 H), 5.99 (d, J = 7.2Hz, 1 H), 4.25-4.22 (m, 1 H), 4.08-4.03 (m, 1 H), 3.96 (s, 3 H), 3.86-3.83(m, 1 H), 3.78-3.74 (m, 2 H), 3.42-3.30 (m, 1 H), 2.13-2.06 (m, 1 H), 2.05-2.01 (m, 4 H), 1.85-1.79 (m, 1 H), 1.01-0.90 (m, 2 H), 0.70-0.60 (m, 2 H).

[0736] 25.5 Preparation of methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate

[0737]

[0738] To a solution of 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-hydroxy-benzoic acid methyl ester (1.15 g, 2.72 mmol, 1 eq) in THF (20 mL) was added NaH (325 mg, 8.15 mmol, 60% purity, 3 eq) at 0°C and stirred for 10 min. 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (PhNTf2, 2.91 g, 8.15 mmol, 3 eq) in THF (30 mL) was then added to the reaction. The mixture was stirred at 25°C for 1 hr. TLC showed the reaction was complete. The residue was poured into ice water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 4). The product was washed with water (3%), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate (1.2 g, 79.5% yield) as a yellow solid. 1 HNMR (CDCl3, 400 MHz) δ, 8.15 (s, 1 H), 7.84 (s, 1 H), 7.32 (s, 1 H), 7.07 (s,1 H), 5.05 (d, J = 7.2 Hz, 1 H), 4.45-4.38 (m, 1 H), 3.95 (s, 3 H), 3.89-3.85(m, 2 H), 3.81-3.78 (m, 1 H), 3.32-3.25 (m, 1 H), 2.20-2.11 (m, 2 H), 2.03(s, 3 H), 1.89-1.81 (m, 1 H), 1.15-1.11 (m, 2 H), 0.82-0.78 (m, 2 H).

[0739] 25.6 Preparation of methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)benzoate

[0740]

[0741] Methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate (0.5 g, 900 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-3-yl)-2,6-dimethyl ... The mixture was degassed in 2% ethanol (10 mL) and purged with N₂ three times. The mixture was then heated to 120°C and stirred at 120°C under an N₂ atmosphere for 2 h. TLC indicated the reaction was complete. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl conditions) to give methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (160 mg, 34.2% yield) as a yellow solid.

[0742] 25.7 Preparation of (trans)-3-[[2-[(7-cyclopropyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0743]

[0744] To a solution of methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (0.13 g, 250 umol, 1 eq) in THF (2 mL) at 0°C was added NaBH4 (28.4 mg, 750 umol, 3 eq). The mixture was stirred at 25°C for 1 h. TLC showed the reaction was complete. The reaction mixture was quenched by the addition of H2O (2 mL) at 0°C and adjusted to pH = 4 with aq. HCl (2N). 6, and then filtered to give (trans)-3-[[2-[(7-cyclopropyl-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (70.8 mg, 69.8% yield, 96.9% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1 H), 8.23 ​​(s, 1 H), 7.83 (s, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.53 (s, 1 H), 6.87 (s, 1H), 4.99-4.88 (m, 2 H), 4.39-4.28 (m, 1 H), 3.92-3.81 (m, 2 H), 3.31-3.19 (m, 2 H), 3.14 (t, J = 10.4 Hz, 1 H), 2.48-2.41 (m, 1 H), 2.22-2.14 (m, 1 H),1.99 (s, 3 H), 1.93-1.80 (m, 1 H), 1.03-0.95 (m, 2 H), 0.87-0.77 (m, 2 H). MS(ESI):C 21 H 24 The calculated mass of BN5O3 is 405.20, and the found m / z is 406.2 [M+H] + . HPLC: 96.90% (220nm), 96.88% (254nm).

[0745] 26. Preparation of (trans)-3-[[2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0746]

[0747] 26.1 Preparation of (5-amino-2-bromophenyl)methanol

[0748]

[0749] To a solution of 5-amino-2-bromo-benzoic acid methyl ester (5 g, 21.7 mmol, 1 eq) in THF (50 mL) at 0°C was added DIBAL-H (1 M in THF, 86.9 mL, 4 eq) dropwise, followed by stirring at 0°C for 1 hour. TLC indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous Na2CO3 (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 1:1) to afford (5-amino-2-bromophenyl)methanol (4.3 g) as a yellow solid.

