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

Abstract

The present disclosure describes boron-containing pyrimidine compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their medical uses. The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions where modulation of JAK is desirable. Also described is a method of treating inflammation, autoimmune diseases, cancer, and other conditions that are susceptible to the effects of Janus kinase inhibition by administering a compound 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 into tyrosine and serine / threonine kinases. Aberrant kinase activity resulting from mutations, overexpression, or inappropriate regulation, dysregulation, or deregulation, as well as overproduction or underproduction of growth factors or cytokines, has been implicated in many diseases including, but not limited to, cancer, cardiovascular disease, allergy, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Aberrant kinase activity induces various biological cell responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell motility that have been implicated in the aforementioned and related diseases. Thus, protein kinases are emerging as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2) plays a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). When bound to their receptors, cytokines activate JAK, which then phosphorylates the cytokine receptor, thereby creating a docking site for signal transduction molecules, particularly members of the signal transducer and activator of transcription (STAT) family, which ultimately leads to gene expression, thereby stimulating a biological response such as an itch signal. Activation of the JAK-STAT pathway also results in several other auxiliary bioactivities that contribute to inflammatory and pruritic processes that contribute to acute allergy in animals but also exacerbate clinical symptoms and may contribute to chronic allergy.

[0002] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease that affects approximately 20% of children and up to 10% of adults, imposing a significant economic and social burden due to the direct medical costs and productivity losses in individuals with AD. The burden of AD is thought to be mainly related to the limited treatment options. Furthermore, according to the AD treatment guidelines, there is no standard of care, and treatment can be adjusted according to individual needs. Topical interventions are central to AD therapy. To date, topical corticosteroids are the first-line treatment. However, their use can be limited by potential local and systemic adverse effects. Topical calcineurin inhibitors are classified as second-line anti-inflammatory therapies for AD, which have advantages in long-term maintenance and application to special sites. Topical calcineurin inhibitors inhibit calcineurin-dependent T cell activation; however, the black box warning regarding the potential for developing malignancies with the use of topical calcineurin inhibitors reduces patient compliance with the treatment.

[0003] Psoriasis and psoriatic arthritis are associated with abnormal inflammation and the production of pro-inflammatory mediators. Psoriasis and psoriatic arthritis are inflammatory diseases that share overlapping features and common immunological mechanisms. Psoriasis is a systemic disease in the sense that it primarily affects the skin, but up to 40% of individuals with psoriasis can progress to develop psoriatic arthritis. Psoriatic arthritis typically affects the peripheral joints and may sometimes affect the spine and sacroiliac joint regions. Enthesitis, dactylitis, and nail changes, such as pitting and discoloration, are also common signs of psoriatic disease in patients with joint lesions.

[0004] Pruritus is generally a significant clinical sign associated with flea-related dermatitis in dogs. Medical management of pruritus may be required if the cause of the itch cannot be identified or if the itch is not removed by treatment of the underlying disease. However, control of itch with antihistamines is usually ineffective, and treatment with glucocorticoids may be effective but is not ideal for long-term use due to adverse side effects including excessive hunger, thirst, and urination, and increased risk of diabetes and urinary tract infections.

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

[0006] Various classes of compounds have been shown to inhibit JAK enzymes. For example, US 8,133,899 B2 (to Pfizer) discloses the use of pyrrolo[2,3-D]pyrimidine compounds as JAK inhibitors. In particular, oclacitinib (APOQUEL®) is a cyclohexylaminopyrrolopyrimidine that has been demonstrated to be a Janus kinase inhibitor that controls the 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 applications US 2020 / 0339585, WO 2009 / 114512 A1, WO 2021 / 003501 A1, and US Patent No. 7,598,257 B2.

[0007] Published patent applications filed by Merck Sharp & Dohme Corporation and Intervet Inc. regarding pyrazole carboxamide 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 WO2020221914 A1 (all of which are hereby incorporated by reference in their entirety).

[0008] Pyrazole carboxamide Janus kinase 1 inhibitors are also described by 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).

Summary of the Invention

Problems to be Solved by the Invention

[0009] There remains a need for therapies that target and modulate JAK kinases for the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and conditions where modulation of JAK modulation is desirable.

[0010] Any of the foregoing applications, and all documents cited therein or during their prosecution (the "application cited documents"), and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein (the "documents cited herein"), and all documents cited or referenced in the documents cited herein are incorporated herein by reference together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any product mentioned in any document referred to herein or incorporated herein by reference.

[0011] The citation or identification of any document in this application is not an admission that such document is available as prior art.

Means for Solving the Problems

[0012] The present disclosure provides boron-containing compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their medical uses. The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and symptoms where modulation of JAK is desirable. Also described herein is a method of treating inflammation, autoimmune diseases, cancer, and other conditions susceptible to the effects of JAK inhibition by administering a compound 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 them, and their medical uses. The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and symptoms where modulation of JAK is desirable.

[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; A is selected from the group consisting of benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1H benzo[c][1,2]oxaborolin-1-ol, and 2H-benzo[e][1,2]oxaborolin-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-borabenz[cd]azuline or derivatives thereof, for example, a moiety selected from any one of A1 - A7 as defined herein, and the variable elements R 1~11 , R 11a , and R 12~13 are defined herein.

[0015]

Chemical formula

[0016] One embodiment of the present disclosure includes a method of treating a patient having a disease or disorder susceptible to modulation of 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, nummular allergic 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 disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer. In one aspect, the disease or disorder is one or more of atopic dermatitis, nummular allergic dermatitis, psoriasis, and rheumatoid arthritis. In one aspect, the compound is administered in an amount that perturbs an immunomodulatory pathway in a cell. In one aspect, the perturbation results in an effect on the JAK-STAT pathway.

[0017] 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 having an inflammatory condition.

[0018] One embodiment of the present disclosure includes a composition comprising a compound of the present disclosure and a pharmaceutically or veterinarily acceptable carrier.

[0019] 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.

[0020] In another aspect, the present disclosure provides a method of treating inflammation, autoimmune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound described herein.

[0021] In one embodiment of the present disclosure, there is provided a method of treating one or more diseases or disorders among inflammation, autoimmune dysfunction, and cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure. In one aspect, the disease or disorder is atopic dermatitis, contact allergic 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 domestic mammals, breeding mammals, or companion animals. In one aspect, the subject is selected from cows, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, and cats. In one aspect, the subject is a human.

[0022] One embodiment of the present disclosure includes a compound of the present disclosure for use in a medicament.

[0023] One embodiment of the present disclosure includes a compound of the present disclosure for the manufacture of a medicament for the treatment of one or more diseases or disorders among inflammation, autoimmune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

[0024] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the treatment of one or more diseases or disorders among inflammation, autoimmune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

[0025] Even if not specifically described, one or more aspects and embodiments may be incorporated into different embodiments. That is, all aspects and embodiments can be combined in any way or combination.

[0026] The headings used in this specification are for organization purposes only and are not intended to be used to limit the scope of the description or the claims. Throughout this application, the word "may" is used in a permissive sense (i.e., having the potential to) rather than in a mandatory sense (i.e., must). Similarly, the words "include", "including", and "includes" mean including the recited variable elements but not limited thereto.

[0027] These and other embodiments are disclosed in or are obvious from and thereby included in the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0028] In a first aspect, the present disclosure provides a boron-containing pyrimidine compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and their medical uses.

[0029] The compounds of the present disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, autoimmune diseases, cancer, and other disorders and symptoms where modulation of JAK is desirable.

[0030] In one embodiment, the present disclosure provides a compound of formula (I), (Ia), or (Ib):

CHEMICAL FORMULA

Chemical formula

[0031] In one embodiment of the compound of formula I described herein, X1 is -C(R 6 )(R 7 )-, X2 is selected from -C(R 6 )(R 7 )- or X2 contains the bond between X1 and X3, X3 is -C(R 6 )(R 7 )-, R 1 is selected from hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two members of the above group may optionally be independently substituted with one or more halogens, R 2 is selected from hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two members of the group of R 2 may optionally be independently substituted with one or more halogens, Each R 3 is independently selected from hydrogen, C 1~ 6 alkyl, and C 3~7 cycloalkyl, and the last two members of the group of R 3 may optionally be independently substituted with 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 hydrogen, -C 1~6 alkyl, C 3~7 cycloalkyl, C 1~6Alkyl(oxy), and C 3~7 Selected from the group consisting of cycloalkyl(oxy), wherein said R 6 And R 7 The last four members of the group may each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, and R 6 And R 7 May be linked to form a ring, Each R 12 Is independently selected from the group consisting of hydrogen, halogen, and C 1~6 Alkyl, Each R 13 Is independently selected from the group consisting of 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- to 7-membered heterocycloalkyl, and the last seven members of the group of said R 13 May each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy.

[0032] In yet another embodiment of the compounds of formula I described herein, X1 is selected from the group consisting of -O-, and -C(R 6 )(R 7 )-, X2 is selected from the group consisting of -O-, and -C(R 6 )(R 7 )- or X2 contains the bond between X1 and X3, X3 is -C(R 6 )(R 7 )-, provided that X1 and X2 cannot both be -O-, R 1 Is hydrogen, C 1~6Alkyl, and C 3~7 selected from the group consisting of cycloalkyl, and the last two members of the above group may optionally be independently substituted with one or more halogens, R 2 is hydrogen, C 1~6 alkyl, and C 3~7 selected from the group consisting of cycloalkyl, and the last two members of the above group of R 2 may optionally be independently substituted with one or more halogens, each R 3 is independently hydrogen, C 1~ 6 alkyl, and C 3~7 selected from the group consisting of cycloalkyl, and the last two members of the above group of R 3 may optionally be independently substituted with 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 hydrogen, -C 1~6 alkyl, C 3~7 cycloalkyl, C 1~6 alkyl(oxy), and C 3~7 selected from the group consisting of cycloalkyl(oxy), and the last four members of the above group of R 6 and R 7 may optionally be independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy, and R 6 and R 7 may be linked to form a ring, each R 12 is independently selected from the group consisting of hydrogen, halogen, and C 1~6 alkyl, each R 13 is independently 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- to 7-membered heterocycloalkyl, selected from the group consisting of, said R 13 The last seven members of the group may optionally be substituted independently of each other with one or more substituents selected from the group consisting of halogen and hydroxy.

[0033] In one embodiment of the compound of formula I described herein, R 1 is selected from the group consisting of hydrogen and C 1~6 alkyl, R 2 is selected from the group consisting of hydrogen and C 1~6 alkyl, Each R 3 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1~6 alkyl, C 1~6 alkyl may optionally be substituted with one or more of halogen, R 12 is hydrogen, Each R 13 is independently 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- to 7-membered heterocycloalkyl, selected from the group consisting of, said R 13 The last seven members of the group may optionally be substituted independently of each other with one or more substituents selected from the group consisting of halogen and hydroxy.

[0034] In one embodiment of the compounds of formula I described herein, R 1 , R 2 , and R 3 are hydrogen, R4 is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1~6 alkyl, and C 1~6 alkyl may be optionally substituted with one or more halogens, each R 11 is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two substituents may be optionally substituted independently of each other with one or more halogens, each R 11a is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two substituents may be optionally substituted independently of each other with one or more halogens, R 12 is hydrogen, each R 13 is independently selected from the group consisting of hydrogen, halogen, cyano, C 1~6 alkyl, C 3~7 cycloalkyl, and C 1~6 alkyl(oxy), and the last three members of the group of said R 13 may be optionally substituted independently of each other with one or more halogens.

[0035] In one embodiment, the disclosure is a compound of formula (Ia) or (Ib) [wherein, X1 is selected from the group consisting of -O-, -N(R 5 )-, and -C(R 6 )(R 7 )-, X2 is -O-, -N(R5 )-, and -C(R 6 )(R 7 )-selected from the group consisting of, or X2 includes the bond between X1 and X3, X3 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 )-selected from the group consisting of, provided that X1 and X2 cannot both be -O-, and X2 and X3 cannot both be -O-, R 1 is hydrogen, halogen (when X3 is -C(R 7 )(R 8 )-), hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy) selected from the group consisting of, and the last four members of the above group of R 1 may be optionally substituted independently of each other with one or more halogens, R 2 is hydrogen, C 1~6 alkyl, C 3~7 cycloalkyl, C 1~6 alkyl(oxy), and C 3~7 cycloalkyl(oxy) selected from the group consisting of, and the last four members of the above group of R 2 may be optionally substituted independently of each other with one or more halogens, Each R 3 is independently 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) selected from the group consisting of, and the last four members of the above group of R 3 may be optionally substituted independently of each other with 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 the group consisting of benzo[c][1,2]oxaborol-1(3H)-ol, 3,4-dihydro-1H benzo[c][1,2]oxaborinin-1-ol, and 2H-benzo[e][1,2]oxaborinin-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-borabenz[cd]azulene or derivatives thereof, for example, A1 to A7: [Chemical Structure] selected from the group consisting of any one of the parts of TIFF2025520489000007.tif34140, R 5 is 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), and the above members of the group of R other than hydrogen 5 may be optionally substituted independently of each other with one or more substituents selected from the group consisting of C 1~6 alkyl and halogen, provided that halogen may not be adjacent to a heteroatom, R 6 and R 7 each independently is 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- to 7-membered heterocycloalkyl, -(C 1~3- alkyl)-(4- to 7-membered heterocycloalkyl), -heteroaryl, and -(C 1~3 -alkyl)-(heteroaryl), selected from the group consisting of, the last 15 members of the group of said R 6 and R 7 may optionally be independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy, R 6 and R 7 may be linked to form a ring, R 8 and R 9 each independently is 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 -alkoxyl)-(C 2~6 -alkyl), -(C 2~3 -alkyl(oxy)-(C 3~6-(cycloalkyl), 4- to 7-membered heterocycloalkyl, -(C 1~3 -alkyl)-(4- to 7-membered heterocycloalkyl), -heteroaryl, and -(C 1~3 -alkyl)-(heteroaryl), selected from the group consisting of, wherein said R 8 and R 9 in the last 14 members of the group may each independently be optionally substituted with one or more halogens, or R 8 and R 9 may be linked to form a ring, R 10 is 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 -alkoxyl)-(C 2~6 -alkyl), -(C 2~3 -alkyl(oxy)-(C 3~6 -cycloalkyl), 4- to 7-membered heterocycloalkyl, -(C 1~3 -alkyl)-(4- to 7-membered heterocycloalkyl), -heteroaryl, and -(C 1~3 -alkyl)-(heteroaryl), selected from the group consisting of, wherein the last 13 members of said R 10 group may each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, provided that said optional substitution may not be geminal, each R 11 is independently hydrogen, halogen, C 1~6 alkyl, C 3~7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1~6 alkyl(oxy), and C 3~7 cycloalkyl(oxy), selected from the group consisting of, wherein said R 11The last four members of the group may be optionally substituted independently of one another with one or more substituents selected from the group consisting of halogen and hydroxy, provided that R 11 when adjacent to oxygen, R 11 is not halogen and two adjacent R 11 may be connected to provide a fused cycloalkyl, such as cyclopropyl, each R 11a is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 3~7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1~6 alkyl(oxy), and C 3~7 cycloalkyl(oxy), and the last four members of the group of said R 11 may be optionally substituted independently of one another with one or more substituents selected from the group consisting of halogen and hydroxy, provided that R 11 when adjacent to oxygen, R 11 is not halogen and two adjacent R 11 may be connected to provide a fused cycloalkyl, such as cyclopropyl, each R 12 is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, each R 13 is independently selected from the group consisting of 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- to 7-membered heterocycloalkyl, -(C 1~3 -alkyl)-(4- to 7-membered heterocycloalkyl), -N-(R 5 )(R5 ), -SO2-(R 5 ), -SO2-(R 5 )(R 5 ), -S(O)-(R 5 ), and -S-(R 5 ), selected from the group consisting of, wherein said R 13 The last 14 members of the group may optionally be independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy] or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof is provided.

[0036] In one embodiment of the compound of formula (Ia) or (Ib) described herein, X1 is -C(R 6 )(R 7 ), X2 is selected from -C(R 6 )(R 7 ), or X2 comprises a bond between X1 and X3, X3 is -C(R 6 )(R 7 ), R 1 is selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, the last two members of the above group may optionally be independently substituted with one or more halogens, R 2 is selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, the last two members of the group of said R 2 may optionally be independently substituted with one or more halogens, Each R 3 is independently selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, the last two members of the group of said R 3 may optionally be independently substituted with 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 each independently selected from the group consisting of hydrogen, C 1~6 alkyl, C 3~7 cycloalkyl, C 1~6 alkyl(oxy), and C 3~7 cycloalkyl(oxy), and the last four members of the group of said R 6 and R 7 may each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, and R 6 and R 7 may be linked to form a ring, each R 12 is independently selected from the group consisting of hydrogen, halogen, and C 1~6 alkyl, each R 13 is independently selected from the group consisting of 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, and the last seven members of the group of said R 13 may each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy.

[0037] In another embodiment of the compounds of formula (Ia) or (Ib) described herein, R 1 is selected from the group consisting of hydrogen and C 1~6 alkyl, R 2 is selected from the group consisting of hydrogen and C 1~6 alkyl, each R3 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, 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 the group consisting of hydrogen and C 1~6 alkyl, C 1~6 alkyl may be optionally substituted with one or more halogens, R 12 is hydrogen, each R 13 is independently selected from the group consisting of 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, and the last seven members of the group of the above R 13 may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogen and hydroxy.

[0038] In yet another embodiment of the compound of formula (Ia) or (Ib) described herein, R 1 , R 2 and R 3 are hydrogen, R4 is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1~6 alkyl, C 1~6 alkyl may be optionally substituted with one or more halogens, each R 11is, independently, hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, selected from the group consisting of, and the last two substituents may optionally be independently substituted with one or more halogens, each R 11a is, independently, hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, selected from the group consisting of, and the last two substituents may optionally be independently substituted with one or more halogens, R 12 is hydrogen, each R 13 is, independently, hydrogen, halogen, cyano, C 1~6 alkyl, C 3~7 cycloalkyl, and C 1~6 alkyl(oxy), selected from the group consisting of, and the last three members of the group of said R 13 may optionally be independently substituted with one or more halogens.

[0039] In yet another embodiment of the compounds of formula (Ia) or (Ib) described herein, X1 is selected from the group consisting of -O-, -N(R 5 ), and -C(R 6 )(R 7 ), X2 is selected from the group consisting of -O-, -N(R 5 ), and -C(R 6 )(R 7 ), or X2 contains the bond between X1 and X3, X3 is -C(R 6 )(R 7 ), provided that X1 and X2 cannot both be -O-, R 1 is selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two members of the above group may optionally be independently substituted with one or more halogens, R 2 is selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two members of the above group may optionally be independently substituted with one or more halogens, each R 3 is independently selected from the group consisting of hydrogen, C 1~6 alkyl, and C 3~7 cycloalkyl, and the last two members of the above group may optionally be independently substituted with one or more halogens, R4 is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1~6 alkyl, C 3~7 cycloalkyl, C 1~6 alkyl(oxy), and C 3~7 cycloalkyl(oxy), and the last four members of the above group may optionally be independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy, R 6 and R 7 may be linked to form a ring, each R 12 is independently selected from the group consisting of hydrogen, halogen, and C 1~6 alkyl.

[0040] In another embodiment of the compound of formula (Ia) or (Ib) described herein, X1 is selected from the group consisting of -O-, -N(R 5 )-, and -C(R 6 )(R 7 )-, X2 is selected from the group consisting of -O- and -C(R 6 )(R 7 )-, provided that X1 and X2 cannot both be -O-, or X2 includes the bond between X1 and X3, X3 is -C(R 6)(R 7 )-wherein R 1 is selected from the group consisting of hydrogen and C 1~6 alkyl, R 2 is selected from the group consisting of hydrogen and C 1~6 alkyl, each R 3 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R4 is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1~6 alkyl, where the C 1~6 alkyl is optionally substituted with one or more of halogen, R 12 is hydrogen, each R 13 is independently selected from the group consisting of 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, and the last seven members of the group of said R 13 are optionally substituted independently of each other with one or more substituents selected from the group consisting of halogen and hydroxy.

[0041] In another embodiment of the compound of formula (Ia) or (Ib) described herein, X2 is -C(R 6 )(R 7 )-, X3 is -C(R 6 )(R 7 )-, R 1 and R2 and R 3 is hydrogen, R4 is selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl, R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with one or more halogens, each R 11 is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, the last two members of the group of said R 11 may be optionally substituted independently of each other with one or more halogens, each R 11a is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, and C 3~7 cycloalkyl, the last two members of the group of said R 11 may be optionally substituted independently of each other with one or more halogens, each R 12 is hydrogen, each R 13 is independently selected from the group consisting of hydrogen, halogen, cyano, C 1~6 alkyl, C 3~7 cycloalkyl, and C 1~6 alkyl(oxy), the last three members of the group of said R 13 may be optionally substituted independently of each other with one or more halogens.

[0042] In one embodiment, the disclosure is a compound selected from the group shown in Table 1 below:

[0043]

Table 1

[0044] In one embodiment, the present disclosure is a compound selected from the group shown in Table 2 below:

[0045] [Table 2] TIFF2025520489000011.tif210170TIFF2025520489000012.tif42170

[0046] In one embodiment, the present disclosure provides a compound selected from the group consisting of Examples 1 to 24 and Examples 25 to 50 (Tables 1 and 2), and the compound has the trans relative stereochemistry represented by Formulas (Ia) and (Ib):

[0047] [Chemical formula]

[0048] In one embodiment, the present disclosure provides a compound selected from the group consisting of Examples 1 to 25 (shown in Table 1) and Examples 26 to 50 (shown in Table 2), and has the trans relative stereochemistry represented by Formula (Ia).

[0049] In one embodiment, the present disclosure provides a compound selected from the group consisting of Examples 1 to 25 (shown in Table 1) and Examples 26 to 50 (shown in Table 2), and has the trans relative stereochemistry represented by Formula (Ib).

[0050] Definitions The terms used herein shall have their ordinary meanings in the art unless otherwise specified. The organic moieties referred to in the definitions of the variable elements of the compounds of Formulas (I), (Ia), and (Ib) are general terms for the individual lists of the individual group members, similar to the term halogen. The prefix Cn to Cm (or Cn - m) indicates, in each case, the possible number of carbon atoms in the group.

[0051] As used herein, the term "animal" includes all mammals, birds, and fish, and also includes all vertebrates. Animals include, but are not limited to, cats, dogs, cows, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. Animals also include individual animals at all stages of development, including the embryonic and fetal stages. In some embodiments, the animal is a non-human animal.

[0052] The term "enriched" means a weight:weight ratio that is advantageously at least approximately 1.05 or more for the enantiomer (eutomer) that exhibits significant in vitro and in vivo activity.

[0053] In one embodiment, the compounds of the present disclosure are JAK1 inhibitors that are selective compared to JAK2. Determination of the relative selectivity of a given compound for JAK1 inhibition is defined as the relative ratio of (JAK2 IC 50 value / JAK1 IC 50 value). In one embodiment, for a given compound, the relative ratio of (JAK2 IC 50 value / JAK1 IC 50 value) is at least 2. In yet another embodiment, for a given compound, the relative ratio of JAK2 IC 50 value / JAK1 IC 50 value) is at least 5. In another embodiment, the relative ratio of JAK2 IC 50 / JAK1 IC 50 is preferably at least 10. In one embodiment, the ratio of JAK2 IC 50 / JAK1 IC 50 is greater than 10.

[0054] The term "treating" or "treatment" includes alleviating, ameliorating, reducing, or otherwise lessening the signs and symptoms associated with a disease or disorder.

[0055] "Therapeutically effective amount" means the amount of a drug or pharmaceutical agent that will induce a biological or medical response of a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0056] The term "composition" as in a pharmaceutical composition encompasses not only a product containing the active ingredient(s) and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, but also any product directly or indirectly resulting from the combination, complex formation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition prepared by mixing a compound of formula (I), (Ia), and (Ib) or a mixture thereof with a pharmaceutically acceptable excipient.

[0057] The term "optionally substituted" means "unsubstituted or substituted", and thus the general structural formulas described herein encompass not only compounds containing the indicated optional substituents, but also compounds not containing the optional substituents.

[0058] When referring to the compounds disclosed herein, the following terms have the following meanings unless otherwise indicated. The following definitions are intended to clarify the defined terms and are not intended to be limiting. If a particular term used herein is not specifically defined, such term should not be considered to be uncertain. Rather, the terms are used within the scope of their generally recognized meanings.

[0059] As used herein, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms. The hydrocarbon chain can be either straight-chain or branched-chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. Similarly, an "alkenyl" group refers to an alkyl group having one or more double bonds within the chain, and an "alkynyl" group refers to an alkyl group having one or more triple bonds within the chain.

[0060] As used herein, "halogen" or "halo" refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0061] As used herein, "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms, in which at least one hydrogen atom is substituted with a halogen, including perhalo groups in which all hydrogen atoms are replaced with halogen atoms. The haloalkyl chain can be either straight-chain or branched-chain. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a "haloalkenyl" group refers to a haloalkyl group having one or more double bonds in the chain, and a "haloalkynyl" group refers to a haloalkyl group having one or more triple bonds in the chain.

[0062] Further, an "alkylene" linker group refers to a divalent alkyl group, i.e., (CH2) x (wherein x is from 1 to 20, preferably from 1 to 8, preferably from 1 to 6, more preferably from 1 to 3).

[0063] As used herein, "hydroxyalkyl" refers to an alkyl group as defined herein substituted with one or more -OH groups. Similarly, a "hydroxyalkenyl" group refers to a haloalkyl group having one or more double bonds in the chain, and a "hydroxyalkynyl" group refers to a haloalkyl group having one or more triple bonds in the chain.

[0064] As used herein, "aryl" refers to a substituted or unsubstituted carbocyclic aromatic ring system, either pendant or fused, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indane, or biphenyl. A preferred aryl group is phenyl.

[0065] As used herein, "cycloalkyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their partially saturated forms, such as cyclohexenyl and cyclohexadienyl. Further, bridged rings, such as adamantane, are included within the definition of "cycloalkyl".

[0066] As used herein, the term "heterocyclyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms in which one or more carbon atoms are replaced by heteroatoms selected from O, N, S, or Si, each N, S, or Si may be oxidized, and each N may be quaternized. The heterocyclyl group can be attached to the remainder of the molecule via a heteroatom. Heterocyclyl does not include heteroaryl.

[0067] As used herein, the term "heteroaryl" or "heterocyclic aromatic" refers to an aromatic ring group having from 5 to 14 ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, sulfur, or silicon). They include monocyclic rings, and polycyclic rings in which a monocyclic heterocyclic aromatic ring is fused to one or more other carbocyclic aromatic rings or heterocyclic aromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of monocyclic 6-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

[0068] The terms "arylalkyl", "heteroarylalkyl", and "heterocyclylalkyl" refer to groups in which an aryl, heteroaryl, or heterocyclyl group is linked via an alkyl group. Examples include benzyl, phenethyl, pyridylmethyl, and the like. These terms also include alkyl linking groups in which a carbon atom, such as a methylene group, is replaced, for example, by an oxygen atom. Examples include phenoxymethyl, pyrid-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 bonded to a CH2 group, thus being a CH2Ph group. The 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 1 to 5 substituents, or in another embodiment, 2 to 3 substituents.

[0069] As used herein, "optionally substituted" refers to the replacement of a hydrogen atom that would otherwise be present in place of a substituent. When discussing a ring system, optional substitution is typically by 1, 2, or 3 substituents that replace the normally present hydrogen. However, when referring to straight-chain and branched moieties, the number of substitutions may be greater and may occur anywhere hydrogen is present. The substitutions may be the same or different.

[0070] Those by a plurality of substituents may be the same or different. Exemplary substituents 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, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, where each of these may be linked via 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 may also include =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =N-CN, =NH, or =NR'. For each of these, each may be linked via an alkylene linker, (CH2)x (where x is 1, 2, or 3). Each occurrence of R' is the same or different. In some embodiments, R' represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or in some embodiments, when two R's are each bonded to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing 4 to 6 ring atoms.

[0071] As used herein, the terms veterinary or veterinarily, or pharmaceutically or pharmaceutically acceptable salt refer to any salt of a compound disclosed herein that retains its biological properties and is not toxic or otherwise undesirable for veterinary or pharmaceutical use. The general use of the terms pharmaceutically or pharmaceutically is intended to cover either veterinary or veterinarily. These terms may be used interchangeably where the context permits.

[0072] Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include acid addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, and the like.

[0073] As salts, by way of further example only, salts of non-toxic organic or inorganic acids may be mentioned, 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)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethane-disulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, gluconates, benzoates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, cinnamates, muconates and the like.

[0074] Examples of inorganic bases which may be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

[0075] Examples of organic bases that can be used to form base addition salts include, but are not limited to, metal alkoxides such as 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 cycloaliphatic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.

[0076] The base may be a quaternary ammonium hydroxide in which one or more of the alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that can be used in accordance with the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, and tetramethylammonium hydroxide, preferably choline hydroxide. The alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that can be used in accordance with the present disclosure include methylamine, ethylamine, diethylamine, and triethylamine. The substituted alkylamine base may 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 in accordance with the present disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (deanol), tromethamine, ethanolamine, and diolamine.

[0077] Stereoisomers and polymorphic forms In certain instances, the substituents shown may contribute to optical and / or steric isomerism. Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of those atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. A molecule having at least one stereocenter can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (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 polarization and is designated dextrorotatory or levorotatory (i.e., as the (+)- or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0078] In certain embodiments, the compounds disclosed herein may have one or more chiral centers, and thus such compounds can be produced as racemic mixtures, enantiomerically enriched mixtures, or individual enantiomers. For example, unless otherwise indicated by the stereochemical designation at any position of the formula, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and racemic or other mixtures thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

[0079] In certain embodiments, the compounds disclosed herein are "stereochemically pure." A stereochemically pure compound has a level of stereochemical purity that would be recognized as "pure" by one of ordinary skill in the art. Of course, this level of purity can be less than 100%. In certain embodiments, "stereochemically pure" refers to a compound that substantially does not contain another isomer, i.e., contains less than at least about 85%. In certain embodiments, the compound contains other isomers less than 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%.

[0080] In addition, the compounds disclosed herein ("active agents") may exist as hydrates or solvates in which a particular stoichiometric amount of water or solvent is associated with the molecule in the crystalline form. The compositions of the present disclosure may include hydrates and solvates of the active agent. In some embodiments, the compositions of the present disclosure may include up to 15% (w / w), up to 20% (w / w), or up to 30% (w / w) of a particular solid form.

[0081] As used herein, the terms "subject" and "patient" may be used interchangeably herein. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal, such as a dog or a cat. In further embodiments, 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, e.g., a cynomolgus monkey or a chimpanzee.

[0082] In addition, pharmaceutically acceptable prodrugs of the compounds represented by formula (I), formula (Ia), and formula (Ib) are also included in the present disclosure. A pharmaceutically acceptable prodrug refers to a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs are those described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198. The term "prodrug" is used throughout this specification to describe any pharmaceutically acceptable form of a compound that provides the active compound upon 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 the compounds of the present disclosure. Typical examples of prodrugs include compounds having a biologically labile protecting group on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.

[0083] This disclosure includes all pharmaceutically acceptable isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure include isotopes of hydrogen, such as 2 H and 3 H, isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, isotopes of phosphorus, such as 32 P, and isotopes of sulfur, such as 35 S. Certain isotopically labeled compounds of this disclosure, such as those incorporating radioactive isotopes, can be useful in drug or substrate tissue distribution studies. Tritium, a radioactive isotope, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of the ease of their incorporation and the ready means of detection. Substitution with heavier isotopes, such as deuterium, i.e., 2 H, can result in certain therapeutic advantages derived from higher metabolic stability, such as an increase in in vivo half-life or a reduction in required dosage, and may therefore be preferred in some situations. Positron emitting isotopes, such as 11 C, 18 F, 15 O and 13Substitution by N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or using appropriate isotopically labeled reagents in place of the unlabeled reagents used heretofore, by processes similar to those described in the appended examples. In one aspect, the present disclosure provides a process for preparing a compound of any of the embodiments of formula (I), formula (Ia), and formula (Ib) described herein.

[0084] Compositions and Methods of Administration The compounds of formula (I), formula (Ia), and formula (Ib) used in the methods disclosed herein, in certain embodiments, can be used alone, in the form of salts where appropriate, a veterinary composition or a pharmaceutical composition comprising at least one compound of formula (I), formula (Ia), and formula (Ib), or in combination with one or more compatible veterinary or pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with another agent, and administered. Compositions are provided that include derivatives or salts of the compounds of formula (I), formula (Ia), and formula (Ib), and acceptable excipients, carriers, or diluents. The compositions may also be in various forms including, but not limited to, oral formulations, injectable formulations, and topical, transdermal, or subcutaneous formulations. The specific route chosen by the practitioner depends on factors such as the physicochemical properties of the pharmaceutical or therapeutic agent, the condition of the host, and economics.

[0085] In one aspect, the present disclosure provides a method of treating a patient having a disease or disorder susceptible to modulation of JAK, comprising administering a therapeutically effective amount of a compound described herein, such as any of the embodiments of a compound according to formula (I), (Ia), or (Ib).

[0086] In one embodiment, the present disclosure provides a method of treating a patient having a disease or disorder that can be ameliorated by selective inhibition of Janus kinase JAK 1 compared to JAK 2.

[0087] In one embodiment, the present disclosure is a method of treating a patient having a disease or disorder with a therapeutically effective amount of a compound of embodiments of formula (I), formula (Ia), and formula (Ib), wherein the disease or disorder is atopic dermatitis, nummular allergic 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 disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, atherosclerosis, and cancer, and provides a method that is one or more of these.

[0088] In one embodiment, the present disclosure is a method of treating a patient as described above, wherein the disease or disorder is one or more of atopic dermatitis, nummular allergic dermatitis, psoriasis, and rheumatoid arthritis, and provides a method.

[0089] According to one embodiment, the present disclosure is a method of treating a patient having a disease or disorder susceptible to modulation of JAK, comprising administering an amount of a compound according to the present disclosure in an amount that perturbs an immune regulatory pathway in a cell. In one such embodiment, the perturbation results in an effect on the JAK-STAT pathway.

[0090] In one aspect, the present disclosure is a method of inhibiting JAK in mammalian cells, comprising contacting the mammalian cells with a compound according to any embodiment of formula (I), (Ia), or (Ib), and provides a method. In certain embodiments, the mammalian cells are cells from a subject having an inflammatory condition.

[0091] In one aspect, the present disclosure provides a composition comprising a compound according to any embodiment of formula (I), formula (Ia) or formula (Ib), and a pharmaceutically or veterinarily acceptable carrier.

[0092] The composition can be in a form suitable for oral use, such as a nutritional supplement, a troche, a lozenge, a chewable, a tablet, a hard or soft capsule, an emulsion, an aqueous or oily suspension, an aqueous or oily solution, a dispersible powder or granule, a syrup, or an elixir. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of veterinary or pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents, and preservatives to provide a refined and palatable preparation. In certain 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 chewable drug delivery formulations. An issue associated with the administration of oral formulations to animals is that the therapeutic agent often results in an unpleasant taste, odor, or texture, which causes the animal to reject the composition. This is further exacerbated by hard and unpalatable compositions.

[0093] Oral veterinary compositions in the form of a soft chewable composition ("soft chew"), or palatable chewable tablets, are generally convenient for administration to certain animals, particularly cats and dogs, and can be effectively used to administer veterinary drugs to these animals. However, many oral compositions containing active agents with a bitter or unpleasant taste are not well accepted by cats and dogs. Further, if the bioavailability of the active agent from the oral dosage form is not sufficient or varies, the required exposure of the animal to the active ingredient may not be sufficient to provide the desired efficacy. Such issues often result in low or suboptimal efficacy, and control of parasites.

[0094] Chewable dosage forms for drug delivery are well known in the pharmaceutical art. In the pharmaceutical industry, it is known that the act of chewing can increase the surface area of the available active ingredient and thus increase the rate of absorption by the gastrointestinal tract. Chewable systems are also advantageous when it is desirable to make the active ingredient locally available in the oral or pharyngeal region for both local effects and / or systemic absorption. Additionally, chewable dosage forms are also utilized to facilitate drug administration in pediatric and geriatric patients. Examples of chewable dosage forms can be found in U.S. Pat. Nos. 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.

[0095] Palatability and "mouth feel" are important characteristics to consider when providing a dosage form or matrix for an active pharmaceutical or drug. Unfortunately, many pharmaceuticals and other active ingredients have a bitter or other unpleasant taste, or an unacceptable mouth feel, due to the gritty or powdery nature of the compound, or both. These characteristics make it difficult to incorporate such active ingredients into the current state-of-the-art for chewable dosage forms, because the unpleasant taste and / or mouth feel make compliance by the user less likely. Poorly palatable oral veterinary dosage forms result in low acceptance of the medicine by the animal being treated and low levels of compliance. Accordingly, there is a need for improved oral veterinary dosage forms that are palatable and well accepted by the animal being treated.

[0096] Another problem with oral veterinary compositions, particularly soft chewable 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 gastrointestinal tract.

[0097] U.S. Patent No. 7,955,632 (incorporated herein by reference) describes an orally acceptable, edible, soft chewable pharmaceutical vehicle for the delivery of a pharmaceutically acceptable active ingredient to an animal, and a method of making the same.

[0098] Furthermore, 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 pharmaceutical active agent, and WO 2009 / 02451A2 and US 2011 / 0059988 to Heckeroth et al. describe various compositions for oral administration to animals (all incorporated herein by reference).

[0099] Traditionally, in veterinary formulations, palatability has been achieved by including animal by-products or flavorants of animal origin in the formulation. For example, it is common to include excipients such as chicken powder, liver powder, beef, ham, fish, or products derived from rawhide in dog chews to make them attractive and palatable to dogs. See, for example, all of U.S. Patent Nos. 6,086,940, 6,093,441, 6,159,516, 6,110,521, 5,827,565, 6,093,427 to Axelrod et al. (all incorporated herein by reference).

[0100] Exceptionally palatable, soft chewable oral veterinary compositions that provide high bioavailability of the active agent are all described in U.S. Patent Nos. 9,259,417, 9,233,100, 9,931,320, 10,596,156 to Soll et al. (all incorporated herein by reference).

[0101] A lozenge is a solid composition containing one or more active ingredients that is intended to dissolve or disintegrate slowly in the oral cavity by passive incubation in the oral cavity or by actively sucking or chewing. These can be used for systemic action when the drug is absorbed through the inner lining of the cheek or esophagus or swallowed. In particular, soft lozenges may be chewed or slowly dissolved in the mouth. These dosage forms have the advantage of being flavored and are therefore easy to administer to both human and animal patients; have a manufacturing process that is easy to modify, can be patient-specific; can deliver an accurate amount of the active ingredient to the oral cavity and the digestive system; and can keep the drug in contact with the oral cavity or esophageal lumen for a long time.

[0102] Tablets can contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect over a longer period of time.

[0103] Preparations 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 an oily medium such as peanut oil, liquid paraffin or olive oil.

[0104] The composition may also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phosphatides such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, bitter agents, flavoring agents, and preservatives.

[0105] In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are very suitable as liquid carrier vehicles. A microemulsion is a quaternary system comprising an aqueous phase, an oil phase, a surfactant, and a co-surfactant. They are translucent and isotropic liquids. A microemulsion is composed of a stable dispersion of tiny droplets of the aqueous phase in the oil phase, or conversely, a stable dispersion of tiny droplets of the oil phase in the aqueous phase. The size of these tiny droplets is less than 200 nm (1000 - 100,000 nm in an emulsion). The interfacial film is composed of alternating surfactant (SA) and co-surfactant (Co-SA) molecules, which enable the microemulsion to form spontaneously by reducing the interfacial tension. In one embodiment of the oil phase, the oil phase can be formed from a mineral oil or a vegetable oil, from an unsaturated polyglycosylated glyceride, or from a triglyceride, or from a mixture of such compounds. In one embodiment of the oil phase, the oil phase is composed of triglycerides. In another embodiment of the oil phase, the triglycerides are medium-chain triglycerides such as C8 - C 10It is capric acid / capric acid triglyceride. In another embodiment, the oil phase will occupy a % v / v range selected from the group consisting of about 2 to about 15%, about 7 to about 10%, and about 8 to about 9% v / v of the microemulsion. Examples of the aqueous phase include water, or glycol derivatives such as propylene glycol, glycol ether, polyethylene glycol or glycerol. In one embodiment of the glycol derivative, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will occupy a ratio of about 1 to about 4% v / v in the microemulsion. Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolated C8-C 10 Glycerides or polyglyceryl-6 dioleate may be mentioned. In addition to these surfactants, co-surfactants include short-chain alcohols such as ethanol and propanol. Some compounds are common to the three components described above, such as the aqueous phase, surfactant and co-surfactant. However, using different compounds for each component of the same formulation is well within the skill level of the practitioner. For example, in one embodiment regarding the amount of surfactant / co-surfactant, the ratio of co-surfactant to surfactant can be about 1 / 10 to about 1 / 2. In another embodiment regarding the amount of co-surfactant, there will be about 25 to about 75% v / v of surfactant and about 10 to about 55% v / v of co-surfactant in the microemulsion.