[0750] 26.2 Preparation of (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0751]

[0752] A solution of (5-amino-2-bromo-phenyl)methanol (2 g, 9.90 mmol, 1 eq), (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (2.5 g, 9.90 mmol, 1 eq), and TFA (1.69 g, 14.8 mmol, 1.5 eq) in i-PrOH (40 mL) was degassed and purged with N₂ three times. The mixture was then stirred at 80°C under an N₂ atmosphere for 12 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (20 mL) to give (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (5 g, crude) as a yellow oil.

[0753] 26.3 Preparation of (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0754]

[0755] To a mixture of (trans)-3-[[2-[4-bromo-3-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (4.9 g, 11.7 mmol, 1 eq) and 2,4-lutidine (5 g, 46.8 mmol, 4 eq) in THF (40 mL) under N₂ was added [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (6.2 g, 23.4 mmol, 2 eq), and the mixture was stirred at 0°C for 1 h. TLC indicated the reaction was complete. The reaction mixture was quenched with aq. NH₄Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 1:1) to give (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (5 g, 80% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.97 (d, J = 2.4 Hz,1H), 7.73 (s, 1H), 7.64 (dd, J = 2.8, 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H),6.66 (d, J = 8.4 Hz, 1H), 4.64 (s, 2H), 4.55 - 4.35 (m, 1H), 3.87 (m, 2H),3.30 - 3.19 (m, 2H), 3.13 (t, J = 10.8 Hz, 1H), 2.22 - 2.10 (m, 1H), 1.91 -1.77 (m, 1H), 0.94 (s, 9H), 0.12 (s, 6H).

[0756] 26.4 Preparation of (trans)-3-((2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0757]

[0758] Five reactions were performed in parallel. For each reaction, (trans)-3-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (1 g, 1.88 mmol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.70 g, 7.51 mmol, 4 eq), KOAc (552 mg, 5.63 mmol, 3 eq) and Pd(PPh3)2Cl2 (131 mg, 187 umol, 0.1 eq) were mixed in distilled water. The mixture in 20 mL of oxane was degassed and purged with N2 three times, and then the mixture was stirred at 120°C under N2 atmosphere for 1 hour. TLC indicated the reaction was complete. Five parallel reactions were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 (250 50mm 10 um); mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 10 min), to give (trans)-3-((2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (5 g, crude) as a yellow oil.

[0759] 26.5 Preparation of (3R,4S)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0760]

[0761] To a mixture of (trans)-3-[[2-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (4.5 g, 7.96 mmol, 1 eq) in THF (50 mL) was added aq. HCl (6 M, 5.3 mL, 4 eq), and the mixture was stirred at 40°C under N2 atmosphere for 1 h. LCMS indicated the reaction was complete, and the desired MS was observed. The reaction mixture was filtered and the filter cake was washed with MeCN (10 mL) and dried in vacuo to give (trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (1.5 g, 51% yield) as a white solid which was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm Hg)). 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​EtOH]; B%: 60%-60%, 6 min), affording (trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (343 mg, 99.34% purity, 100% ee, first peak, RT = 1.424 min) stereoisomer 1 as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.28 (s, 1H), 8.90 (s, 1H), 7.96 (s,1H), 7.79 (d, J = 0.8 Hz, 1H), 7.61 - 7.50 (m, 2H), 6.83 (m, 1H), 4.99 - 1.96 (s, 3H), 1.91 - 1.78 (m, 1H). MS (ESI): C 18 H 20 The calculated mass of BN5O3 is 365.17, and the measured m / z is 364.0 [MH] -HPLC: 99.34% (220 nm), 99.9% (254 nm). (Trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (185 mg, 99.40% purity, 99.90% ee, second peak, RT = 1.737 min) stereoisomer 2 was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.61 -7.55 (m, 1H), 7.54 - 7.49 (m, 1H), 6.99 (m, 1H), 4.99 - 4.86 (m, 2H), 4.52 -4.39 (m, 1H), 3.90 (m, 2H), 3.29 - 3.20 (m, 2H), 3.15 (t, J = 10.8 Hz, 1H), 2.18 (m, 1H), 1.97 (s, 3H), 1.92 - 1.79 (m, 1H). MS (ESI): C 18 H 20 The calculated mass of BN5O3 is 365.17, and the measured m / z is 364.1 [MH] - . HPLC: 99.40% (220 nm), 99.95% (254 nm).