[0106] The oily suspension can be formulated 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, solid paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid or other known preservatives.

[0107] The aqueous suspension may contain an active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylenesorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening and / or bittering agents such as those described herein.

[0108] Dispersible powders and granules suitable for the preparation of aqueous suspension agents by the addition of water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents, and suspending agents are already exemplified by those described above. Additional excipients, such as sweeteners, bittering agents, flavoring agents and coloring agents may also be present.

[0109] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, flavoring agent(s) and coloring agent(s).

[0110] The composition can be in the form of an aqueous or oily suspension for sterile injection. This suspension can be formulated according to known techniques using the suitable dispersants or wetting agents and suspending agents described above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3 - butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Co - solvents such as ethanol, propylene glycol or polyethylene glycol can also be used. Preservatives such as phenol or benzyl alcohol may be used.

[0111] In addition, sterile fixed oils have been conventionally used as solvents or suspending media. For this purpose, any non - irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid have been found to be used in the preparation of injectables.

[0112] Examples of topical, transdermal and subcutaneous preparations include emulsion agents, cream agents, ointment agents, gel agents or paste agents.

[0113] Examples of organic solvents that can be used include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl esters, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene 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.

[0114] As a vehicle or diluent, the compositions of the present disclosure include vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons, or alternatively, for example, medium-chain (e.g., C8-C 12 ) triglycerides may be included.

[0115] The dosage form may contain from about 0.5 mg to about 5 g of the active agent.

[0116] 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.

[0117] The compounds of formula (I), formula (a), and formula (IVb) may be used as such or in the form of their preparations or formulations as a combination.

[0118] The compounds of formula (I), formula (Ia) and formula (Ib) according to the present disclosure may be combined, for example, with one or more agents having the same active region to increase activity, or with a substance having a different active region to broaden the range of activity, for example. As an example, a combination of a compound of formula (I) (or formula (Ia) and formula (Ib)) with one or more of an additional JAK inhibitor or a JAK / signal transducer and activator of transcription (JAK / STAT) modulator may provide a therapeutic advantage. Examples of JAK inhibitors that may be useful as combination agents include baricitinib, ruxolitinib, filgotinib, CYT387, upadacitinib, fedratinib, peficitinib, lestaurtinib, pacritinib, octostatinib, selduxolitinib, and tofacitinib.

[0119] The compounds of formula (I), formula (Ia) or formula (Ib) according to the present disclosure may be combined with one or more additional pharmaceutical or veterinary active agents. Additional additional active agents that may be used in the methods provided herein in combination with the compounds of formula (I), (Ia) or (Ib) include, but are not limited to, disease-modifying antirheumatic drugs (DMARDs, such as cyclosporine A and methotrexate), anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, mycophenolate mofetil, biological agents, TNF-a inhibitors (such as etanercept), Cox-2 inhibitors (such as celecoxib), 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 salts, 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 prednisone or dexamethasone.

[0120] In some embodiments, the second active agent can include, but is not limited to, an anti-inflammatory agent, such as an NSAID, and the NSAID can include, but is not limited to, diclofenac (e.g., ARTHROTEC®), diflunisal (e.g., DOLOBID®), etodolac (e.g., LODINE®), fenoprofen (e.g., NALFON®), ibuprofen (e.g., ADVIL®, CHILDREN'S ADVIL / MOTRIN®, MEDIPREN®, MOTRIN®, NUPRIN®, or PEDIACARE FEVER®), indomethacin (e.g., ARTHREXIN®), ketoprofen (e.g., ORUVAIL®), ketorolac (e.g., TORADOL®), fosfomycin trometamol (e.g., MONURAL®), meclofenamate (e.g., MECLOMEN®), nabumetone (e.g., RELAFEN®), naproxen (e.g., ANAPROX®, ANAPROX® DS, EC-NAPROSYN®, NAPRELAN®, or NAPROSYN®), oxaprozin (e.g., DAYPRO®), piroxicam (e.g., FELDENE®), sulindac (e.g., CLINORIL®), and tolmetin (e.g., TOLECTIN® DS or TOLECTIN®).

[0121] In other embodiments, the second active agent can include, but is not limited to, a disease-modifying anti-rheumatic drug (e.g., a DMARD) or an immunosuppressive agent, such as, but not limited to, methotrexate (e.g., RHEUMATREX®), sulfasalazine (e.g., AZULFIDINE®), and cyclosporine (e.g., SANDIMMUNE® or NEROAL®; and including cyclosporine A).

[0122] In other embodiments, the second active agent can include mycophenolate mofetil (e.g., CellCept®), which is widely used in organ transplantation and is an immunosuppressant that is gaining support in the treatment of autoimmune and inflammatory skin disorders, among others.

[0123] In further embodiments, the second active agent can include biologics such as etanercept (e.g., ENBREL®), infliximab (e.g., REMICADE®), and adalimumab (e.g., HUMIRA®), among others.

[0124] In yet further embodiments of interest, the second active agent can include Cox-2 inhibitors such as celecoxib (e.g., CELEBREX®), firocoxib (e.g., PREVICOX®), valdecoxib (e.g., BEXTRA®), and meloxicam (e.g., MOBIC®, METACAM®), among others.

[0125] In a further embodiment, the second active agent includes veterinary therapeutic agents well-known in the art (see, e.g., Plumb’s Veterinary Drug Handbook, 5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005)), and includes, but is not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide sulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B desoxycholate, lipid-based amphotericin B, ampicillin, amprolium, antacids (oral), antivenin, 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 subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budesonide, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitriol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cephalexin, cefazolin sodium, cefixime, chlorothiazide, cefoperazone sodium, cefotaxime sodium,Cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, cefotiam hexetil, cefotiam, ceftriaxone sodium (ceftiaxone sodium), cephalexin, cephalosporin, cefapirin, carbon (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide, clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam (claonazepam), clonidine, cloprostenol sodium, dichlorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, deconate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthol, dexrazoxane (dexraazoxane), dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenhydramine, disopyramide phosphate, dobutamine, doxart / DSS, droperidol mesylate, domperidone, dopamine, dramectine, doxapram, doxepin, doxorubicin, doxycycline, calcium disodium edetate. Calcium EDTA, edrophonium chloride, enalapril / enalaprilat, enoxaparin sodium, enrofloxacin,Ephedrine Sulfate, Epinephrine, Epoetin / Erythropoietin, Eprinomectin, Epsiprantel, Erythromycin, Esmolol, Estradiol Cypionate, Etacrynic Acid / Sodium Etacrynate, Ethanol (Alcohol), Sodium Etidronate, Etodolac, Etomidate, Euthanasia Agents with 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, Gliquidone, Glucagon, Glucocorticoid Agents, Glucosamine / Chondroitin Sulfate, Glutamine, Glyburide, Glycerin (Oral), Glycopyrrolate, Gonadorelin, Griseofulvin, Guaifenesin, Halothane, Hemoglobin Glutamer-200 (OXYGLOBIN (R)), Heparin, Hetastarch, Sodium Hyaluronate, Hydrazaline, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydromorphone, Hydroxyurea, Hydroxyzine, Ifosfamide, Imidacloprid, Imidocarb Dipropionate, Imipenem-Cilastatin Sodium, Imipramine, Inamrinone Lactate, Insulin, Interferon Alpha-2a (Recombinant Human), Iodide (Sodium / Potassium), Tocohn (Syrup), Ipodate Sodium, 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), lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, mesadone, metazolamide, methenamine mandelate / methenamine hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole, mexiletine, mibolerone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, nandrolone decanoate, naproxen, opioid agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, opioid antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancrelipase, pancuronium bromide, paromomycin sulfate, paroxetine, pencillamine, penicillin general information, penicillin, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine,Phenypropanolamine, phenytoin sodium, pheromone, parenteral phosphate, phytomenadione / vitamin K-1, pimobendan, piperazine, pyrrolnitrin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisone / prednisolone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, Japanese butterbur hydrophilic mucilage, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline / high osmotic laxative, selamectin, selegiline / l-deprenyl, sertraline, sevelamer, sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatotropin, sotolol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sodium sulfachloropyridazine, sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadimethoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafine, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyrotropin, thiamulin, ticarcillin disodium, tiletamine / zolazepam, tilmicosin, tiopronin, tobramycin sulfate, tocainide, trazoline, telfenamic acid, topiramate, tramadol,It may include triamcinolone acetonide, trientine, trilostane, trimepraxine tartrate with prednisone, tripelennamine, tyrosin, ursodiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vincristine sulfate, vinblastine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, and zonisamide, and mixtures thereof.

[0126] One or more of these additional active agents can be administered in the same or different dosage schedules via the same or different routes of administration, in accordance with standard pharmaceutical practice known to those skilled in the art, as part of the same or different dosage forms.

[0127] Pharmaceutical preparations containing the compounds of formulas (Ia), (Ib), and (I) for delivery to humans or other mammals are preferably unit dosage forms in which the preparation is further divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation containing an individual amount of the preparation, such as a packaged tablet, capsule, and powder in a vial or ampoule. Also, the unit dosage form may be the capsule, tablet or lozenge itself, or it may be an appropriate number of any of these in packaged form.

[0128] The amount of the active ingredient in the unit dosage preparation can vary or be adjusted from about 0.1 mg to about 1000 mg according to the specific use and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents if desired. In the therapeutic use for the treatment or alleviation of inflammation, autoimmune diseases, and cancer in humans or other mammals, the compounds utilized in the treatment method are administered at an initial dosage of about 0.1 mg / kg to about 100 mg / kg per interval, about 0.1 mg / kg to about 50.0 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 can be daily, weekly, monthly, every three months, every six months, or annually.

[0129] The dosage can vary according to the requirements of the patient, such as the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound(s) used. The determination of the appropriate dosage and route of administration for a particular situation is within the scope of the practitioner's skill. Generally, treatment will be initiated at a lower dosage that is less than the optimal dosage of the compound, and this can be increased gradually until the optimal effect is achieved under the particular circumstances of the condition. For convenience, the total daily dosage may, if desired, be divided and administered in small portions throughout the day.

[0130] In therapeutic use, the compounds of formula (Ia), (Ib), and (I) are useful in the manufacture of a medicament for a method of treating any condition where inhibition of JAK is desirable, including but not limited to cancer, neuroinflammation, inflammatory airway diseases, ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, and atopic dermatitis. In one or more embodiments, one or more of the compounds of formula (Ia), (Ib), and (I) are useful in the treatment of one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Behçet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), 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.

[0131] In one aspect, the present disclosure provides a method of treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (Ia), or (Ib) as an embodiment herein.

[0132] In one embodiment, the present disclosure provides a method of treating atopic dermatitis, nummular allergic dermatitis, psoriasis, or rheumatoid arthritis, the method comprising administering to a subject in need thereof an effective amount of a compound of 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.

[0133] In one embodiment, the present disclosure provides a method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, the method comprising administering to a subject in need thereof an effective amount of a compound according to any embodiment herein of formula (I), (Ia), or (Ib), wherein the subject is a mammal.

[0134] In one embodiment, the present disclosure provides a method for treating one or more diseases or disorders of inflammation, autoimmune dysfunction, and cancer, the method comprising administering to a subject in need thereof an effective amount of a compound according to any embodiment herein of formula (I), (Ia), or (Ib), wherein the subject is selected from one or more of livestock mammals, breeding mammals, and companion animals. In one embodiment, the mammal is one or more of human, cow, sheep, goat, llama, alpaca, pig, horse, donkey, dog, and cat. In one embodiment, the mammal is human, dog, or cat.

[0135] In one aspect, the present disclosure provides a compound for use in a medicament, 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 herein of formula (I), (Ia), and (Ib) for the manufacture of a medicament for the treatment of one or more diseases or disorders including inflammation, autoimmune dysfunction, and cancer. In one embodiment, the present disclosure provides the use of a compound according to any embodiment herein of formula (I), (Ia), or (Ib) for the manufacture of a medicament for the treatment of a disease or disorder that can be improved by selective inhibition of Janus kinase JAK 1 compared to JAK 2. In one embodiment, the disease or disorder is atopic dermatitis, nummular allergic dermatitis, psoriasis, or rheumatoid arthritis. In one aspect, the present disclosure provides the use of a compound according to an embodiment herein of formula (I), (Ia) or (Ib) and a second active agent in the manufacture of a medicament for the treatment of a disease or disorder that can be improved by selective inhibition of Janus kinase JAK 1 compared to JAK 2. In one aspect, the present disclosure provides the use of a compound according to an embodiment herein of formula (I), (Ia), or (Ib) for the treatment of one or more diseases or disorders including inflammation, autoimmune dysfunction, and cancer. In one embodiment, the disease or disorder is atopic dermatitis, nummular allergic dermatitis, psoriasis, or rheumatoid arthritis.

[0136] The present disclosure expressly encompasses the compounds described herein, including their salt forms, and their salt forms. The present disclosure also encompasses the compounds presented herein, including their stereoisomers. The compounds encompassed by the present disclosure include, in some embodiments, compounds selected from Tables 1 and 2 described herein.

[0137] Compositions containing a therapeutically acceptable amount of any of the compounds described herein are within the scope of the present disclosure. The compositions 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 in whole or in part, directly or indirectly, by JAK. The compositions may further comprise additional active agents as described herein.

Examples

[0138] Experimental procedures: The following examples provide a more detailed description of the process conditions for preparing the compounds of the present disclosure. However, it should be understood that the present disclosure is not intended to be limited by the details of the following schemes or modes of preparation as fully described herein and recited in the claims.

[0139] Certain abbreviations may be used when describing the examples of the present disclosure. The abbreviations are considered to be used consistently within the generally accepted scope of use by those skilled in the art.

[0140] Chemical examples In the following schemes, general substituents are represented by assignments that may not be consistent with the formulas of the present disclosure. The following schemes should be followed for the schemes and provide clues for such substituents that do not apply to the formulas of the present disclosure.

[0141] The following abbreviations are used in the chemical example schemes herein.

[0142]

Table 3

[0143] Synthesis of general intermediates. Preparation of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile

[0144]

Chem.

[0145] Preparation of 6-(p-toluenesulfonyl)-6-azabicyclo[3.1.0]hexane

[0146]

Chem.

[0147] Two reaction mixtures were carried out in parallel. To a mixture of cyclopentene (50 g, 734 mmol, 64.9 mL, 1 equiv) and sodium [chloro(p-toluenesulfonyl)amino] (184 g, 807 mmol, 1.1 equiv) in MeCN (2.5 L), phenyltrimethylammonium tribromide (27.6 g, 73.4 mmol, 0.1 equiv) was added portionwise at 25 °C under N2. The mixture was stirred at 25 °C for 48 h. TLC indicated that the reaction was complete. The combined reactants were combined and concentrated under vacuum to give a residue. The residue was quenched with H2O (2 L) and extracted with EtOAc (1 L twice). 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 (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 4 / 1) to give 6-(p-toluenesulfonyl)-6-azabicyclo[3.1.0]hexane (125 g, 35.8% yield) as a white solid. 1 1H 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, 2 H).

[0148] Preparation of N-(trans)-2-cyanocyclopentyl)-4-methylbenzenesulfonamide

[0149]

Chem.

[0150] Two reactions were carried out in parallel. For each, to a solution of 6-(p-toluenesulfonyl)-6-azabicyclo[3.1.0]hexane (55 g, 231 mmol, 1 equiv) in THF (550 mL) were added dropwise TMSCN (34.4 g, 347 mmol, 43.5 mL, 1.5 equiv) and TBAF (1 M in THF, 46.3 mL, 0.2 equiv) at 20 °C under N₂. After addition, the mixture was heated and stirred at 45 °C for 16 h. TLC indicated that the reaction was complete. The two reaction mixtures were combined, poured into H₂O (1 L), and extracted with EtOAc (1 L three times). The combined organic layers were washed with brine (500 mL three times), 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 with a 0 - 50% ethyl acetate / petroleum ether gradient, 200 mL / min) to afford N-(trans)-(2-cyanocyclopentyl)-4-methyl-benzenesulfonamide (100 g, 81.8% yield) as a yellow solid. 1 ¹H 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 - 1.55 ppm (m, 1H).

[0151] Preparation of tert-butyl ((trans)-2-cyanocyclopentyl)(tosyl)carbamate

[0152] [Chemistry]

[0153] To a solution of N-(trans)-(2-cyanocyclopentyl)-4-methyl-benzenesulfonamide (95 g, 359 mmol, 1 equiv) in MeCN (1520 mL) were added Boc2O (117 g, 539 mmol, 124 mL, 1.5 equiv) and DMAP (13.1 g, 108 mmol, 0.3 equiv) at 20 °C under N2. After addition, the mixture was heated and stirred at 45 °C for 2 h. TLC indicated that 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 (registered trademark); 220 g SepaFlash (registered trademark) Silica Flash Column, eluent with a gradient of 0 - 30% ethyl acetate / petroleum ether, 200 mL / min) to give tert-butyl ((trans)-2-cyanocyclopentyl)(tosyl)carbamate (130 g, 99.2% yield) as an off-white solid. 1 1H 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).

[0154] Preparation of tert-butyl ((trans)-2-cyanocyclopentyl)carbamate

[0155] [Chemistry]

[0156] Three reactions were carried out in parallel. To each solution of tert-butyl ((trans)-2-cyanocyclopentyl)-N-(p-toluenesulfonyl)carbamate (32 g, 87.8 mmol, 1 equiv) in MeOH (480 mL), Mg (14.9 g, 612 mmol, 7 equiv) was carefully added at 20 °C under N2 over 0.5 h. After the addition, the reaction mixture was stirred at 20 °C for an additional 0.5 h. TLC indicated completion of the reaction. The three reaction mixtures were combined, diluted with DCM (500 mL), and poured into 1 N aqueous HCl solution (500 mL). The mixture was adjusted to pH 5 at 0 °C with 2 N aqueous HCl solution and extracted with DCM (300 mL three times). The organic phase was then washed with saturated aqueous NaHCO3 solution (100 mL three times), the combined organic layers were washed with brine (100 mL twice), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 220 g SepaFlash (registered trademark) Silica Flash Column, eluent with 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 H NMR (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).

[0157] Preparation of (trans)-2-aminocyclopentanecarbonitrile hydrochloride

[0158]

Chemical Structure

[0159] A mixture of tert-butyl ((trans)-2-cyanocyclopentyl)carbamate (62 g, 294 mmol, 1 equiv) in EtOAc (900 mL) was added with HCl / EtOAc (4 M, 221 mL, 3 equiv) at 0 °C. The mixture was stirred at 20 °C for 1 h. A white solid formed after 30 min of reaction. TLC indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was concentrated under vacuum 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).

[0160] Preparation of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile

[0161]

Chemical Structure

[0162] To a mixture of 2,4-dichloro-5-methyl-pyrimidine (22.4 g, 136 mmol, 1 equiv) and (trans)-2-aminocyclopentanecarbonitrile hydrochloride (20 g, 136.4 mmol, 1 equiv) in DMA (200 mL) was added DIEA (105 mmol, 818 mL, 6 equiv) at 20 °C. The mixture was heated and stirred at 140 °C for 8 h. TLC indicated that the reaction was complete. The reaction mixture was poured into H2O (1 L) and then 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).

[0163] (trans)-2-((2-Chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile Preparation

[0164]

Chem.

[0165] Preparation of 7-Tosyl-7-azabicyclo[4.1.0]heptane

[0166]

Chem.

[0167] Two reactions were carried out in parallel. For each, to a mixture of cyclohexene (25 g, 304 mmol, 30.8 mL, 1 equiv) in MeCN (500 mL), sodium [chloro(p-tolylsulfonyl)amino] (86.6 g, 380 mmol, 1.25 equiv) and phenyltrimethylammonium tribromide (11.4 g, 30.4 mmol, 0.1 equiv) were added at 0 °C, then the mixture was heated and stirred at 25 °C for 16 h. TLC indicated that the reaction was complete. The two parallel reaction products were combined, the reaction mixture was quenched by the addition of water (200 mL) at 0 °C, and then extracted with DCM (200 mL three times). The combined organic layers were washed with brine (200 mL twice), 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 / 0 - 20 / 1) to give 7-tosyl-7-azabicyclo[4.1.0]heptane (66 g, 43.1% yield) as a colorless oil. 11H 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).