[0762] 27. Preparation of (trans)-3-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0763]

[0764] 27.1 Preparation of methyl 2-bromo-5-((4-(((trans)-4-cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzoate

[0765]

[0766] To (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (700 mg, 2.49 mmol, 90% purity, 1 eq) in di To a solution of 5-[ ... The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 100-0% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-bromo-5-((4-(((trans)-4-cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzoate as a yellow solid (950 mg, 82% yield). 1 H NMR (DMSO-d 6, 400 MHz) δ 7.82(s, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.96 (s, 1H),5.06-5.04 (m, 1H), 4.39-4.37 (m, 1H), 4.16-4.10 (m, 1H), 3.95 (s, 3H), 3.89-3.86 (m, 2H), 3.82-3.79 (m, 1H), 3.32-3.29 (m, 1H), 2.48 (s, 3H), 2.18-2.11(m, 1H), 2.02 (s, 3H), 1.86-1.82 (m, 1H).

[0767] 27.2 Preparation of 5-[[4-[(4-cyanotetrahydropyran-3-yl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-3-methyl-benzoic acid methyl ester

[0768]

[0769] Nine reactions were performed in parallel. For each reaction, 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (123 mg, 543 umol, 2.5 eq), 2-bromo-5-[[4-[(4-cyanotetrahydropyran-3-yl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoic acid methyl ester (100 mg, 217 umol, 1 eq), KOAc (53 mg, 543 umol, 2.5 eq) and Pd(PPh3)2Cl2 (15 mg, 21.7 umol, 0.1 eq) were mixed in distilled water. The mixture was stirred at 120°C under a nitrogen atmosphere for 1 h in 2% dextrose (5 mL). Nine parallel reactions were combined, and the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient @ 50 mL / min) to afford 5-[[4-[((trans)-4-cyanotetrahydropyran-3-yl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoic acid methyl ester (1.1 g, crude) as a brown solid, which was used directly in the next step.

[0770] 27.4 Preparation of (trans)-3-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0771]

[0772] To a solution of 5-[[4-[((trans)4-cyanotetrahydropyran-3-yl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoic acid methyl ester (1 g, 2.03 mmol, 1 eq) in THF (10 mL) and MeOH (2 mL) at 0°C was added NaBH4 (767 mg, 20.2 mmol, 10 eq) portionwise. Following the addition, the reaction was allowed to warm to 25°C and stirred for 1 h. The mixture was adjusted to pH = 4 with aq. HCl (2N), H2O (30 mL) was added, and then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna 80 30mm 3 μm; mobile phase: [water (0.04% HCl)-MEOH]; B%: 10%-30%, 8 min), gave (trans)-3-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (127.4 mg, 16% yield) as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 10.16 (s, 1H), 8.86 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 4.94-4.93 (m, 2H), 4.43-4.38 (m,1H), 4.91-3.85 (m, 2H), 3.23-3.14 (m, 3H), 2.44 (s, 3H), 2.20-2.13 (m, 1H), 2.02 (s, 3H), 1.87-1.83 (m, 1H). MS (ESI): C 19 H 22 The calculated mass of BN5O3 is 379.22, and the found m / z is 380.2 [M+H] + . HPLC: 92.4% (220 nm), 89.52% (254 nm).