[0168] Preparation of N-((trans)-2-cyanocyclohexyl)-4-methylbenzenesulfonamide

[0169]

Chemical Structure

[0170] To a mixture of 7-(p-toluenesulfonyl)-7-azabicyclo[4,1,0]heptane (60 g, 238 mmol, 1 equiv) in THF (600 mL) was added TMSCN (35.5 g, 358 mmol, 1.5 equiv) and TBAF (1 M in THF, 47.7 mL, 0.2 equiv) at 25 °C, and then the mixture was stirred at 25 °C for 2 h. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of water (300 mL) at 0 °C and then extracted with DCM (300 mL three times). The combined organic layers were washed with brine (10 mL twice), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-((trans)-2-cyanocyclohexyl)-4-methylbenzenesulfonamide (70 g, crude) as a brown solid. 1 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).

[0171] Preparation of tert-butyl ((trans)-2-cyanocyclohexyl)-N-(p-toluenesulfonyl)carbamate

[0172]

Chemical formula

[0173] Two reactions were carried out in parallel. For each, to a mixture of N-((trans)-2-cyanocyclohexyl)-4-methyl-benzenesulfonamide (30 g, 107 mmol, 1 equiv) in MeCN (300 mL) were added Boc2O (35.2 g, 161 mmol, 1.5 equiv) and DMAP (3.95 g, 32.3 mmol, 0.3 equiv) at 20 °C, and then the mixture was stirred at 40 °C for 2 h. TLC indicated that the reaction was complete. The two parallel reaction products were combined, the reaction was quenched by the addition of water (300 mL) at 0 °C, and then extracted with DCM (300 mL three times). The combined organic layers were washed with brine (300 mL twice), 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 / 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).

[0174] Preparation of tert-butyl ((trans)-2-cyanocyclohexyl)carbamate

[0175] [Chemical formula]

[0176] Two reactions were carried out in parallel. For each, 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, and then the mixture was stirred at 20 °C under N2 for 0.5 h. TLC indicated that the reaction was complete. The two parallel reactions were combined, the mixture was diluted with DCM (500 mL) and poured into aqueous HCl (1 N, 500 mL). Then, the pH was adjusted to 5 at 0 °C with aqueous HCl (2 N), and the mixture was extracted with DCM (300 mL, 3 times). The organic phase was then washed with saturated aqueous NaHCO3. The combined organic layers were washed with brine (200 mL, 2 times), 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 / 0 to 2 / 1) to give tert-butyl (trans)-2-cyanocyclohexyl)carbamate (28 g, 90% yield) as a white solid. 1 H NMR (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).

[0177] (Preparation of (trans)-2-aminocyclohexanecarbonitrile hydrochloride)

[0178] [Chemical formula]

[0179] To a mixture of tert-butyl (trans)-2-cyanocyclohexyl)carbamate (38 g, 169 mmol, 1 equiv) in EtOAc (100 mL), HCl / EtOAc (4 M, 300 mL) was added at 20 °C, and then the mixture was stirred at 20 °C for 1 h. TLC indicated that 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).

[0180] (Preparation of (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile)

[0181] [Chemical formula]

[0182] Two reactions were carried out in parallel. For each, to a mixture of (trans)-2-aminocyclohexanecarbonitrile hydrochloride (13 g, 80.9 mmol, 1 equiv) in DMA (150 mL), 2,4-dichloro-5-methyl-pyrimidine (13.2 g, 80.9 mmol, 1 equiv) and DIPEA (62.7 g, 485 mmol, 6 equiv) were added at 20 °C, and then the mixture was stirred at 140 °C for 12 h. TLC indicated that the reaction was complete. The two parallel reaction products were combined, the reaction was quenched by the addition of water (100 mL) at 0 °C, and then extracted with DCM (100 mL three times). The combined organic layers were washed with brine (100 mL twice), 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 / 0 - 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 = 8.0 Hz, 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).

[0183] Preparation of (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0184]

Chemical formula

[0185] Preparation of 7-tosyl-3-oxa-7-azabicyclo[4,1,0]heptane

[0186]

Chemical formula

[0187] Two reactions were carried out in parallel. To a mixture of 3,6-dihydro-2H-pyran (100 g, 1.18 mol, 1 equiv) in MeCN (2 L), phenyltrimethylammonium tribromide (67 g, 179 mmol, 0.15 equiv) and chloroamine-T (406 g, 1.78 mol, 1.5 equiv) were added portionwise under N2. The mixture was then stirred at 25 °C for 12 h under a N2 atmosphere. TLC indicated that the reaction was complete. The combined reaction mixture was quenched by the addition of H2O (1 L) at 25 °C, extracted with MTBE (2 L three times), and the combined organic layers were washed with brine (1 L twice), 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.

[0188] Preparation of N-(trans)-(4-cyanotetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

[0189]

Chemical formula

[0190] Six reactions were carried out in parallel. To each solution of 7-tosyl-3-oxa-7-azabicyclo[4.1.0]heptane (100 g crude, 395 mmol, 1 equiv) in THF (1 L), TBAF (1 M in THF, 178 mL, 0.45 equiv) and TMSCN (137 g, 1.4 mol, 173 mL, 3.5 equiv) were added portionwise under N₂. The mixture was then stirred at 70 °C for 3 h under a N₂ atmosphere. TLC indicated that 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, three times). The combined organic layers were washed with brine (3 L, twice), 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 - 0 / 1) to afford the 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).

[0191] Preparation of tert-butyl-((trans)-(4-cyanotetrahydro-2H-pyran-3-yl)(tosyl)carbamate

[0192]

Chemical Structure

[0193] Four reactions were carried out in parallel. To each solution of N-(trans)-(4-cyanotetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide (80 g, 285 mmol, 1 equiv) in MeCN (600 mL), Boc2O (93 g, 428 mmol, 98 mL, 1.5 equiv) and DMAP (10.5 g, 86 mmol, 0.3 equiv) were added portionwise under N2. The mixture was stirred at 40 °C for 2 h. TLC indicated that the reaction was complete. The four reaction mixtures were combined, quenched by the addition of H2O (2 L) at 25 °C, concentrated under reduced pressure to remove MeCN, then extracted with EtOAc (2 L three times), and the combined organic layers were washed with brine (2 L twice), 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 / 0 to 3 / 1) to afford 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).

[0194] Preparation of tert-butyl-((trans)-4-cyanotetrahydro-2H-pyran-3-yl)carbamate

[0195]

Chemical formula

[0196] Six reactions were carried out in parallel. To each solution of tert-butyl ((trans)(4-cyanotetrahydro-2H-pyran-3-yl)(tosyl)carbamate (50 g, 131 mmol, 1 equiv) in MeOH (800 mL), Mg (26 g, 1.1 mol, 8.2 equiv) was carefully added portionwise at 25 °C. With the generation of heat (exotherm) and foaming, the resulting suspension was stirred at 25 °C for 1 h. TLC indicated that the reaction was complete. The six reaction mixtures were combined, poured into ice water (2.5 L), then adjusted to pH 5 with aqueous HCl (2 N) and extracted with EtOAc (1.5 L three times). The combined organic layers were washed with brine (3 L twice), 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) as a white solid. 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).

[0197] Preparation of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (hydrogen chloride)

[0198]

Chemical Structure

[0199] HCl / EtOAc (4 M, 1.7 L) was slowly added to tert-butyl ((trans)-4-cyanotetrahydro-2H-pyran-3-yl)carbamate (170 g, 751 mmol, 1 equiv) at 25 °C. After the addition, the reaction mixture was stirred at 25 °C for 1 h. A solid precipitated after 30 min of reaction. TLC indicated that 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).

[0200] Preparation of (trans)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0201]

Chemical Structure

[0202] To a solution of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (82 g, 504 mmol, 1 equiv, HCl) in DMA (1 L) was added DIPEA (391 g, 3.02 mol, 525 mL, 6 equiv) and 2,4-dichloro-5-methyl-pyrimidine (82.5 g, 504 mmol, 1 equiv), and then the mixture was stirred at 135 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was quenched at 20 °C by the addition of H2O (4 L), and then extracted with EtOAc (2 L three times). The combined organic layers were washed with brine (2 L twice), 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 h 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 1H 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). This material (20 g) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm×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 1H 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 (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) were obtained.

[0203] Preparation of (trans)-3-((2,5-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0204]

Chemical formula

[0205] A mixture of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (2 g, 15.8 mmol, 1 equiv., HCl salt), 2,4,5-trichloropyrimidine (2.91 g, 15.8 mmol, 1 equiv.), and DIEA (4.10 g, 31.7 mmol, 5.52 mL, 2 equiv.) in DMA (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 100 °C for 12 h under an N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (100 mL three times). The combined organic layers were washed with brine (80 mL twice), 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 with a 0 - 65% ethyl acetate / petroleum ether gradient, 80 mL / min) to give (trans)-3-((2,5-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (1.2 g, 27.7% yield) as a pale yellow oil. 1 1H 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).

[0206] Preparation of (trans)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0207]

Chemical Structure

[0208] To a solution of (trans)-3-aminotetrahydro-2H-pyran-4-carbonitrile (500 mg, 3.07 mmol, 1 equiv., HCl salt) in DMA (5 mL) was added DIEA (1.6 g, 12.3 mmol, 2 mL, 4 equiv.) and 2,4-dichloro-5-fluoro-pyrimidine (513 mg, 3.07 mmol, 1 equiv.) at 25 °C, and then the mixture was stirred at 100 °C for 12 h. TLC indicated that 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 three times), and the combined organic layers were washed with brine (10 mL twice), 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 with 0 - 25% ethyl acetate / petroleum ether gradient, 50 mL / min) to afford (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).

[0209] Preparation of (trans)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanecarbonitrile

[0210]

Chemical Structure

[0211] A mixture of (trans)-2-aminocyclohexanecarbonitrile (1 g, 6.22 mmol, 1 equiv., HCl salt) in DMA (10 mL) was added with DIEA (4.83 g, 37.3 mmol, 6.5 mL, 6 equiv.) and 2,4-dichloro-5-fluoro-pyrimidine (1.04 g, 6.22 mmol, 1 equiv.) at 25 °C, and then the mixture was stirred at 140 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of H2O (40 mL) at 25 °C and then extracted with EtOAc (20 mL three times). The combined organic layers were washed with brine (50 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was triturated with MTBE (10 mL) at 25 °C for 30 min to give (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).

[0212] Preparation of (trans)-2-((2,5-dichloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0213]

Chemical Structure

[0214] A mixture of (trans)-2-aminocyclohexanecarbonitrile (2.00 g, 12.4 mmol, 1 equiv., HCl salt), 2,4,5-trichloropyrimidine (2.28 g, 12.4 mmol, 1 equiv.), and DIEA (9.65 g, 74.7 mmol, 13.0 mL, 6 equiv.) in DMA (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 140 °C for 12 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL, three times). The combined organic layers were washed with brine (30 mL, twice), 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 with a gradient of 0 - 35% ethyl acetate / petroleum ether, 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).

[0215] Preparation of 3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0216]

Chemical Structure

[0217] To a solution of 2-aminotetrahydropyran-4-carbonitrile (2 g, 12.3 mmol, 1 equiv, HCl) in THF (20 mL) was added DIEA (4.77 g, 36.9 mmol, 6.4 mL, 3 equiv) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.20 g, 14.7 mmol, 1.2 equiv) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS indicated 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 preparative HPLC (column: Xtimate C18 10u 250mm*80mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20% - 55%, 30 min) to afford (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).

[0218] Preparation of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0219]

Chemical Structure

[0220] A solution of (trans)-2-aminocyclohexanecarbonitrile (2 g, 12.4 mmol, 1 equiv, HCl) in THF (20 mL) was added with DIEA (4.83 g, 37.3 mmol, 3 equiv) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.24 g, 14.9 mmol, 1.2 equiv) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Xtimate C18 10u 250mm*80mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35% - 75%, 35 min) to give (trans)-2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (900 mg, 23.7% yield) as a yellow solid. 1 H 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).

[0221] Preparation of (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0222]

Chemical Structure

[0223] A solution of (trans)-2-aminocyclopentanecarbonitrile (2 g, 13.6 mmol, 1 equiv., HCl) in THF (20 mL) was added with 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.96 g, 13.6 mmol, 1 equiv.) and DIEA (5.29 g, 40.9 mmol, 7.13 mL, 3 equiv.) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250*70mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30% - 60%, 20 min) to afford (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (1.37 g, 34.5% yield) as a white solid. 1 H NMR (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).

[0224] Synthesis Examples (for the compounds in Tables 1 and 2) 1. Preparation of (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0225]

Chemical Structure

[0226] 1.1 Preparation of methyl 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate

[0227] [Chem.]

[0228] A mixture of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (2.00 g, 8.45 mmol, 1 equiv), methyl 5-amino-2-bromo-benzoate (2.14 g, 9.29 mmol, 1.1 equiv) and TsOH·H2O (3.21 g, 16.9 mmol, 2 equiv) in dioxane (60 mL) was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under vacuum to give a residue. The residue was quenched with saturated aqueous Na2CO3 solution (50 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum 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 grey solid. 1 1H 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).

[0229] 1.2 Preparation of Methyl 5-((4-(((trans)-2-Cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate

[0230] [Chemical Structure]

[0231] A mixture of methyl 2-bromo-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzoate (500 mg, 1.16 mmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (656 mg, 2.90 mmol, 2.5 equiv), Pd(PPh3)2Cl2 (81 mg, 116 μmol, 0.1 equiv) and KOAc (285 mg, 2.90 mmol, 2.5 equiv) in dioxane (20 mL) was heated and stirred at 120 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was then concentrated under vacuum 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).

[0232] Preparation of 1.3 (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0233]

Chemical formula

[0234] 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 equiv) in THF (10 mL) and MeOH (2 mL) was added NaBH4 (204 mg, 5.40 mmol, 5 equiv) portionwise at 0 °C. After addition, the reaction mixture was warmed to 25 °C and stirred at 25 °C for 1 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was carefully quenched with aqueous HCl (1 N, 5 mL) and diluted with H2O (10 mL). The mixture was extracted with EtOAc (10 mL for 3 times). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was triturated with a mixed solvent of MeCN (5 mL) and H2O (2 mL) to afford (trans)-2-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (48.3 mg, 11.6% yield) as a white solid. 1 1H NMR (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).

[0235] 2. Preparation of (trans)-2-((2-((1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0236]

Chem.

[0237] 2.1 Preparation of Methyl 2-Bromo-5-[[4-[(trans)-(2-Cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate

[0238]

Chem.

[0239] To a mixture of (trans)-2-[(2-Chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (1.40 g, 5.91 mmol, 1 equiv) and methyl 5-amino-2-bromo-3-methyl-benzoate (1.59 g, 6.51 mmol, 1.1 equiv) in dioxane (15 mL), TsOH·H2O (2.25 g, 11.8 mmol, 2 equiv) was added all at once at 20 °C under N2. The mixture was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was filtered and the white filter cake was washed with EtOAc (10 mL) to give 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. 11H 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).

[0240] 2.2 Preparation of Methyl 5-[[4-[(2-Cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-benzoate

[0241] [Chemical formula]

[0242] To a mixture of methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (600 mg, 1.35 mmol, 1 equiv) 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 equiv) in dioxane (6 mL), KOAc (331 mg, 3.38 mmol, 2.5 equiv) and Pd(PPh3)2Cl2 (94 mg, 135 μmol, 0.1 equiv) were added at once at 20 °C under N2. The mixture was stirred at 120 °C for 1 h. TLC indicated that 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 to give 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.

[0243] 2.3 (trans)-2-((2-((1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile Preparation

[0244]

Chem.

[0245] To a mixture of 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, 1.89 mmol, 1 equiv) in THF (10 mL) and MeOH (1 mL), NaBH4 (178 mg, 4.71 mmol, 2.5 equiv) was added portionwise at 0 °C. After the addition, the reaction mixture was warmed to 20 °C and stirred at 20 °C for 1 h. TLC indicated the completion of the reaction. The reaction mixture was adjusted to pH = 6 with aqueous HCl (2N). The mixture was extracted with EtOAc (3 times with 10 mL). The combined organic layers were washed with brine (2 times with 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; 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. 11H NMR (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, Observed m / z 364.2 [M+H] + . HPLC: 96.69% (220 nm), 96.77% (254 nm).

[0246] 3. Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0247]

Chemical formula

[0248] 3.1 Preparation of methyl 2-amino-3-chloro-5-nitro-benzoate

[0249]

Chemical formula

[0250] Three reactions were carried out in parallel. For each, NCS (8.85 g, 66.2 mmol, 1.3 eq) was added to a solution of methyl 2-amino-5-nitro-benzoate (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 that 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, whereupon a yellow precipitate formed and was collected. The yellow precipitate was washed with H2O (80 mL twice) and petroleum ether (50 mL twice) to afford methyl 2-amino-3-chloro-5-nitro-benzoate (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).

[0251] 3.2 Preparation of methyl 2-bromo-3-chloro-5-nitro-benzoate

[0252]

Chemical formula

[0253] Three reactions were carried out in parallel. For each, 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 that the reaction was complete. The three parallel reaction products were combined, poured into H2O (350 mL), and extracted with EtOAc (100 mL three times). The combined organic layers were washed with saturated aqueous Na2SO3 (100 mL three times). The combined organic layers were then washed with brine (100 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-bromo-3-chloro-5-nitro-benzoate (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).

[0254] 3.3 Preparation of methyl 5-amino-2-bromo-3-chloro-benzoate

[0255]

Chemical formula

[0256] Three reactions were carried out in parallel. For each, to a mixture of methyl 2-bromo-3-chloro-5-nitro-benzoate (11 g, 37.3 mmol, 1 equiv) in EtOH (120 mL) and H2O (40 mL), Fe (6.26 g, 112 mmol, 3 equiv) and NH4Cl (3.00 g, 56.0 mmol, 1.5 equiv) were added at once at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 h. TLC indicated that the reaction was complete. The three parallel reaction products 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 three times). The combined organic layers were washed with brine (250 mL three times), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-amino-2-bromo-3-chloro-benzoate (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).

[0257] Preparation of (5-amino-2-bromo-3-chloro-phenyl)methanol

[0258]

Chemical formula

[0259] To a solution of methyl 5-amino-2-bromo-3-chloro-benzoate (10 g, 37.8 mmol, 1 equiv) in THF (150 mL), DIBAL-H (1 M, 113 mL, 3 equiv) was added dropwise at -60 °C. The mixture was stirred at -60 °C for 2 h. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous sodium carbonate solution (500 mL) at 0 °C, and then extracted with EtOAc (70 mL, 3 times). The combined organic layers were washed with brine (200 mL, 2 times), 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 afford (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 = 5.6 Hz, 1H), 4.37 (d, J = 5.6 Hz, 2H).

[0260] Preparation of 3.5 (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0261]

Chemical Structure

[0262] Five reactions were carried out in parallel. For each, TsOH·H2O (603 mg, 3.17 mmol, 1.5 eq) was added to a solution of (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) in dioxane (15 mL) at 25 °C. The mixture was heated to 90 °C and stirred at 90 °C for 5 h. TLC indicated that the reaction was complete. The five parallel reaction products were combined, the reaction was quenched by the addition of saturated aqueous NaHCO3 (80 mL) at 0 °C, and extracted with EtOAc (30 mL three times). The combined organic layers were washed with brine (80 mL twice), 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 to give (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 H NMR (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).

[0263] 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

[0264] [Chem.]

[0265] 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 equiv) and 2,6-dimethylpyridine (2.08 g, 19.2 mmol, 2.3 mL, 3 equiv) in THF (60 mL) was added TBSOTf (2.54 g, 9.62 mmol, 2.2 mL, 1.5 equiv) at 0 °C. The mixture was stirred at 25 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NH4Cl solution (80 mL) and then extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 40 mL), 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 afford (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 1H 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).

[0266] 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

[0267]

Chemical Structure

[0268] Six reactions were carried out in parallel. For each, a mixture of (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 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (492 mg, 2.18 mmol, 3 equiv), KOAc (214 mg, 2.18 mmol, 3 equiv) and Pd(PPh3)2Cl2 (51 mg, 72.6 μmol, 0.1 equiv) in dioxane (6 mL) was degassed and purged with N2 three times. The mixture was then heated to 120 °C and stirred at 120 °C for 40 min under a N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was observed. The six parallel reaction products were cooled to room temperature, combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50 mm*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]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (1.2 g, mixture) as a white solid. 11H 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).

[0269] Preparation of 3.8 (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0270]

Chem.

[0271] 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]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (mixture, 1.2 g, 1.16 mmol, 1 equiv) in THF (10 mL) was added with HCl (6 M, 775 μL, 4 equiv) at 0 °C. The mixture was heated to 40 °C and stirred at 40 °C for 1 h. LCMS indicated that the reaction was complete and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with MeCN (15 mL) at 25 °C for 10 min to obtain the racemic product (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-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]oxaborol-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) to give (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (stereoisomer 1) (335.9 mg, 97.10% purity, 98.96% ee, the first peak, Rt = 3.898 min) as a white solid. 1 H NMR (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 Calculated mass of C 18 H 19 BCIN5O2 is 383.13, measured m / z is 384.1 [M + H] + . HPLC: 97.10% (220 nm), 98.17% (254 nm); and 370 mg of stereoisomer 2 was obtained, which contained isopropanol residue. This was further purified by preparative HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (HCl) - ACN]; B%: 5% - 35%, 8 minutes) to remove the isopropanol residue, and (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile (stereoisomer 2) (332.9 mg, 97.31% purity, 97.80% ee, the second peak, Rt = 4.470 minutes) was obtained as a white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 10.40 (br s, 1H), 9.05 (br s, 1H), 8.10 (br s, 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 19Calculated mass of BClN5O2: 383.13, measured m / z: 384.1 [M+H] + . HPLC: 97.31% (220 nm), 97.90% (254 nm).

[0272] 4. Preparation of (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0273]

Chem.

[0274] 4.1 Preparation of methyl 2-amino-3-methoxy-benzoate

[0275]

Chem.

[0276] A solution of 2-amino-3-methoxy-benzoic acid (40.0 g, 239 mmol, 1 eq) in MeOH (500 mL) was added dropwise with a solution of H2SO4 (1.32 mol, 70 mL, 5.5 eq) at 0 °C over 5 minutes under N2 at 0 °C. After the addition, the reaction mixture was heated and stirred at 95 °C for 16 hours. TLC indicated that the reaction was complete. The reaction mixture was adjusted to pH 7 at 0 °C with saturated aqueous Na2CO3 solution (1 L) and extracted with ethyl acetate (3 × 500 mL). The combined organic phases were washed with brine (2 × 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to give methyl 2-amino-3-methoxy-benzoate (43 g, 99% yield) as a white solid. 1 H NMR (CDCl 3,(400 MHz) δ 7.40 (d, J = 8.4 Hz, 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).

[0277] Preparation of Methyl 2-Amino-5-iodo-3-methoxy-benzoate

[0278]

Chemical Structure

[0279] To a mixture of methyl 2-amino-3-methoxy-benzoate (43.0 g, 237 mmol, 1 equivalent) in EtOH (500 mL), Ag2SO4 (77.6 g, 249 mmol, 1.05 equivalents) and I2 (63.2 g, 249 mmol, 1.05 equivalents) were added at once at 20 °C. The mixture was stirred at 20 °C for 5 h. TLC indicated that 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, 3 times). The combined organic phases were washed with saturated aqueous Na2SO3 solution (400 mL, 2 times) and brine (150 mL, 2 times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give methyl 2-amino-5-iodo-3-methoxy-benzoate (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).

[0280] Preparation of Methyl 2-Bromo-5-iodo-3-methoxy-benzoate

[0281]

Chemical Structure

[0282] To a solution of methyl 2-amino-5-iodo-3-methoxy-benzoate (45.0 g, 146 mmol, 1 equiv) in MeCN (600 mL) was added CuBr2 (66.4 g, 297 mmol, 2.03 equiv) at 25 °C. The mixture was stirred at 25 °C for 20 min, then tert-butyl nitrite (264 mmol, 31 mL, 1.8 equiv) was added dropwise at 10 °C over 10 min. The reaction mixture was stirred at 10 °C for an additional 30 min, the mixture was heated, and stirred at 60 °C for 12 h. The residue was poured into ice water (1 L) and saturated aqueous Na2CO3 solution (600 mL). The aqueous phase was extracted with ethyl acetate (500 mL three times). The combined organic phases were washed with saturated aqueous Na2SO3 solution (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to give methyl 2-bromo-5-iodo-3-methoxy-benzoate (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).

[0283] 4.4 Preparation of methyl 2,5-dibromo-3-hydroxy-benzoate

[0284]

Chemical formula

[0285] To a solution of methyl 2-bromo-5-iodo-3-methoxy-benzoate (33.0 g, 88.9 mmol, 1 equiv) in DCM (400 mL), BBr3 (267 mmol, 25.7 mL, 3 equiv) was slowly added at 0 °C under N2. After the addition, the reaction mixture was warmed to 20 °C and stirred for 1 h. TLC indicated the completion of the reaction. To the reaction mixture, MeOH (2.67 mol, 108 mL, 30 equiv) was slowly added, 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 three times). The combined organic phases were washed with brine (400 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to afford methyl 2,5-dibromo-3-hydroxy-benzoate (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).

[0286] 4.5 Preparation of methyl 2,5-dibromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate

[0287]

Chemical Structure

[0288] To a mixture of methyl 2,5-dibromo-3-hydroxy-benzoate (8.0 g, 25.8 mmol, 1 equiv) and 2-bromoethoxy-tert-butyl-dimethyl-silane (9.26 g, 38.7 mmol, 1.5 equiv) in DMF (80 mL), K2CO3 (7.13 g, 51.6 mmol, 2 equiv) and NaI (774 mg, 5.16 mmol, 0.2 equiv) were added at once at 20 °C under N2. The mixture was heated to 60 °C and stirred for 16 h. TLC indicated that 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, 3 times). The combined organic phases were washed with brine (50 mL, 2 times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 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).

[0289] 4.6 Preparation of methyl 2-bromo-5-(tert-butoxycarbonylamino)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate

[0290]

Chemical formula

[0291] A mixture of methyl 2,5-dibromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate (5.0 g, 10.6 mmol, 1 equiv) and NH2Boc (1.38 g, 11.7 mmol, 1.1 equiv) in dioxane (80 mL) was added with Pd(OAc)2 (239 mg, 1.07 mmol, 0.1 equiv), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (617 mg, 1.07 mmol, 0.1 equiv) and Cs2CO3 (6.96 g, 21.36 mmol, 2 equiv) at 20 °C under N2 all at once. The mixture was heated to 100 °C and stirred for 16 h. TLC indicated that the reaction was complete. The reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to give 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 = 5.2 Hz, 2H), 3.92 (s, 3H), 1.52 (s, 9H), 0.91 (s, 9H), 0.12 (s, 6H).

[0292] Preparation of tert-butyl N-[4-bromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-(hydroxymethyl)phenyl]carbamate

[0293]

Chemical Structure

[0294] A mixture of methyl 2-bromo-5-(tert-butoxycarbonylamino)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]benzoate (4.0 g, 7.93 mmol, 1 equiv) in THF (40 mL) was added dropwise with MeOH (49.4 mmol, 2.00 mL, 6.23 equiv) and LiBH4 (2 M in THF, 15 mL, 3.78 equiv) at 0 °C under N2. After the addition, the reaction mixture was warmed to 20 °C and stirred for 4 h. TLC indicated the completion of the reaction. The mixture was poured into ice water (100 mL), and the aqueous phase was adjusted to pH 7 - 8 with aqueous HCl solution (2 N). The aqueous phase was extracted with ethyl acetate (50 mL, 3 times). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 3 / 1) to afford 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).

[0295] 4.8 Preparation of tert-butyl N-[7-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-1-hydroxy-3H-2,1-benzoxaborol-5-yl]carbamate

[0296]

Chemical Structure

[0297] A mixture of tert-butyl N-[4-bromo-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-(hydroxymethyl)phenyl]carbamate (4.0 g, 8.39 mmol, 1 equiv) in dioxane (120 mL) was added KOAc (2.47 g, 25.2 mmol, 3 equiv), Pd(dppf)Cl2 (614 mg, 840 μmol, 0.1 equiv) 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 equiv) at 25 °C under N2 all at once. Then the mixture was heated to 100 °C and stirred for 16 h. TLC indicated that the reaction was complete. The reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 - 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).

[0298] 4.9 Preparation of tert-butyl (7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-yl)carbamate

[0299]

Chemical Structure

[0300] 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 μmol, 1 equiv) in THF (10 mL) was added dropwise with aqueous HCl solution (3 M, 1.18 mL, 6 equiv) at 0 °C. After the addition, the reaction mixture was heated and stirred at 40 °C for 30 min. TLC indicated the completion of the reaction. The mixture was poured into ice water (6 mL). The aqueous phase was extracted with ethyl acetate (5 mL, 3 times). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1) and further purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*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-borabenzo[cd]azulen-4-yl)carbamate (43.2 mg, 99.58% purity) as an off-white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 9.57 (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 1H 18 alculated mass of C11H18BNO5 291.13, found m / z 290.2 [M-H] - . HPLC: 99.58% (220 nm), 99.68% (254 nm).

[0301] 4.10 Preparation of 7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-amine hydrochloride

[0302]

Chem.

[0303] To a mixture of tert-butyl (7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-yl)carbamate (1.0 g, 3.44 mmol, 1 equiv) in EtOAc (10 mL), HCl / EtOAc (4 M, 40 mL, 46.58 equiv) was added dropwise at 20 °C. After the addition, the reaction mixture was heated and stirred at 40 °C for 2 h. Then the mixture was cooled to 10 °C and stirred, and a solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate (10 mL, twice), and dried under vacuum to obtain 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-borabenzo[cd]azulen-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 Calculated mass for BClNO3 227.05, found m / z 192.2 [M+H] + . HPLC: 96.86% (220 nm), 98.77% (254 nm).

[0304] Preparation of 4.11 (trans)-2-((2-((7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile

[0305]

Chemical Structure

[0306] A mixture of 7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-amine hydrochloride (50 mg, 219 μmol, 1 equiv., HCl salt) and (trans)-2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (57.2 mg, 241 μmol, 1.1 equiv.) in 2-methylbutan-2-ol (2 mL) was added with BrettPhos Pd G3 (19.9 mg, 21.9 μmol, 0.1 equiv.), Brettphos (11.8 mg, 21.9 μmol, 0.1 equiv.) and Cs2CO3 (214 mg, 659 μmol, 3 equiv.) at 20 °C under N2 all at once. The mixture was heated to 100 °C and stirred for 16 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; 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-borabenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (63 mg, 99.18% purity) as a white solid. 1 H NMR (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 alculated mass for CBN5O3 391.18, found m / z 392.0 [M+H] +. HPLC: 99.18% (220 nm), 98.79% (254 nm).

[0307] 5. Preparation of (trans)-2-[[5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclopentane-1-carbonitrile

[0308]

Chem.

[0309] 5.1 Preparation of methyl 2-bromo-5-[[5-chloro-4-[(trans)(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]benzoate

[0310]

Chem.

[0311] A mixture of (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclopentane-1-carbonitrile (2.20 g, 8.56 mmol, 1 eq), methyl 5-amino-2-bromo-benzoate (2.17 g, 9.41 mmol, 1.1 eq) and TsOH·H2O (3.26 g, 17.1 mmol, 2 eq) in dioxane (60 mL) was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under vacuum to give a residue. The residue was triturated with a mixed solvent of EtOAc (50 mL) and saturated aqueous Na2CO3 (50 mL), and the resulting suspension was filtered. The filter cake was dried under vacuum 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.

[0312] Preparation 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

[0313]

Chem.

[0314] A mixture of methyl 2-bromo-5-[[5-chloro-4-[(2-cyanocyclopentyl)amino]pyrimidin-2-yl]amino]benzoate (2.00 g, 4.44 mmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (2.51 g, 11.0 mmol, 2.5 equiv), Pd(PPh3)2Cl2 (311 mg, 443 μmol, 0.1 equiv) and KOAc (1.09 g, 11.0 mmol, 2.5 equiv) in dioxane (60 mL) was heated and stirred at 120 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under vacuum 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).

[0315] Preparation of 5.3 (trans)-2-[[5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0316] [Chemical formula]

[0317] 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 equiv) in THF (100 mL) and MeOH (5 mL) was added NaBH4 (1.96 g, 51.6 mmol, 5 equiv) portionwise at 0 °C. After the addition, the reaction mixture was warmed to 25 °C and stirred at 25 °C for 1 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was carefully quenched with aqueous HCl (1 N, 5 mL) and diluted with H2O (20 mL). The mixture was extracted with EtOAc (50 mL twice). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 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).

[0318] 6. Preparation of (trans)2-[[2-[[1-Hydroxy-7-(trifluoromethyl)-3H-2,1-benzoxaborol-5-yl]amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0319]

Chemical Structure

[0320] 6.1 Preparation of Methyl 2-Bromo-5-[[4-[(2-Cyanocyclopentyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzoate

[0321]

Chemical Structure

[0322] To a mixture of 2-[(2-Chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (2.00 g, 8.45 mmol, 1 equiv) and methyl 5-amino-2-bromo-3-(trifluoromethyl)benzoate (2.77 g, 9.29 mmol, 1.1 equiv) in dioxane (20 mL), TsOH·H2O (3.21 g, 16.9 mmol, 2 equiv) was added at once at 20 °C. The mixture was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was adjusted to pH = 9 with saturated aqueous Na2CO3. The mixture was extracted with EtOAc (3 times with 40 mL). The combined organic layers were washed with brine (2 times with 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 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. 11H 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).

[0323] 6.2 2 - [[2 - [4 - Bromo - 3 - (hydroxymethyl) - 5 - (trifluoromethyl)anilino] - 5 - methyl - pyrimidin - 4 - yl]amino]cyclopentanecarbonitrile Preparation

[0324] [Chemical formula]

[0325] 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 equiv) in THF (15 mL), LiBH4 (4 M in THF, 1.63 mL, 5 equiv) was added dropwise at 0 °C. The mixture was heated and stirred at 50 °C for 8 h. TLC indicated that the reaction was complete. The reaction was quenched with ice water (30 mL) and adjusted to pH = 2 with aqueous HCl (2 N). A white solid precipitated and was filtered. The filter cake was washed with H2O (10 mL) to give 2 - [[2 - [4 - bromo - 3 - (hydroxymethyl) - 5 - (trifluoromethyl)anilino] - 5 - methyl - pyrimidin - 4 - yl]amino]cyclopentanecarbonitrile (0.45 g, crude). 11H NMR (CDCl3, 400 MHz) δ 8.54 (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).

[0326] Preparation of 6.3 (trans)-2-[[2-[[1-hydroxy-7-(trifluoromethyl)-3H-2,1-benzoxaborol-5-yl]amino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0327]

Chemical Structure

[0328] Five reactions were carried out in parallel. For each, to a mixture of 2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclopentanecarbonitrile (60 mg, 127 μmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (72 mg, 318 μmol, 2.5 equiv) in dioxane (2 mL), KOAc (31 mg, 318 μmol, 2.5 equiv) and Pd(PPh3)2Cl2 (8.95 mg, 12.7 μmol, 0.1 equiv) were added at once at 20 °C under N2. The mixture was heated and stirred at 120 °C for 10 h. LCMS indicated that the reaction was complete and the desired MS was observed. The five parallel reaction products were combined, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 20% - 30%, 8 min) to give 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 BO4 calculated mass, 417.16, m / z found 418.2 [M+H] + . HPLC: 99.09% (220 nm), 99.29 (254 nm).

[0329] 7. Preparation of (trans)-2-((2-((2-Hydroxy-2H-benzo[e][1,2]oxaborinin-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclopentane-1-carbonitrile

[0330]

Chem.

[0331] To a mixture of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclopentanecarbonitrile (100 mg, 422 μmol, 1 equiv) and 2-hydroxy-1,2-benzooxaborinin-6-amine (83.4 mg, 422 μmol, 1 equiv, HCl) in dioxane (5 mL) was added TsOH·H2O (121 mg, 634 μmol, 1.5 equiv) at 20 °C, and the mixture was stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*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]oxaborinin-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 Calculated mass of BN5O2: 361.17, measured m / z: 362.2 [M + H] + . HPLC: 95.13% (220 nm), 97.25% (254 nm).

[0332] 8. Preparation of (trans)2 - [[2 - [(1 - hydroxy - 3H - 2,1 - benzoxaborol - 5 - yl)amino] - 5 - methyl - pyrimidin - 4 - yl]amino]cyclohexane - 1 - carbonitrile

[0333]

Chemical Structure

[0334] 8.1 Preparation of methyl 2 - bromo - 5 - [[4 - [(trans) - (2 - cyanocyclohexyl)amino] - 5 - methyl - pyrimidin - 2 - yl]amino]benzoate

[0335]

Chemical Structure

[0336] To a mixture of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (1.30 g, 5.18 mmol, 1 equiv) and methyl 5-amino-2-bromo-benzoate (1.43 g, 6.22 mmol, 1.2 equiv) in dioxane (20 mL) was added TsOH·H2O (1.97 g, 10.3 mmol, 2 equiv) at once at 20 °C. The mixture was heated and stirred at 80 °C for 12 h. TLC indicated that 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 to give 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).

[0337] 8.2 Preparation 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

[0338]

Chemical Structure

[0339] A mixture of methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]benzoate (800 mg, 1.80 mmol, 1 equiv) 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 equiv) in dioxane (10 mL) was added KOAc (442 mg, 4.50 mmol, 2.5 equiv) and Pd(PPh3)2Cl2 (253 mg, 360 μmol, 0.2 equiv) at once at 20 °C under N2. The mixture was heated and stirred at 120 °C for 1 h. TLC indicated that 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.

[0340] 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

[0341]

Chemical Structure

[0342] 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 equiv) in THF (10 mL) and MeOH (1 mL) was added NaBH4 (159 mg, 4.19 mmol, 2.5 equiv) portionwise at 0 °C. After the addition, the reaction mixture was warmed to 20 °C and stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH = 6 with aqueous HCl solution (2 N). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 18% - 43%, 7 min) to give (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) δ 12.37 (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 Calculated mass for C18H22BClN5O2, 363.19, found m / z 364.2 [M+H] +. HPLC: 96.51% (220 nm), 99.68 (254 nm).

[0343] 9. Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0344]

Chem.

[0345] 9.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid

[0346]

Chem.

[0347] To a mixture of 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 equiv) in H2SO4 (70 mL, 98% purity) was added a solution of KNO3 (4.70 g, 46.5 mmol, 1 equiv) in H2SO4 (30 mL, 98% purity) dropwise at 0 °C over 0.5 h, and the mixture was stirred at 0 °C for 2.5 h. TLC indicated that the reaction was complete. The reaction mixture was poured into ice H2O (200 mL), and the resulting solid was filtered. The filter cake was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (150 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 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 = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 2.63 (s, 3H).

[0348] 9.2 Preparation of methyl 2-bromo-3-methyl-5-nitro-benzoate

[0349]

Chem.

[0350] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.00 g, 30.8 mmol, 1 equiv) in MeOH (80 mL), SOCl2 (61.5 mmol, 4.46 mL, 2 equiv) was added at 0 °C. After the addition, the reaction mixture was heated and stirred at 80 °C for 12 h. TLC indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (80 mL), adjusted to pH 7 with saturated aqueous NaHCO3, and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (50 mL, 3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 80 g SepaFlash (registered trademark) Silica Flash Column, eluent with a gradient of 0 - 15% ethyl acetate / petroleum ether, 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) δ 8.35 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H) 2.59 (s, 3H).

[0351] 9.3 Preparation of Methyl 5-Amino-2-bromo-3-methyl-benzoate

[0352]

Chem.

[0353] To a mixture of methyl 2-bromo-3-methyl-5-nitro-benzoate (6 g, 21.9 mmol, 1 equiv) in EtOH (80 mL) and H2O (20 mL), NH4Cl (4.68 g, 87.6 mmol, 4 equiv) and Fe (4.89 g, 87.6 mmol, 4 equiv) were added at 25 °C under N2. The mixture was stirred at 80 °C for 1 h. TLC indicated that the reaction was complete. The reaction mixture 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 methyl 5-amino-2-bromo-3-methyl-benzoate as a yellow oil (5 g, 93% yield). 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).