[0773] 28. Preparation of (trans)-3-[[2-[(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0774]

[0775] 28.1 Preparation of (trans)-3-((2-((3-acetyl-4-bromophenyl)amino-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0776]

[0777] Two reactions were performed in parallel. For each reaction, 1-(5-amino-2-bromo-phenyl)ethanone (212 mg, 989 umol, 1 eq) and (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (250 mg, 989 umol, 1 eq) were added to the mixture at 20°C in a 2% argon slurry. To a solution of 1,4-dimethyl-1-oxadiazole (3 mL) was added TsOH (256 mg, 1.48 mmol, 1.5 eq). The mixture was heated at 80°C and stirred for 16 h. TLC indicated the reaction was complete. The two parallel reactions were combined and concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (10 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO₃. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 36 mL / min) to give (trans)-3-[[2-(3-acetyl-4-bromo-anilino)-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile as a yellow solid (450 mg). 1 H NMR (DMSO-d 6,400 MHz) δ 9.30 (s, 1H), 8.11 (s,1H), 7.80 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.74(d, J = 8.4 Hz, 1H), 4.50-4.40 (m, 1H), 3.90-3.80 (m, 2H), 3.30-3.10 (m, 2H), 2.55 (s, 3H), 2.17 (q, J = 10.4 Hz, 1H), 2.20-1.80 (m, 5H).

[0778] 28.2 Preparation of (trans)-3-[[2-[4-bromo-3-(1-hydroxyethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0779]

[0780] To a solution of (trans)-3-[[2-(3-acetyl-4-bromo-anilino)-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (300 mg, 697 umol, 1 eq) in THF (3 mL) at 0°C was added NaBH4 (380 mg, 10.0 mmol, 14 eq) and MeOH (0.3 mL). Following the addition, the reaction was allowed to warm to 25°C and stirred for 1 h. Saturated aq. NH4Cl (10 mL) was added to the reaction mixture at 0°C, and the pH was adjusted to 5 with aq. HCl (2N), followed by extraction with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-[[2-[4-bromo-3-(1-hydroxyethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (200 mg, 66.3% yield) as a brown solid.

[0781] 28.3 Preparation of (trans)-3-[[2-[(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0782]

[0783] Four reactions were performed in parallel. For each reaction, (trans)-3-[[2-[4-bromo-3-(1-hydroxyethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (50 mg, 115 umol, 1 eq), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinan-3-yl (52 mg, 231 umol, 2 eq), Pd(PPh3)2Cl2 (16 mg, 23.1 umol, 0.2 eq), KOAc (28 mg, 289 umol, 2.5 eq) were added in distilled water. The mixture in 2 mL of oxane (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120°C under N2 atmosphere for 30 min. LCMS showed that the reaction was complete, and the desired MS was observed. The four parallel reactions were combined, and the mixture was poured into saturated aq. NH4Cl (10 mL) at 0°C, then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna 80 30mm 3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%-45%, 8 min), to give a crude product (100 mg, crude). The crude product was further purified by prep-HPLC (column: Phenomenex Luna 80 30mm 3 μm; mobile phase: [water (0.04% HCl)-MEOH]; B%: 15%-20%, 8 min), to give a mixture of isomers of (trans)-3-[[2-[(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile (36.7 mg) as a white solid. 1 H NMR (DMSO-d 6,400 MHz) δ 10.45 (s, 1H), 9.09 (s, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.76-7.65 (m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 5.25-5.15 (m, 1H), 4.50-4.40 (m, 1H), 3.95-3.85 (m, 2H), 3.30-3.20 (m, 3H), 2.25-2.10 (m, 1H), 2.06 (s, 3H), 1.85-1.70 (m, 1H), 1.45-1.40 (m, 3H). MS (ESI): C 19 H 22 The calculated mass of BN5O3 is 379.18, and the found m / z is 380.2 [M+H] + . HPLC: 99.96% (220 nm), 99.97% (254 nm).

[0784] 29. Preparation of (trans)-3-[[2-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0785]

[0786] 29.1 Preparation of (5-amino-2-bromo-3-fluoro-phenyl)methanol

[0787]

[0788] To a solution of methyl 5-amino-2-bromo-3-fluoro-benzoate (5.7 g, 23.0 mmol, 1 eq) in THF (60 mL) at -60°C was added DIBAL-H (1 M in THF, 57.5 mL, 2.5 eq) dropwise. The mixture was stirred at -60°C for 0.5 h. After the addition, the reaction was allowed to warm to 0°C and stirred at 0°C for 1.5 h. TLC indicated the reaction was complete. The reaction mixture was quenched by the addition of aqueous potassium sodium tartrate solution (100 mL) at 0°C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether at 25 °C for 30 min to give (5-amino-2-bromo-3-fluoro-phenyl)methanol (5 g, 98% yield) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz) δ 6.63 (s, 1 H), 6.34 (dd,J = 2.8, 7.6 Hz, 1 H), 5.57 (s, 2 H), 5.33 (t, J = 6...