[0354] 9.4 Preparation of methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate

[0355]

Chemical Structure

[0356] To a mixture of (trans)-2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (2.00 g, 7.98 mmol, 1 equiv) and methyl 5-amino-2-bromo-3-methyl-benzoate (2.14 g, 8.77 mmol, 1.1 equiv) in dioxane (40 mL), 4-methylbenzenesulfonic acid hydrate (3.03 g, 16.0 mmol, 2 equiv) was added at once at 20 °C under N2. The mixture was heated to 80 °C and stirred for 16 h. TLC indicated that the reaction was complete. The mixture was poured into ice water (80 mL), and the aqueous phase was adjusted to pH 5 - 6 with saturated aqueous Na2CO3. The resulting mixture was diluted with EtOAc (30 mL three times), and then the suspension was filtered. The filter cake was washed with water (30 mL twice) and dried under vacuum to give a residue. The residue was purified by trituration with MTBE (30 mL) at 20 °C for 0.5 h to give 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.

[0357] 9.5 Preparation 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

[0358]

Chemical formula

[0359] Three reactions were carried out in parallel. For each, to a mixture of methyl 2-bromo-5-[[4-[((trans)-2-cyanocyclohexyl)amino]-5-methyl-pyrimidin-2-yl]amino]-3-methyl-benzoate (200 mg, 436 μmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (246 mg, 1.09 mmol, 2.5 equiv) in dioxane (6 mL), AcOK (107 mg, 1.09 mmol, 2.5 equiv) and Pd(PPh3)2Cl2 (15.3 mg, 21.8 μmol, 0.05 equiv) were added at once at 20 °C under N2. The mixture was heated and stirred at 120 °C for 1 h. TLC indicated that the reaction was complete. The three parallel reaction products were combined, the reaction mixture was filtered and concentrated under vacuum to give a residue. The crude product was triturated with MTBE (20 mL) at 20 °C for 0.5 h to give 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 grey solid. 1 H NMR (CDCl3, 400 MHz) δ 7.97 (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).

[0360] Preparation of (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0361]

Chem.

[0362] To a solution of methyl 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 μmol, 1 equiv) and MeOH (0.5 mL) in THF (6 mL) was added NaBH4 (57.7 mg, 1.53 mmol, 5 equiv) at 0 °C. After addition, the reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction was quenched with H2O (10 mL) and adjusted to pH 5 with aqueous HCl (2N). EtOAc (10 mL) was added to the reaction mixture, and then a precipitate formed. The precipitate was filtered to give (trans)-2-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (28 mg, 95.47% purity). 1 1H NMR (DMSO-d6, 400 MHz) 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 1H 24 alculated mass of C19H25BN5O2 377.20, found m / z 378.2 [M+H] +. HPLC: 95.47% (220 nm), 94.36% (254 nm).

[0363] 10. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0364]

Chem.

[0365] 10.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0366]

Chem.

[0367] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (3 g, 12.6 mmol, 1 equiv) in i-PrOH (30 mL) was added TFA (2.89 g, 25.37 mmol, 1.90 mL, 2 equiv) and 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (3.50 g, 13.95 mmol, 1.1 equiv) at 20 °C. The mixture was heated to 90 °C and stirred at 90 °C for 16 h. A solid precipitated after 3 h of reaction time. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain the crude product. The crude product was triturated with aqueous NaHCO3 solution (40 mL) at 20 °C for 30 min and then filtered. The filtered 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. 11H 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).

[0368] 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

[0369]

Chemical formula

[0370] 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 equiv) and 2,6-dimethylpyridine (5.76 g, 53.2 mmol, 4 equiv) in THF (60 mL) was added dropwise with TBSOTf (7.04 g, 26.6 mmol, 6.12 mL, 2 equiv) at 0 °C. The mixture was stirred at 25 °C for 3 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL) at 0 °C and extracted with ethyl acetate (50 mL twice). 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).

[0371] 10.3 Preparation 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

[0372]

Chem.

[0373] Five reactions were carried out in parallel. For each, 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (800 mg, 3.54 mmol, 5 eq), KOAC (208 mg, 2.12 mmol, 3 eq) and Pd(PPh3)2Cl2 (50 mg, 70.8 μmol, 0.1 eq) were added to a solution of (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 μmol, 1 eq) in dioxane (12 mL) at 20 °C. The mixture was then stirred at 120 °C for 40 min under a N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, and the five parallel reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm #10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45% - 75%, 20 min) to give 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. 11H 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).

[0374] Preparation of 10.4 (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0375]

Chemical Structure

[0376] 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 equiv) in THF (20 mL) was added with HCl (6 M, 2.26 mL, 4 equiv) at 20 °C. The mixture was stirred at 40 °C for 1 h. LCMS indicated that the reaction was complete and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MeCN (15 mL) at 25 °C for 10 min to afford the 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) to give (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, the first peak, Rt = 1.280 min) as a white solid, stereoisomer 1. 1 H NMR (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): C19H 21 Calculated mass for BClN5O2 397.15, m / z found 398.0 [M+H] +. HPLC: 95.79% (220 nm), 95.88% (254 nm). And as a white solid, (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. 1 1H NMR (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), 6.78 (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 Calculated mass for BClN5O2 397.15, measured m / z 398.1 [M+H] + . HPLC: 96.14% (220 nm), 99.69% (254 nm) was obtained.

[0377] 11. Preparation of (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0378]

Chemical Structure

[0379] Preparation of 11.1 (trans)-2-[[2-[4-bromo-3-(hydroxymethyl)-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0380]

Chem.

[0381] To a mixture of [5-amino-2-bromo-3-(trifluoromethyl)phenyl]methanol (3.6 g, 13.3 mmol, 1 equiv) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (3.34 g, 13.3 mmol, 1 equiv) in i-PrOH (40 mL) was added TFA (2.28 g, 20.0 mmol, 1.5 mL, 1.5 equiv) at 25 °C all at once. The mixture was stirred at 90 °C for 5 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was cooled to room temperature and a large amount of precipitate formed. The mixture was filtered and the filter cake was triturated with saturated aqueous NaHCO3 to give 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).

[0382] Preparation of 11.2 (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(trifluoromethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0383]

Chemical formula

[0384] 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 equiv) and 2,6-dimethylpyridine (2.34 g, 21.7 mmol, 2.6 mL, 3 equiv) in THF (100 mL) was added dropwise with TBSOTf (2.87 g, 10.8 mmol, 2.5 mL, 1.5 equiv) at 0 °C. After the addition, the reaction mixture was warmed to 25 °C and stirred for 3 h. TLC indicated the completion of the reaction. The reaction mixture was quenched with saturated aqueous NH4Cl solution (80 mL) at 0 °C and then extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL, 2 times), 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).

[0385] Preparation of 11.3 (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

[0386]

Chemical formula

[0387] Four reactions were carried out in parallel. For each, a mixture of (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 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.8 g, 7.97 mmol, 4.8 equiv), Pd(PPh3)2Cl2 (117 mg, 167 μmol, 0.1 equiv), and KOAc (492 mg, 5.01 mmol, 3 equiv) in dioxane (20 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 40 min under a N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was observed. The four parallel reaction products were combined, filtered, and the filter cake was washed with EtOAc (90 mL twice). The filtrate was concentrated under reduced pressure to give a residue (6 g, crude). The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent with a 0 - 100% ethyl acetate / petroleum ether gradient, 75 mL / min) to give a crude product, which was further purified by preparative HPLC (column: C18 (250*50 mm*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).

[0388] Preparation of 11.4 (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0389]

Chemical formula

[0390] 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 equiv) in THF (20 mL) was added dropwise with HCl (6 M, 2.64 mL, 5 equiv) at 0 °C. The mixture was stirred at 40 °C for 0.5 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was cooled to room temperature and a large amount of 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]oxaborol-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 material was separated by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm * 50 mm, 10 μm); mobile phase: [0.1% NH₃H₂O in MeOH]; B%: 40% - 40%, 5 min) to give an off - white solid, (trans)-2 - ((2 - ((1 - hydroxy - 7 - (trifluoromethyl)-1,3 - dihydrobenzo[c][1,2]oxaborol - 5 - yl)amino)-5 - methylpyrimidin - 4 - yl)amino)cyclohexane - 1 - carbonitrile (557 mg, 99.90% ee, the first peak, Rt = 1.246 min), stereoisomer 1. 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 Calculated mass for CBF₃N₅O₂ is 431.17, measured m / z 432.3 [M + H] +. HPLC: 99.25% (220 nm), 99.33% (254 nm) and (trans)-2-((2-((1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile as an off-white solid (551.7 mg, 99.34% ee, second peak, Rt = 1.443 min), stereoisomer 2. 1 H NMR (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 Calculated mass for CBF3N5O2 431.17, found m / z 432.3 [M+H] + . HPLC: 97.52% (220 nm), 98.26% (254 nm) was obtained.

[0391]

[0392]

Chemical Structure

[0393] 12.1 Preparation of methyl 2-amino-3-bromo-5-nitrobenzoate

[0394]

Chem.

[0395] To a solution of methyl 2-amino-5-nitro-benzoate (60 g, 305 mmol, 1 equiv) in DMF (700 mL), NBS (70.7 g, 397 mmol, 1.3 equiv) was added at 35 °C. The mixture was stirred at 35 °C for 12 h. A solid precipitated after 3 h of reaction. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain the crude product (filter cake). The crude product was triturated with MTBE (50 mL) at 25 °C for 1 h to give methyl 2-amino-3-bromo-5-nitro-benzoate (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).

[0396] 12.2 Preparation of methyl 2-amino-3-cyano-5-nitrobenzoate

[0397]

Chem.

[0398] A mixture of methyl 2-amino-3-bromo-5-nitro-benzoate (70 g, 254 mmol, 1 equiv), Zn (3.50 g, 53.5 mmol, 0.21 equiv), Zn(CN)₂ (59.7 g, 508 mmol, 2 equiv), Pd₂(dba)₃ (6.99 g, 7.63 mmol, 0.03 equiv) and 1,1-bis(diphenylphosphino)ferrocene (DPPF, 8.47 g, 15.2 mmol, 0.06 equiv) in DMA (600 mL) was degassed and purged with N₂ three times, and then the mixture was stirred at 110 °C for 1 h under a N₂ atmosphere. TLC indicated that the reaction was complete. The reaction mixture was diluted with H₂O (3 L) and extracted with EtOAc (1 L three times). The combined organic layers were washed with brine (500 mL twice), 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 give methyl 2-amino-3-cyano-5-nitro-benzoate (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)

[0399] 12.3 Preparation of methyl 2-bromo-3-cyano-5-nitrobenzoate

[0400]

Chemical formula

[0401] 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), methyl 2-amino-3-cyano-5-nitro-benzoate (30 g, 135 mmol, 1 eq) was added portionwise at 65 °C. The mixture was stirred at 65 °C for 1 h. LCMS indicated that 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 times). The combined organic layers were washed with brine (300 mL, 2 times), 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 with a 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).

[0402] 12.4 Preparation of methyl 5-amino-2-bromo-3-cyanobenzoate

[0403]

Chemical Structure

[0404] To a solution of methyl 2-bromo-3-cyano-5-nitro-benzoate (30 g, 105 mmol, 1 equiv) in EtOH (200 mL) and H2O (100 mL) were added Fe (13.5 g, 242 mmol, 2.3 equiv) and NH4Cl (12.9 g, 242 mmol, 2.3 equiv). The mixture was stirred at 70 °C for 2 h. LCMS indicated that 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 times). The combined organic layers were washed with brine (300 mL, 3 times), 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 give methyl 5-amino-2-bromo-3-cyano-benzoate (22 g, 81.9% yield) as a gray solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.27 - 7.00 (m, 2H), 6.05 (s, 2H), 3.84 (s, 3H).

[0405] 12.5 Preparation of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile

[0406]

Chem.

[0407] To a solution of methyl 5-amino-2-bromo-3-cyano-benzoate (22 g, 86.2 mmol, 1 equiv) in THF (200 mL), LiBH4 (4 M in THF, 64.7 mL, 259 mmol, 3 equiv) was added at 25 °C. The mixture was stirred at 35 °C for 12 h. LCMS indicated that the reaction was complete and the desired mass was detected. The reaction mixture was quenched by the addition of H2O (300 mL) at 0 °C and adjusted to pH 2 with aqueous HCl (2 M). The resulting solution was extracted with ethyl acetate (300 mL, 3 times). The combined organic layers were washed with brine (200 mL, 2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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).

[0408] 12.6 Preparation of 2-bromo-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-3-(hydroxymethyl)benzonitrile

[0409]

Chemical Structure

[0410] A mixture of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile (4.12 g, 18.1 mmol, 1.3 equiv), 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexanecarbonitrile (3.5 g, 13.9 mmol, 1 equiv), and TFA (2.39 g, 20.9 mmol, 1.55 mL, 1.5 equiv) in i-PrOH (40 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85 °C for 12 h under a N2 atmosphere. LCMS indicated that 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 aqueous NaHCO3 (20 mL) at 25 °C for 2 h to give 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).

[0411] 12.7 Preparation of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile

[0412]

Chemical Structure

[0413] 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 equiv) in THF (50 mL) was added with 2,6-dimethylpyridine (1.78 g, 16.6 mmol, 1.94 mL, 3 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (2.20 g, 8.33 mmol, 1.91 mL, 1.5 equiv) at 25 °C. The mixture was stirred at 35 °C for 2 h. LCMS indicated that the reactants were completely consumed and one 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 times). 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 give 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).

[0414] Preparation of 12.9 (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyano-4-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)boronic acid

[0415] [Chemical formula]

[0416] Six reactions were carried out in parallel. For each, a mixture of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (500 mg, 899 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.42 g, 6.30 mmol, 7 equiv), KOAc (264 mg, 2.70 mmol, 3 equiv), Pd(PPh3)2Cl2 (63.1 mg, 90.0 μmol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 1 h under a N2 atmosphere. LCMS indicated that the reactants were completely consumed and the desired compound was detected. The six parallel reactions were combined, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 250*50 mm*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.

[0417] 12.10 Preparation of 5-((4-(((trans)-2-Cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile

[0418] [Chemical formula]

[0419] 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 equiv) in THF (10 mL) was added aqueous HCl solution (6 M, 640 μL, 4 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. Thereafter, a solid precipitated. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was filtered to obtain the compound 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile as a white solid (360 mg, yield 95%, purity 99%). 11H 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 (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 36% - 36%, 6 min) to give 5-((4-(((trans)-2-cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile (80.8 mg, 99.62% purity, 99.42% ee, the first peak, Rt = 1.108 min) as a white solid, stereoisomer 1; 1 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 CBN6O2 is 388.18, the measured m / z is 389.2 [M+H] +. HPLC: 99.62% (220 nm), 99.60% (254 nm). And 5-((4-(((trans)-2-Cyanocyclohexyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile (72.0 mg, 99.62% purity, 98.64% ee, the second peak, Rt = 1.499 min) as a white solid, stereoisomer 2. 1 1H 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 1 21 alculated mass of C19H20BN6O2 is 388.18, measured m / z 387.1 [M-H] - . HPLC: 99.62% (220 nm), 100.0% (254 nm) was obtained.

[0420] 13. Preparation of (trans)-2-((2-((7,8-Dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0421]

Chemical Structure

[0422] To a mixture of 7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-4-amine (50 mg, 219 μmol, 1 equiv, HCl) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (60.6 mg, 241 μmol, 1.1 equiv) in 2-methylbutan-2-ol (3 mL), BrettPhos Pd G3 (19.9 mg, 21.9 μmol, 0.1 equiv), BRETTPHOS (11.8 mg, 21.9 μmol, 0.1 equiv) and Cs2CO3 (214 mg, 659 μmol, 3 equiv) were added at once at 20 °C under N2. The mixture was heated to 100 °C and stirred for 16 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; 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-borabenzo[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 alculated mass for CBN5O3 405.20, m / z found 404.3 [M-H] -. HPLC: 95.34% (220 nm), 90.93% (254 nm).

[0423] 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

[0424]

Chem.

[0425] 14.1 Preparation of methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate

[0426]

Chem.

[0427] To a mixture of methyl 5-amino-2-bromo-benzoate (5.00 g, 21.7 mmol, 1 equiv) in MeOH (35 mL), Boc2O (10.4 g, 47.8 mmol, 2.2 equiv) and Na2CO3 (6.91 g, 65.2 mmol, 3 equiv) were added at 20 °C. The mixture was stirred at 20 °C for 24 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove methanol, and the resulting residue was quenched with H2O (50 mL) and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 40 g SepaFlash (registered trademark) Silica Flash Column, eluent with a gradient of 0 - 13% ethyl acetate / petroleum ether, flow rate 75 mL / min) to afford methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate as a yellow solid (6.00 g, 83.6% yield). 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).

[0428] 14.2 Preparation of 2-(5-amino-2-bromo-phenyl)propan-2-ol

[0429] [Chemical formula]

[0430] To a solution of MeMgBr (3 M in diethyl ether, 48.5 mL, 12 equiv) in THF (40 mL) was added methyl 2-bromo-5-(tert-butoxycarbonylamino)benzoate (4.00 g, 12.1 mmol, 1 equiv) at 0 °C over 0.5 h. After addition, the reaction mixture was warmed to 35 °C and stirred for 5.5 h. TLC indicated completion of the reaction. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL), adjusted to pH 6 with 2 N HCl at 0 °C, and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 40 g SepaFlash (registered trademark) Silica Flash Column, eluent with a gradient of 0 - 30% ethyl acetate / petroleum ether, 75 mL / min) to afford 2-(5-amino-2-bromo-phenyl)propan-2-ol (2.3 g, 82% yield) as a yellow solid. 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).

[0431] Preparation of 14.3 2-[[2-[4-bromo-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0432]

Chem.

[0433] To a solution of 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (700 mg, 2.79 mmol, 1 equiv) in dioxane (20 mL) were added 2-(5-amino-2-bromo-phenyl)propan-2-ol (697 mg, 3.03 mmol, 1.09 equiv) and TsOH·H2O (797 mg, 4.19 mmol, 1.5 equiv) at 25 °C under N2, and the mixture was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with H2O (20 mL), adjusted to pH 7 at 0 °C with saturated aqueous NaHCO3, and then extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), 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).

[0434] Preparation of 14.4 (trans)-2-[[2-[(1-Hydroxy-3,3-dimethyl-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile hydrochloride

[0435]

Chemical formula

[0436] Five reactions were carried out in parallel. For each, to a solution of (trans)-2-[[2-[4-bromo-3-(1-hydroxy-1-methyl-ethyl)anilino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 225 μmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (127 mg, 563 μmol, 2.5 equiv) in dioxane (5 ml), KOAc (44.2 mg, 450 μmol, 2 equiv) and Pd(PPh3)2Cl2 (15.8 mg, 22.5 μmol, 0.1 equiv) were added at 25 °C under N2. The mixture was heated and stirred at 120 °C for 0.5 h. TLC indicated that the reaction was complete. The five parallel reaction products were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 18% - 32%, 7 min) to give (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 27 Calculated mass of BClN5O2: 391.22, measured m / z: 392.3 [M+H] + . HPLC: 95.81% (220 nm), 96.45% (254 nm)

[0437] 15. Preparation of (trans)-2-[[2-[(2-Hydroxy-1,2-benzoxaborinin-6-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0438]

Chemical Structure

[0439] 15.1 Preparation of 2-[[2-[(4-Methoxyphenyl)methylamino]-5-methyl-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0440]

Chemical Structure

[0441] (trans)-2-[(2-Chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (600 mg, 2.39 mmol, 1 equiv) and PMBNH2 (6.36 g, 46 mmol, 6 mL, 19 equiv) were stirred at 100 °C for 4 h. TLC indicated that the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL) and adjusted to pH 5 with aqueous HCl (2 N). The aqueous solution was extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 2 times), 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 = 5 / 1 - 0 / 1) to afford (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).

[0442] 15.2 Preparation of 2-[(2-Amino-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile

[0443]

Chemical Structure

[0444] A mixture of (trans)-2-[[2-[(4-methoxyphenyl)methylamino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile (300 mg, 853 μmol, 1 equiv) in TFA (3 mL) was stirred at 20 °C for 3 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was diluted with 20 mL of water and extracted with DCM (3 times with 10 mL). 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.

[0445] 15.3 Preparation of (trans)-2-[[2-[(2-hydroxy-1,2-benzoxaborinin-6-yl)amino]-5-methyl-pyrimidin-4-yl]amino]cyclohexane-1-carbonitrile

[0446]

Chemical formula

[0447] A mixture of 6-bromo-2-hydroxy-1,2-benzoxaborinine (100 mg, 444 μmol, 1 equiv), (trans)-2-[(2-amino-5-methyl-pyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (103 mg, 444 μmol, 1 equiv), K2CO3 (123 mg, 889 μmol, 2 equiv), Pd2(dba)3 (20 mg, 22 μmol, 0.05 equiv) and t-Bu Xphos (19 mg, 44 μmol, 0.1 equiv) in i-PrOH (6 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 2 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (10 mL) at 20 °C and then extracted with EtOAc (5 mL three times). The combined organic layers were washed with brine (10 mL three times), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25% - 50%, 10 min) to afford (trans)-2-[[2-[(2-hydroxy-1,2-benzoxaborinine-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 = 12.0 Hz, 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 22 Calculated mass of BN5O2: 375.19, measured m / z: 374.3 [M - H] - . HPLC: 98.55% (220 nm), 99.53% (254 nm).

[0448] 16. Preparation of (trans)-2-((2-((2-Hydroxy-3-methyl-2H-benzo[e][1,2]oxaborinin-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0449]

Chemical Structure

[0450] 16.1 Preparation of tert-Butyl N-(2-Hydroxy-3-methyl-1,2-benzooxaborinin-6-yl)carbamate

[0451]

Chemical Structure

[0452] Three reactions were carried out in parallel. For each, to a mixture of 6-bromo-2-hydroxy-3-methyl-1,2-benzoxaborinine (200 mg, 837 μmol, 1 equiv) and tert-butyl carbamate (118 mg, 1.0 mmol, 1.2 equiv) in dioxane (3 mL), t-Bu Xphos (36 mg, 83.7 μmol, 0.1 equiv), K3PO4 (355 mg, 1.67 mmol, 2 equiv) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (t-Bu Xphos Pd G3, 66 mg, 83.7 μmol, 0.1 equiv) were added all at once at 25 °C under N2. The mixture was heated and stirred at 100 °C for 10 h. TLC indicated that the reaction was complete. The three parallel reaction products were combined, filtered, and the filtrate was 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 with a gradient of 70–80% ethyl acetate / petroleum ether, 60 mL / min) to give tert-butyl N-(2-hydroxy-3-methyl-1,2-benzoxaborinin-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).

[0453] 16.2 Preparation of 2-hydroxy-3-methyl-1,2-benzoxaborinin-6-amine hydrochloride

[0454]

Chemical formula

[0455] To a mixture of tert-butyl N-(2-hydroxy-3-methyl-1,2-benzoxaborinin-6-yl)carbamate (500 mg, 1.27 mmol, 70% purity, 1 eq) in EtOAc (3 mL), HCl / EtOAc (4 N, 6.36 mL, 20 eq) was added at once at 25 °C under N2. The mixture was stirred at 25 °C for 2 h. TLC indicated that the reaction was complete. The mixture was concentrated to give a residue. The residue was triturated with EtOAc (2 mL) to afford 2-hydroxy-3-methyl-1,2-benzoxaborinin-6-amine hydrochloride (150 mg, 55% yield, HCl salt) as a yellow solid. 1 1H 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).

[0456] Preparation of 16.3 (trans)-2-((2-((2-hydroxy-3-methyl-2H-benzo[e][1,2]oxaborinin-6-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0457]

Chemical Structure

[0458] Two reactions were carried out in parallel. For each, TsOH·H2O (81 mg, 472 μmol, 1 equiv) was added in one portion to a mixture of 2-hydroxy-3-methyl-1,2-benzoxaborinin-6-amine hydrochloride (100 mg, 472 μmol, 1 equiv, HCl salt) and 2-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (119 mg, 472 μmol, 1 equiv) in dioxane (5 mL) at 25 °C under N2. The mixture was heated and stirred at 80 °C for 15 h. TLC indicated that the reaction was complete. The two parallel reaction products were combined and concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (10 mL), washed with saturated aqueous NaHCO3 solution (5 mL three times), 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]oxaborinin-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 alculated for C19H25BN5O2 mass 389.20, m / z found 390.3 [M+H] +. HPLC: 99.68% (220 nm), 99.75% (254 nm).

[0459] 17. Preparation of (trans)-2-((5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0460]

Chem.

[0461] 17.1 Preparation of methyl 2-bromo-5-((5-chloro-4-((trans)-2-cyanocyclohexyl)amino)pyrimidin-2-yl)amino)benzoate

[0462]

Chem.

[0463] A mixture of (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexane-1-carbonitrile (2.30 g, 8.48 mmol, 1 equiv), methyl 5-amino-2-bromo-benzoate (2.15 g, 9.33 mmol, 1.1 equiv) and TsOH·H2O (3.23 g, 16.9 mmol, 2 equiv) in dioxane (60 mL) was heated and stirred at 80 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was cooled and concentrated in vacuo to give a residue. The residue was triturated with a mixed solvent of EtOAc (50 mL) and saturated aqueous Na2CO3 solution (50 mL) to give 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).

[0464] Preparation 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

[0465]

Chemical Structure

[0466] To a mixture of methyl 2 - bromo - 5 - ((5 - chloro - 4 - (((trans) - 2 - cyanocyclohexyl)amino)pyrimidin - 2 - yl)amino)benzoate (500 mg, 1.08 mmol, 1 equiv) in dioxane (15 mL) were added KOAc (264 mg, 2.69 mmol, 2.5 equiv), Pd(PPh3)2Cl2 (75.5 mg, 107 μmol, 0.1 equiv) 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 equiv) at 25 °C under N2 all at once. The mixture was then heated to 120 °C and stirred for 3 h. TLC indicated that 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 afford 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.

[0467] Preparation of 17.3 (trans)-2-((5-chloro-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0468]

Chemical Structure

[0469] To a mixture of methyl 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 equivalent) in THF (10 mL), MeOH (12.3 mmol, 0.5 mL, 12.3 equivalents) and NaBH4 (95.0 mg, 2.51 mmol, 2.5 equivalents) were added portionwise at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. TLC indicated that the reaction was complete. The mixture was poured into ice water (20 mL), and the aqueous phase was adjusted to pH 5 - 6 with aqueous HCl (2N). The resulting mixture was diluted with ethyl acetate (20 mL), and then the suspension was filtered. The filter cake was washed with water (10 mL three times) and dried under vacuum to obtain 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]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile (132.4 mg, 32% yield, 95.1% purity) as an off-white solid. 1 H 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 Calculated mass of BClN5O2: 383.64, measured m / z: 384.0 [M + H] + . HPLC: 95.1% (220 nm), 93.88% (254 nm).

[0470] 18. Preparation of 5 - ((4 - (((trans) - 2 - cyanocyclopentyl)amino) - 5 - methylpyrimidin - 2 - yl)amino) - 1 - hydroxy - 1,3 - dihydrobenzo[c][1,2]oxaborole - 7 - carbonitrile

[0471]

Chemical Structure

[0472] 18.1 Preparation of 2 - bromo - 5 - ((4 - (((trans) - 2 - cyanocyclopentyl)amino) - 5 - methylpyrimidin - 2 - yl)amino) - 3 - (hydroxymethyl)benzonitrile

[0473]

Chemical Structure

[0474] To a solution of 5-amino-2-bromo-3-(hydroxymethyl)benzonitrile (3 g, 13.2 mmol, 1 equiv) in i-PrOH (25 mL) were added TFA (2.26 g, 19.8 mmol, 1.47 mL, 1.5 equiv) and 2-((2-chloro-5-methylpyrimidin-4-yl)amino)cyclopentanecarbonitrile (3.13 g, 13.3 mmol, 1 equiv) at 25 °C. The mixture was stirred at 80 °C for 12 h. A solid precipitated after 3 h of reaction. TLC indicated the completion of the reaction. The reaction mixture was filtered to obtain a filter cake. The filter cake was triturated with saturated aqueous 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).

[0475] 18.2 Preparation of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile

[0476]

Chem.

[0477] 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 equiv) in THF (35 mL) was added with 2,6-dimethylpyridine (2.71 g, 25.2 mmol, 2.94 mL, 3 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (3.34 g, 12.6 mmol, 2.90 mL, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (80 mL) at 0 °C and then extracted with EtOAc (3 times 80 mL). The combined organic layers were washed with brine (2 times 50 mL), 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 afford the compound 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile as a white solid (3 g, 65.7% yield). 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).

[0478] 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-dioxaborinan-2-yl)benzonitrile

[0479]

Chem.

[0480] Six reactions were carried out in parallel. For each, a mixture of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)benzonitrile (500 mg, 923 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (834 mg, 3.69 mmol, 4 equiv), KOAc (271 mg, 2.77 mmol, 3 equiv), Pd(PPh3)2Cl2 (64.8 mg, 92.3 μmol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 1 h under an N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was observed. The six parallel reaction products were combined, diluted with H2O (150 mL), and extracted with ethyl acetate (30 mL three times). 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 preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40% - 70%, 10 min) to give 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.

[0481] 18.4 Preparation of 5-((4-(((trans)-2-Cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile

[0482] [Chemical formula]

[0483] 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 equiv) in THF (5 mL) was added HCl (6 M, 2 mL, 7.66 equiv). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the reaction was complete and one major peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (formic acid (FA) conditions; column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [water (FA)-ACN]; B%: 15% - 45%, 20 min) to afford 5-((4-(((trans)-2-cyanocyclopentyl)amino)-5-methylpyrimidin-2-yl)amino)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile (160.5 mg, 28.5% yield) as a white solid. 11H 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 Calculated mass of CBN6O2 374.17, measured m / z 375.1 [M+H] + . HPLC: 96.77% (220 nm), 95.94% (254 nm).

[0484] 19. Preparation of (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0485]

Chemical Structure

[0486] 19.1 Preparation of 2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0487]

Chemical Structure

[0488] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (800 mg, 3.38 mmol, 1 equiv) in i-PrOH (10 mL) were added TFA (578 mg, 5.07 mmol, 375 μL, 1.5 equiv) and (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (917 mg, 3.38 mmol, 1 equiv) at 25 °C. The mixture was stirred at 80 °C for 5 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain a filter cake. The filter cake was triturated with saturated aqueous NaHCO3 (10 mL) to give (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).

[0489] 19.2 Preparation of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0490]

Chem.

[0491] 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 equiv) in THF (20 mL) was added with 2,6-dimethylpyridine (818 mg, 7.64 mmol, 4 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (757 mg, 2.87 mmol, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (30 mL) at 0 °C and then extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (10 mL) to afford (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile as a white solid (600 mg, 53.6% yield). 1 H NMR (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).

[0492] Preparation of 19.3 (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

[0493] [Chemical formula]

[0494] Two reactions were carried out in parallel. For each, a mixture of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile (200 mg, 341 μmol, 1 equivalent), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (540 mg, 2.39 mmol, 7 equivalents), KOAc (100 mg, 1.02 mmol, 3 equivalents), Pd(PPh3)2Cl2 (24 mg, 34.1 μmol, 0.1 equivalent) in dioxane (3 mL) was degassed and purged three times with N2, and then the mixture was stirred at 120 °C for 1 h under a N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was observed. The two parallel reaction products were combined, filtered, and then the residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50% - 90%, 8 min) to obtain (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.

[0495] Preparation of 19.4 (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0496]

Chemical Structure

[0497] 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 μmol, 1 equiv) in THF (5 mL) was added aqueous HCl solution (6 M, 0.2 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with n-pentane (1 mL) to afford (trans)-2-((5-chloro-2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile as a white solid (18.9 mg, 41.4% yield). 11H 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 Calculated mass of BCl2N5O2: 417.09, measured m / z: 418.0 [M+H] + . HPLC: 97.31% (220 nm), 98.50% (254 nm).

[0498] 20. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0499]

Chemical Structure

[0500] 20.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0501]

Chemical Structure

[0502] A solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (1 g, 4.22 mmol, 1 equiv) and (trans)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanecarbonitrile (1.07 g, 4.22 mmol, 1 equiv) in i-PrOH (10 mL) was added dropwise with TFA (1.44 g, 12.7 mmol, 3 equiv) at 25 °C. The resulting mixture was stirred at 80 °C for 12 h. A solid precipitated after 3 h of reaction. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain a residue. The residue was triturated with saturated aqueous NaHCO3 (20 mL) and filtered to give (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, 1 H), 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).

[0503] 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

[0504]

Chemical Structure

[0505] 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 equiv) in THF (10 mL) was added with 2,6-dimethylpyridine (757 mg, 7.07 mmol, 820 uL, 4 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (700 mg, 2.65 mmol, 600 uL, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (20 mL, 2 times), 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 - 5 / 1) to afford (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.

[0506] 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

[0507]

Chemical Structure

[0508] Five reactions were carried out in parallel. For each, a mixture of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 175 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (198 mg, 878 μmol, 5 equiv), KOAc (52 mg, 527 μmol, 3 equiv) and Pd(PPh3)2Cl2 (12 mg, 17.5 μmol, 0.1 equiv) in dioxane (5 mL) was degassed and purged three times with N2, and then the mixture was stirred at 120 °C for 40 min under a N2 atmosphere. TLC indicated that the reaction was complete. The five parallel reaction products 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 - 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.

[0509] 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

[0510]

Chemical Structure

[0511] 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 μmol, 1 equiv) in THF (10 mL) was added with aqueous HCl solution (4 M, 2.0 mL, 9.6 equiv) at 25 °C. The mixture was stirred at 25 °C for 1 h. A solid precipitated. The reaction mixture was filtered to obtain 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-fluoropyrimidin-4-yl]amino]cyclohexanecarbonitrile (81 mg, 24.3% yield, 98.07% purity) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1 H), 8.89 (s, 1 H), 8.01 (d, J = 3.6 Hz, 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 Calculated mass for C14H12BClFN5O2 is 401.12, found m / z 402.2 [M+H] + . HPLC: 98.07% (220 nm), 98.08% (254 nm).

[0512] 21. Preparation of (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0513]

Chem.

[0514] Preparation of 21.1 (trans)-2-((2-((4-bromo-3-chloro-5-(hydroxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0515]

Chem.

[0516] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (500 mg, 2.11 mmol, 1 equiv) in i-PrOH (5 mL) was added TFA (361 mg, 3.17 mmol, 1.5 equiv) and (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (643 mg, 2.11 mmol, 1 equiv) at 25 °C. The mixture was stirred at 80 °C for 4 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered, and the filter cake was triturated with saturated aqueous NaHCO3 (30 mL) and filtered to give (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. 11H 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).

[0517] Preparation of 21.2 (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0518]

Chemical Structure

[0519] A solution of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclohexanecarbonitrile (500 mg, 990 μmol, 1 equiv) in THF (20 mL) was added with 2,6-dimethylpyridine (424 mg, 3.96 mmol, 4 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (393 mg, 1.49 mmol, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (20 mL, 2 times), 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 - 3 / 1) to afford (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile as a white solid (500 mg, 81.5% yield). 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).

[0520] Preparation of 21.3 (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

[0521] [Chemical formula]

[0522] To a solution of (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile (400 mg, 646 μmol, 1 equiv) in dioxane (8 mL) were added Pd(PPh3)2Cl2 (45.3 mg, 64.6 μmol, 0.1 equiv), KOAc (190 mg, 1.94 mmol, 3 equiv), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (729 mg, 3.23 mmol, 5 equiv) at 25 °C. The mixture was stirred at 120 °C for 10 minutes. TLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL three times). The combined organic layers were washed with brine (10 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100*40mm*3um; mobile phase: [water (FA formic acid)-ACN]; B%: 30% - 80%, 8 minutes) to give 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.

[0523] Preparation of 21.4 (trans)-2-((2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0524]

Chemical Structure

[0525] 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 equiv) in THF (2 mL) was added aqueous HCl solution (6 M, 2 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. A solid precipitated. TLC indicated that 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]oxaborol-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 18Calculated mass of BClF3N5O2: 451.12, measured m / z: 449.9 [M-H] - . HPLC: 98.10% (220 nm), 100% (254 nm).

[0526] 22. Preparation of (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0527]

Chem.

[0528] 22.1 Preparation of (trans)-2-[[2-[4-bromo-3-chloro-5-(hydroxymethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0529]

Chem.

[0530] To a solution of (5-amino-2-bromo-3-chloro-phenyl)methanol (500 mg, 2.11 mmol, 1 equiv) in i-PrOH (10 mL) were added (trans)-2-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (614 mg, 1.83 mmol, 1 equiv) and TFA (360 mg, 3.17 mmol, 1.5 equiv) at 25 °C. The mixture was stirred at 80 °C for 12 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain the crude product (filter cake). The crude product was triturated with saturated aqueous 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 1H NMR (DMSO-d6, 400 MHz) δ 10.16 (s, 1 H), 8.33 (s, 1 H), 8.02 (s, 1 H), 7.94 (s, 1 H), 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).

[0531] Preparation of 22.2 (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0532] [Chemical formula]

[0533] 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 equiv) in THF (20 mL) was added with 2,6-dimethylpyridine (716 mg, 6.68 mmol, 780 uL, 4 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (662 mg, 2.51 mmol, 580 uL, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (20 mL, 2 times), 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 - 5 / 1) to afford (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).

[0534] 22.3 Preparation 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

[0535] [Chem.]

[0536] Two reactions were carried out in parallel. For each, a mixture of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile (400 mg, 661 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (746 mg, 3.31 mmol, 5 equiv), Pd(PPh3)2Cl2 (69.6 mg, 99.1 μmol, 0.15 equiv) and KOAc (142 mg, 1.45 mmol, 2.2 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 40 min under a N2 atmosphere. TLC indicated that the reaction was complete. The two parallel reaction products 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 - 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 as a yellow solid (0.5 g, 59.2% yield).

[0537] Preparation of 22.4 (trans)-2-[[2-[(7-chloro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]cyclopentanecarbonitrile

[0538] [Chem.]

[0539] 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 μmol, 1 equiv) in THF (5 mL) was added with aqueous HCl solution (4 M, 2 mL, 10 equiv) at 25 °C. The mixture was stirred at 25 °C for 1 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain 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, 1 H), 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, 3 H), 1.68 - 1.55 (m, 1 H). MS (ESI): C 18 H 16 Calculated mass for C17H16BClF3N5O2 437.10, m / z found 435.9 [M-H] - . HPLC: 97.36% (220 nm), 97.17% (254 nm).

[0540] 23. Preparation of (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0541] [Chemistry]

[0542] Preparation of 23.1 (trans)-2-((2-((4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0543] [Chemistry]

[0544] To a solution of (5-amino-2-bromo-3-fluoro-phenyl)methanol (500 mg, 2.27 mmol, 1 equiv) in i-PrOH (10 mL) was added TFA (388 mg, 3.41 mmol, 1.5 equiv) and (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (616 mg, 2.27 mmol, 1 equiv) at 25 °C. The mixture was stirred at 80 °C for 5 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered to obtain a filter cake. The filter cake was triturated with saturated aqueous 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. 11H 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).

[0545] Preparation of 23.2 (trans)-2-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorophenyl)amino)-5-chloropyrimidin-4-yl)amino)cyclohexanecarbonitrile

[0546]

Chem.

[0547] 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 equiv) and 2,6-dimethylpyridine (801 mg, 7.48 mmol, 870 μL, 4 equiv) in THF (10 mL) was added with TBSOTf (741 mg, 2.80 mmol, 640 μL, 1.5 equiv) at 25 °C. The mixture was then stirred at 25 °C for 2 h. TLC indicated the completion of the reaction. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (20 mL) at 0 °C and then extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (50 mL, 2 times), 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 afford 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 (400 MHz, 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).

[0548] Preparation of (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

[0549] [Chemical formula]

[0550] Five reactions were carried out in parallel. For each, a mixture of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-fluoro-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (100 mg, 175 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (277 mg, 1.23 mmol, 7 equiv), KOAc (51.7 mg, 527 μmol, 3 equiv), Pd(PPh3)2Cl2 (12.3 mg, 17.5 μmol, 0.1 equiv) in dioxane (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 120 °C for 1 h under a N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was observed. The five parallel reaction products were combined, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (formic acid FA)-ACN]; B%: 40% - 70%, 8 min) to give (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.

[0551] Preparation of (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carbonitrile

[0552] [Chemical formula]

[0553] 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 μmol, 1 equiv) in THF (3 mL) was added aqueous HCl solution (6 M, 0.3 mL, 5 equiv) at 25 °C. The mixture was stirred at 25 °C for 1 h. A solid precipitated. LCMS indicated that the reaction was complete and the desired MS was observed. The reaction mixture was filtered to obtain a residue. The residue was triturated with THF (2 mL) and filtered to give (trans)-2-((5-chloro-2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-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 H18 Calculated mass of BClFN5O2: 401.12, measured m / z: 402.1 [M+H] + . HPLC: 99.09% (220 nm), 99.70% (254 nm).