Claims

1. A compound of formula I: (I)， or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, wherein X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-; X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-, and X2 and X3 cannot both be -O-; R1 is selected from hydrogen, halogen (when X3 is -C(R 6 )(R 7 )), hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl (oxy) and C3-7 cycloalkyl (oxy), wherein the above R 1 The last four members of the group may optionally be substituted independently of one another by one or more halogens; R2 is selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 2 The last four members of the group may optionally be substituted independently of one another by one or more halogens; Each R3 is independently selected from hydrogen, halogen (when X1 is -C(R 6 )(R 7 ) ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 3 The last four members of the group may optionally be substituted independently of one another by one or more halogens; R4 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; A is selected from benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborol-1-ol and 2H-benzo[e][1,2]oxaborol-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-borobenzo[cd]azulene or a derivative thereof, such as a moiety selected from any one of A1-A7: R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), in which, except for hydrogen, R 5 The above members of the group may be optionally substituted independently of each other by one or more substituents selected from C 1-6 Alkyl and halogen, but the halogen cannot be adjacent to a heteroatom; R 6 and R 7 are independently selected from hydrogen, halogen, hydroxy, -N(R 8 )(R 9 )、-O(R 10 ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3- alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 6 and R 7 The last fifteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and wherein R 6 and R 7 can be connected together to form a ring; R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl); wherein the above R 8 and R 9 The last fourteen members of the group may optionally be substituted independently of one another by one or more halogens, or R 8 and R 9 can be connected together to form a ring; R 10 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 10 The last thirteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but the optional substitutions cannot be geminal; Each R 11 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 Can be linked to provide a fused cycloalkyl group, such as cyclopropyl; Each R 11a are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 Can be linked to provide a fused cycloalkyl group, such as cyclopropyl; Each R 12 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 cycloalkyl; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -N-(R 5 )(R 5 )、-SO2-(R 5 )、-SO2-(R 5 )(R 5 )、-S(O)-(R 5 ) and -S-(R 5 ), where the above R 13 The last fourteen members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

2. The compound according to claim 1, wherein X1 is -C(R 6 )(R 7 )-; X2 is selected from -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is -C(R 6 )(R 7 )-; R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of one another by one or more halogens; Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of one another by one or more halogens; R4 is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen, -C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be connected together to form a ring; Each R 12 are independently selected from hydrogen, halogen and C 1-6 Alkyl; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

3. A compound according to one or more of claims 1 to 2, wherein X1 is selected from -O- and -C(R 6 )(R 7 )-; X2 is selected from -O- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-; R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of one another by one or more halogens; Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of one another by one or more halogens; R4 is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen, -C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be connected together to form a ring; Each R 12 are independently selected from hydrogen, halogen and C 1-6 Alkyl; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

4. A compound according to one or more of claims 1 to 3, wherein R 1 Selected from hydrogen and C 1-6 alkyl; R 2 Selected from hydrogen and C 1-6 alkyl; Each R 3 are independently selected from hydrogen and C 1-6 alkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more halogens; R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

5. A compound according to one or more of claims 1 to 4, wherein R 1 , R 2 and R 3 It is hydrogen; R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group may be optionally substituted with one or more halogens; Each R 11 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens; Each R 11a are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens; R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13 The last three members of the radical may optionally, independently of one another, be substituted by one or more halogens.

6. A compound of formula (Ia) or (Ib): (I), (Ib), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, in X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-; X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be –O-, and X2 and X3 cannot both be -O-; R 1 is selected from hydrogen, halogen (when X3 is -C(R 7 )(R 8 )-), hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl (oxy) and C3-7 cycloalkyl (oxy), wherein the above R 1 The last four members of the group may optionally be substituted independently of one another by one or more halogens; R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 2 The last four members of the group may optionally be substituted independently of one another by one or more halogens; Each R 3 are independently selected from hydrogen, halogen (when X1 is -C(R 7 )(R 8 ) ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 3 The last four members of the group may optionally be substituted independently of one another by one or more halogens; R4 is selected from 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; A is selected from benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborol-1-ol and 2H-benzo[e][1,2]oxaborol-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-borobenzo[cd]azulene or a derivative thereof, such as a moiety selected from any one of A1-A7: R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), in which, except for hydrogen, R 5 The above members of the group may be optionally substituted independently of each other by one or more substituents selected from C 1-6 Alkyl and halogen, but the halogen cannot be adjacent to a heteroatom; R 6 and R 7 are independently selected from hydrogen, halogen, hydroxy, -N(R 8 )(R 9 )、-O(R 10 ), C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3- alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 6 and R 7 The last fifteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and wherein R 6 and R 7 can be connected together to form a ring; R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 8 and R 9 The last fourteen members of the group may optionally be substituted independently of one another by one or more halogens, or R 8 and R 9 can be connected together to form a ring; R 10 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -COO-C 1-6 Alkyl, -COO-C 3-7 -cycloalkyl, -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkoxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -heteroaryl and -(C 1-3 -alkyl)-(heteroaryl), wherein the above R 10 The last thirteen members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but the optional substitutions cannot be geminal; Each R 11 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 Can be linked to provide a fused cycloalkyl group, such as cyclopropyl; Each R 11a are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 11 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, but when R 11 When adjacent to oxygen, R 11 is not a halogen, and two adjacent R 11 Can be linked to provide a fused cycloalkyl group, such as cyclopropyl; Each R 12 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 cycloalkyl; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl), -(C 2-3 -alkyl(oxy)-(C 3-6 -cycloalkyl), 4-7 membered heterocycloalkyl, -(C 1-3 -alkyl)-(4-7 membered heterocycloalkyl), -N-(R 5 )(R 5 )、-SO2-(R 5 )、-SO2-(R 5 )(R 5 )、-S(O)-(R 5 ) and -S-(R 5 ), where the above R 13 The last fourteen members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

7. The compound according to claim 6, wherein X1 is -C(R 6 )(R 7 )-; X2 is selected from -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is -C(R 6 )(R 7 )-; R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 2 The last two members of the group may optionally be substituted independently of one another by one or more halogens; Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 3 The last two members of the group may optionally be substituted independently of one another by one or more halogens; R4 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl (oxy), wherein the above R 6 and R 7 The last four members of the group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be connected together to form a ring; and Each R 12 are independently selected from hydrogen, halogen and C 1-6 Alkyl; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

8. A compound according to one or more of claims 6-7, wherein R 1 Selected from hydrogen and C 1-6 alkyl; R 2 Selected from hydrogen and C 1-6 alkyl; Each R 3 are independently selected from hydrogen and C 1-6 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more halogens; R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein the above R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

9. A compound according to one or more of claims 6 to 8, wherein R 1 , R 2 and R 3 It is hydrogen; R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group may be optionally substituted with one or more halogens; Each R 11 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens; Each R 11a are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two substituents may be optionally substituted independently of each other by one or more halogens; R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13 The last three members of the radical may optionally, independently of one another, be substituted by one or more halogens.

10. A compound selected from the compounds shown in Table 1 below: Table 1 。 11. The compound according to claim 6, wherein X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-; X2 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-, or X2 contains a bond between X1 and X3; X3 is -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-; R 1 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; R 2 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; Each R 3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the last two members of the above mentioned groups may be optionally substituted independently of one another by one or more halogens; R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl (oxy) and C 3-7 Cycloalkyl(oxy), wherein the last four members of the above group may be optionally substituted independently of one another by one or more substituents selected from halogen and hydroxy, and R 6 and R 7 can be connected together to form a ring; and Each R 12 are independently selected from hydrogen, halogen and C 1-6 alkyl.

12. Compounds according to one or more of claims 6 and 11, wherein X1 is selected from -O-, -N(R 5 )- and -C(R 6 )(R 7 )-; X2 is selected from -O- and -C(R 6 )(R 7 )-, but X1 and X2 cannot both be -O-, or X2 contains the bond between X1 and X3; X3 is -C(R 6 )(R 7 )-; R 1 Selected from hydrogen and C 1-6 alkyl; R 2 Selected from hydrogen and C 1-6 alkyl; Each R 3 are independently selected from hydrogen and C 1-6 alkyl; R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens; R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl(oxy), C 3-7 Cycloalkyl(oxy), -(C 1-3 -alkyl)-(C 3-6 -cycloalkyl), -(C 2-3 -alkyl(oxy)-(C 2-6 -alkyl) and 4-7 membered heterocycloalkyl, wherein said R 13 The last seven members of the group may optionally be substituted independently of one another by one or more substituents selected from halogen and hydroxy.

13. Compounds according to one or more of claims 11 to 12, wherein X2 is -C(R 6 )(R 7 )-; X3 is -C(R 6 )(R 7 )-; R 1 , R 2 and R 3 It is hydrogen; R4 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; R 6 and R 7 are independently selected from hydrogen and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens; Each R 11 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 11 The last two members of the group may optionally be substituted independently of one another by one or more halogens; Each R 11a are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, wherein the above R 11 The last two members of the group may optionally be substituted independently of one another by one or more halogens; Each R 12 is hydrogen; and Each R 13 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl (oxy), wherein the above R 13 The last three members of the radical may optionally, independently of one another, be substituted by one or more halogens.

14. A compound selected from the compounds shown in Table 2 below: Table 2 。 15. The compound according to any one of claims 10 and 14, which is a stereoisomer having trans relative stereochemistry as represented in formula (Ia) and (Ib): (I), (Ib).

16. The compound according to one or more of claims 10 and 14, wherein the compound is a single stereoisomer with trans relative stereochemistry.

17. The compound of claim 16, wherein the compound has a trans stereochemistry represented by Formula (Ia) or Formula (Ib).

18. A process for preparing a compound according to any one of claims 1 to 17.

19. A method of treating a patient suffering from a disease or disorder sensitive to modulation of a JAK, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-17.

20. The method of claim 19, wherein the disease or disorder is a condition that can be ameliorated by selective inhibition of the Janus kinase JAK 1 relative to JAK 2.

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

22. The method of claim 21, wherein the disease or disorder is one or more of atopic dermatitis, flea allergy dermatitis, psoriasis, and rheumatoid arthritis.

23. The method of any one of claims 19-22, wherein the compound is administered in an amount that disrupts an immunoregulatory pathway in a cell.

24. The method of claim 23, wherein the perturbation results in an effect on the JAK-STAT pathway.

25. A method of inhibiting JAK in a mammalian cell, the method comprising contacting the mammalian cell with a compound according to any one of claims 1-17.

26. The method of claim 25, wherein the mammalian cell is a cell from a subject having an inflammatory disorder.

27. A composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically or veterinarily acceptable carrier.

28. A combination comprising a compound according to any one of claims 1 to 17 and one or more other pharmaceutically or veterinarily active substances.

29. A method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction and cancer, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-17.

30. The method of claim 29, wherein the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis, or rheumatoid arthritis.

31. The method of claim 29 or claim 30, wherein the compound is administered orally, parenterally or topically.

32. The method of any one of claims 29-31, wherein the subject is a mammal.

33. The method of claim 32, wherein the mammal is selected from one or more of a livestock mammal, a domesticated mammal, and a companion animal.

34. The method of claim 32, wherein the mammal is selected from one or more of humans, cows, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, and cats.

35. The method of claim 32, wherein the mammal is a human, a dog, or a cat.

36. A compound according to any one of claims 1 to 17 for use in medicine.

37. Use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for treating one or more diseases or disorders of inflammation, autoimmune dysfunction and cancer.

38. The use according to claim 37, wherein the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis or rheumatoid arthritis.

39. The use according to claim 37, wherein the disease or disorder is ameliorated by selective inhibition of the Janus kinase JAK 1 relative to JAK2.

40. Use of a compound according to any one of claims 1-17 and a second active agent for the preparation of a medicament for treating a disease or disorder that can be ameliorated by selective inhibition of the Janus kinase JAK 1 relative to JAK 2.

41. Use of a compound according to any one of claims 1-17 for treating one or more diseases or disorders of inflammation, autoimmune dysfunction and cancer.

42. The use according to claim 41, wherein the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis or rheumatoid arthritis.

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