[0554] 24. Preparation of 2-[[5-chloro-2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0555]

Chem.

[0556] 24.1 Preparation of 2-bromo-3-methyl-5-nitro-benzoic acid

[0557]

Chem.

[0558] Compound 2-bromo-3-methyl-benzoic acid (10 g, 46.5 mmol, 1 equiv.) was dissolved in concentrated H2SO4 (70 mL). KNO3 (4.61 g, 45.5 mmol, 0.98 equiv.) dissolved in H2SO4 (30 mL) was added dropwise to the solution at 0 °C. The mixture was stirred at 0 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was poured into ice water (200 mL) and filtered to obtain 2-bromo-3-methyl-5-nitro-benzoic acid (10.6 g, crude) as a brown solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.55 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 2.63 (s, 3H).

[0559] 24.2 Preparation of methyl 2-bromo-3-methyl-5-nitro-benzoate

[0560]

Chem.

[0561] To a mixture of 2-bromo-3-methyl-5-nitro-benzoic acid (8.5 g, 32.7 mmol, 1 equiv) in MeOH (100 mL) was added thionyl chloride (65.3 mmol, 4.7 mL, 2 equiv) dropwise at 0 °C. The mixture was heated to 80 °C and stirred for 15 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 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).

[0562] 24.3 Preparation of methyl 5-amino-2-bromo-3-methyl-benzoate

[0563]

Chemical formula

[0564] To a solution of methyl 2-bromo-3-methyl-5-nitro-benzoate (7.5 g, 27.3 mmol, 1 equiv) in EtOH (100 mL) and H2O (20 mL) were added NH4Cl (5.86 g, 109 mmol, 4 equiv) and Fe powder (6.11 g, 109 mmol, 4 equiv) at 25 °C. The mixture was stirred at 80 °C for 1 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (50 mL, 2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-amino-2-bromo-3-methyl-benzoate (5.5 g, 82.3% yield) as a brown oil.1 1H 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).

[0565] Preparation of 24.4 (5-Amino-2-bromo-3-methyl-phenyl)methanol

[0566]

Chemical Structure

[0567] To a solution of methyl 5-amino-2-bromo-3-methyl-benzoate (5.5 g, 22.5 mmol, 1 equiv) in THF (50 mL) was added dropwise DIBAL-H (1 M in THF, 90.1 mL, 4 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC indicated that the reaction was complete. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL) at 0 °C, stirred at room temperature for 1 h, filtered, and the filtrate was 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 1H 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).

[0568] Preparation of 24.5 (trans)-2-[[2-[4-Bromo-3-(hydroxymethyl)-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0569]

Chemical Structure

[0570] To a solution of (5-amino-2-bromo-3-methyl-phenyl)methanol (500 mg, 2.31 mmol, 1 equiv) in i-PrOH (5 mL) was added (trans)-2-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarbonitrile (627 mg, 2.31 mmol, 1 equiv) and TFA (395 mg, 3.47 mmol, 256 μL, 1.5 equiv) at 25 °C. The mixture was stirred at 80 °C for 12 h. A solid precipitated. TLC indicated that the reaction was complete. The reaction mixture was filtered to give a residue. The residue was triturated with saturated aqueous 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 = 2.4 Hz, 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).

[0571] 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

[0572]

Chem.

[0573] 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 equiv) in THF (5 mL) was added with 2,6-dimethylpyridine (437 mg, 4.08 mmol, 4 equiv) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (404 mg, 1.53 mmol, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (20 mL, 2 times), 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 - 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 as a yellow solid (500 mg, 86.7% yield). 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1 H), 7.98 (s, 1 H), 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, 3 H), 0.94 (s, 9 H), 0.12 (s, 6 H).

[0574] Preparation of 24.7 (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

[0575]

Chem.

[0576] A mixture of (trans)-2-[[2-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile (500 mg, 884 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (999 mg, 4.42 mmol, 5 equiv), Pd(PPh3)2Cl2 (93 mg, 132 μmol, 0.15 equiv) and KOAc (191 mg, 1.95 mmol, 2.2 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 120 °C for 40 min under a N2 atmosphere. TLC indicated that 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 - 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 as a yellow solid (0.4 g, 75.5% yield).

[0577] Preparation of 24.8 (trans)-2-[[5-chloro-2-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)amino]pyrimidin-4-yl]amino]cyclohexanecarbonitrile

[0578]

Chem.

[0579] 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 μmol, 1 equiv) in THF (5 mL) was added aqueous HCl solution (4 M, 1.67 mL, 10 equiv) at 25 °C. The mixture was stirred at 25 °C for 1 h. A solid precipitated. TLC indicated that 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, 2 H). MS (ESI): C 19 H 21 Calculated mass for C15H21BClN5O2 397.15, found m / z 398.2 [M+H] + . HPLC: 98.68% (220 nm), 98.78% (254 nm).

[0580] 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

[0581]

Chemical formula

[0582] 25.1 Preparation of Methyl 2-Hydroxy-3-Methyl-Benzoate

[0583]

Chemical formula

[0584] Four reactions were carried out in parallel. For each, to a solution of methyl 3-bromo-2-hydroxy-benzoate (8.75 g, 37.8 mmol, 1 equiv) in toluene (360 mL) and water (36 mL) were added cyclopropylboronic acid (13.0 g, 151 mmol, 4 equiv), tricyclohexylphosphane (4.25 g, 15.1 mmol, 4.91 mL, 0.4 equiv), K3PO4 (16.0 g, 75.7 mmol, 2 equiv), and Pd(OAc)2 (850 mg, 3.79 mmol, 0.1 equiv) at 20 °C. The mixture was stirred at 100 °C for 12 h. TLC indicated that the reaction was complete. The four parallel reaction mixtures were combined, poured into H2O (150 mL), and extracted with MTBE (200 mL three times). The combined organic layers were washed with brine (100 mL three times), 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 methyl 2-hydroxy-3-methyl-benzoate (11.5 g, 45.6% yield) as a yellow oil. 11H 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).

[0585] Preparation of Methyl 3 - Cyclopropyl - 2 - hydroxy - 5 - nitro - benzoate

[0586]

Chemical Structure

[0587] Two reactions were carried out in parallel. For each, a solution of methyl 3 - cyclopropyl - 2 - hydroxy - benzoate (8.4 g, 43.7 mmol, 1 equiv) in DCM (35 mL) was cooled to - 10 °C, and then a mixed acid of HNO3 (6.35 g, 65.5 mmol, 4.5 mL, 65% purity, 1.5 equiv) and H2SO4 (15.4 g, 157 mmol, 8.4 mL, 3.61 equiv) was added dropwise at - 10 °C. After the addition, the reaction mixture was warmed to 0 °C and stirred at 0 °C for 2 h. TLC indicated that the reaction was complete. The two parallel reaction mixtures were combined, poured into H2O (100 mL), and extracted with DCM (50 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to give methyl 3 - cyclopropyl - 2 - hydroxy - 5 - nitro - benzoate (10.6 g, 51.1% yield) as a yellow solid. 11H NMR (CDCl3, 400 MHz) δ 11.85 (s, 1 H), 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).

[0588] Preparation of Methyl 5 - Amino - 3 - cyclopropyl - 2 - hydroxy - benzoate

[0589] [Chemical formula]

[0590] To a solution of methyl 3 - cyclopropyl - 2 - hydroxy - 5 - nitro - benzoate (3.5 g, 14.7 mmol, 1 equivalent) in EtOH (53 mL) and water (17 mL), Fe powder (2.47 g, 44.2 mmol, 3 equivalents) and NH4Cl (1.18 g, 22.1 mmol, 1.5 equivalents) were added at 25 °C. The mixture was stirred at 80 °C for 2 h. TLC indicated that 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, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), 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 = 2 / 1 - 3 / 1) to give methyl 5 - amino - 3 - cyclopropyl - 2 - hydroxy - benzoate (2.7 g, 87.2% yield) as a yellow solid. 1 1H NMR (CDCl3, 400 MHz) δ 10.62 (s, 1 H), 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).

[0591] Preparation of Methyl 5-((4-(((trans)-4-Cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-cyclopropyl-2-hydroxybenzoate

[0592] [Chemical Structure]

[0593] To a solution of methyl 5-amino-3-cyclopropyl-2-hydroxy-benzoate (0.85 g, 4.10 mmol, 1 equiv) and (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (1.04 g, 4.10 mmol, 1 equiv) in i-PrOH (34 mL) was added TFA (935 mg, 8.20 mmol, 2 equiv) at 20 °C. The mixture was stirred at 90 °C for 12 h. TLC indicated that the reaction was complete. The residue was poured into H2O (35 mL) and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), 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 = 2 / 1 - 0 / 1) to afford methyl 5-((4-(((trans)-4-cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-cyclopropyl-2-hydroxybenzoate as a yellow solid (1.25 g, 71.9% yield). 11H 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 = 7.2 Hz, 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).

[0594] Preparation of 25.5-methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate

[0595]

Chemical Structure

[0596] A solution of methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-hydroxy-benzoate (1.15 g, 2.72 mmol, 1 equiv) in THF (20 mL) was added with NaH (325 mg, 8.15 mmol, 60% purity, 3 equiv) at 0 °C and stirred for 10 min. Then, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (PhNTf2, 2.91 g, 8.15 mmol, 3 equiv) in THF (30 mL) was added to the reaction mixture. The mixture was stirred at 25 °C for 1 h. TLC indicated the completion of the reaction. The residue was poured into ice water (100 mL) and extracted with EtOAC (50 mL for 3 times). The combined organic layers were washed with brine (30 mL for 3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 - 0 / 1) to give methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate as a yellow solid (1.2 g, 79.5% yield). 1 H NMR (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).

[0597] 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-dioxaborinan-2-yl)benzoate

[0598]

Chemical Structure

[0599] A mixture of methyl 5-((4-(((trans)-4-cyanotetrahydropyran-3-yl]amino]-5-methyl-pyrimidin-2-yl]amino]-3-cyclopropyl-2-(trifluoromethylsulfonyloxy)benzoate (0.5 g, 900 μmol, 1 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (609 mg, 2.70 mmol, 3 equiv), KOAc (265 mg, 2.70 mmol, 3 equiv), Pd(dppf)Cl2 (32.9 mg, 45.0 μmol, 0.05 equiv) and Pd(PPh3)4 (52.0 mg, 45.0 μmol, 0.05 equiv) in dioxane (10 mL) was degassed and purged with N2 three times. Then the mixture was heated to 120 °C and stirred at 120 °C for 2 h under a N2 atmosphere. TLC indicated that the reaction was complete. The residue was poured into water (10 mL) and extracted with EtOAC (10 mL, three times). The combined organic layers were washed with brine (10 mL, three times), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions) to afford 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.

[0600] 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

[0601]

Chemical formula

[0602] 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 μmol, 1 equivalent) in THF (2 mL) was added NaBH4 (28.4 mg, 750 μmol, 3 equivalents) at 0 °C. The mixture was stirred at 25 °C for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was quenched at 0 °C by the addition of H2O (2 mL), adjusted to pH = 6 with aqueous HCl (2 N), 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. 11H 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, 1 H), 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 Calculated mass of BN5O3: 405.20, measured m / z: 406.2 [M+H] + . HPLC: 96.90% (220 nm), 96.88% (254 nm).

[0603] 26. Preparation of (trans)-3-[[2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)amino]-5-methyl-pyrimidin-4-yl]amino]tetrahydropyran-4-carbonitrile

[0604]

Chem.

[0605] 26.1 Preparation of (5-amino-2-bromophenyl)methanol

[0606]

Chem.

[0607] A solution of methyl 5-amino-2-bromo-benzoate (5 g, 21.7 mmol, 1 equiv) in THF (50 mL) was added dropwise with DIBAL-H (1 M in THF, 86.9 mL, 4 equiv) at 0 °C, and then stirred at 0 °C for 1 h. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous Na2CO3 solution (200 mL) and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 1:1) to give (5-amino-2-bromophenyl)methanol (4.3 g) as a yellow solid.

[0608] Preparation of 26.2 (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0609]

Chemical formula

[0610] A mixture of (5-amino-2-bromo-phenyl)methanol (2 g, 9.90 mmol, 1 equiv), (trans)-3-[(2-chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (2.5 g, 9.90 mmol, 1 equiv) and TFA (1.69 g, 14.8 mmol, 1.5 equiv) in i-PrOH (40 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 12 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain 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.

[0611] Preparation of 26.3 (trans)-3-((2-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0612]

Chem.

[0613] 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 equiv) and 2,4-dimethylpyridine (5 g, 46.8 mmol, 4 equiv) in THF (40 mL) was added [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (6.2 g, 23.4 mmol, 2 equiv) under N2, and then the mixture was stirred at 0 °C for 1 h. TLC indicated that the reaction was complete. The reaction mixture was quenched with an aqueous NH4Cl solution (100 mL) and extracted with EtOAc (100 mL three times). 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 as a yellow oil (5 g, 80% yield). 11H 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).

[0614] Preparation of 26.4 (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

[0615] [Chemical formula]

[0616] Five reactions were carried out in parallel. For each, a mixture of (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 equiv), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.70 g, 7.51 mmol, 4 equiv), KOAc (552 mg, 5.63 mmol, 3 equiv) and Pd(PPh3)2Cl2 (131 mg, 187 μmol, 0.1 equiv) in dioxane (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 120 °C for 1 h under a N2 atmosphere. TLC indicated that the reaction was complete. The five parallel reaction products were combined and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: C18 (250*50 mm*10 μm); 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.

[0617] 26.5 Preparation of (3R,4S)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0618]

Chemical Structure

[0619] 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 equiv) in THF (50 mL) was added with aqueous HCl solution (6 M, 5.3 mL, 4 equiv), and then the mixture was stirred at 40 °C for 1 h under a N2 atmosphere. LCMS indicated that 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 under vacuum to obtain (trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-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 * 30 mm, 10 um); mobile phase: [0.1% NH3H2O EtOH]; B%: 60% - 60%, 6 min) to give (trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile (343 mg, 99.34% purity, 100% ee, the first peak, RT = 1.424 min) as a white solid, stereoisomer 1. 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 - 4.87 (m, 2H), 4.50 - 4.40 (m, 1H), 3.95 - 3.84 (m, 2H), 3.31 - 3.19 (m, 2H), 3.14 (t, J = 10.8 Hz, 1H), 2.23 - 2.14 (m, 1H), 1.96 (s, 3H), 1.91 - 1.78 (m, 1H) MS (ESI): C 18 H20 Calculated mass of BN5O3, 365.17 m / z, measured value 364.0 [M-H] - . HPLC: 99.34% (220 nm), 99.9% (254 nm) and (trans)-3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile as a white solid (185 mg, 99.40% purity, 99.90% ee, second peak, RT = 1.737 min), stereoisomer 2. 1 1H 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 Calculated mass of BN5O3, 365.17 m / z, measured value 364.1 [M-H] - . HPLC: 99.40% (220 nm), 99.95% (254 nm) were obtained.

[0620] 27. Preparation of (trans)-3-((2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)amino)-5-methylpyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-carbonitrile

[0621]

Chemical Structure

[0622] Preparation of Methyl 2-Bromo-5-((4-(((trans)-4-Cyanotetrahydro-2H-pyran-3-yl)amino)-5-methylpyrimidin-2-yl)amino)-3-methylbenzoate

[0623]

Chem.

[0624] To a solution of (trans)-3-[(2-Chloro-5-methyl-pyrimidin-4-yl)amino]tetrahydropyran-4-carbonitrile (700 mg, 2.49 mmol, 90% purity, 1 equiv) in dioxane (10 mL) were added TsOH·H2O (711 mg, 3.74 mmol, 1.5 equiv) and methyl 5-amino-2-bromo-...

Claims

1. Compounds of formula I: 【Chemistry 1】 [In the formula, X 1 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, X 2 is selected from the group consisting of -O-, -N(R 5 ), - and -C(R 6 )(R 7 ), or X 2 is a bond between X 1 and X 3 and includes X 3 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, where X 1 and X 2 Both cannot be -O-, X 2 and X 3 Both cannot be -O-. R 1 is hydrogen, halogen (X 3 -C(R 6 )(R 7 ) if ), hydroxy, C 1 ~ 6 Alkyl, C 3 ~ 7 Cycloalkyl, C 1 ~ 6 Alkyl (oxy), and C 3 ~ 7 Selected from the group consisting of cycloalkyl(oxy), the above R 1 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. R 2 is hydrogen, C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 2 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 3 These are, independently, hydrogen, halogen (X 1 -C(R 6 )(R 7 ) if C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 3 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkinyl, -CHO, Cyclopropyl, C 1 ~C 3 Haloalkyl, C 2 ~C 3 Haloalkenil, C 2 ~C 3 Selected from the group consisting of haloalkynyls and partially or completely halogenated cyclopropyls, A is benzo[c][1,2]oxabolol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxabolinin-1-ol, and 2H-benzo[e][1,2]oxabolinin-2-ol, 7,8-dihydro-2H-1,6,9-trioxa-9-borabenzo[cd]azulene or derivatives thereof, for example, A 1 ~A 7 : 【Chemistry 2】 A group consisting of parts selected from any one of the following, R 5 is 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 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 A selection from the group consisting of -alkyl)-(heteroaryl), with R other than hydrogen. 5 The above members of the group are C 1～6 The heteroatom may be optionally substituted independently with one or more substituents selected from the group consisting of alkyls and halogens, provided that the halogens are not adjacent to the heteroatom. R 6 and R 7 are each independently 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- to 7-membered heterocycloalkyl, -(C 1～3- alkyl)-(4- to 7-membered heterocycloalkyl), -heteroaryl, and -(C 1～3 -alkyl)-(heteroaryl), selected from the group consisting of, and the last 15 members of the group of said R 6 and R 7 may each independently be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, and R 6 and R 7 may be linked to form a ring. R 8 and R 9 These are, independently, hydrogen and 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)-(C 2～6 -alkyl), -(C 2～3 -alkyl(oxy)-(C 3～6 -Cycloalkyl), 4-7 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 Selected from the group consisting of -alkyl)-(heteroaryl), the above R 8 and R 9 The last 14 members of the group may be optionally substituted with one or more halogens independently of each other, or R 8 and R 9 They may be connected to form a ring. R 10 is 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)-(C 2～6 -alkyl), -(C 2～3 -alkyl(oxy)-(C 3～6 -Cycloalkyl), 4-7 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 Selected from the group consisting of -alkyl)-(heteroaryl), the above R 10 The last 13 members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that such substitutions do not have to be geminal. Each R 11 These are, independently, hydrogen, halogen, and C 1～6 Alkyl, C 3～7 Cycloalkyl, 4-7 member heterocycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 11 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that R 11 If adjacent to oxygen, R 11 It is not a halogen, but two adjacent R 11 They may be connected to provide a condensed cycloalkyl, such as cyclopropyl. Each R 11a These are, independently, hydrogen, halogen, and C 1～6 Alkyl, C 3～7 Cycloalkyl, 4-7 member heterocycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 11 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that R 11 If adjacent to oxygen, R 11 It is not a halogen, but two adjacent R 11 They may be connected to provide a condensed cycloalkyl, such as cyclopropyl. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl groups, Each R 13 These are independently hydrogen, halogen, cyano, and 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 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -N-(R 5 )(R 5 ), -SO 2 -(R 5 ), -SO 2 -(R 5 )(R 5 ), -S(O)-(R 5 ), and -S-(R 5 Selected from the group consisting of the above R 13 The last 14 members of this group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. or its pharmaceutically acceptable salts, stereoisomers, or tautomers.

2. X 1 -C(R 6 )(R 7 )- and, X 2 -C(R 6 )(R 7 )- Select from or X 2 X 1 and X 3 Includes a union between, X 3 -C(R 6 )(R 7 )- and, R 1 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. R 2 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 2 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 3 These are, independently, hydrogen and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 3 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen, -C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 6 and R 7 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, R 6 and R 7 They may be connected to form a ring. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 Selected from the group consisting of alkyl groups, Each R 13 These are independently hydrogen, halogen, cyano, and 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 Selected from the group consisting of -alkyl and 4- to 7-membered heterocycloalkyl groups, the above R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 1.

3. X 1 -O- and -C(R 6 )(R 7 Selected from the group consisting of )-, X 2 -O- and -C(R 6 )(R 7 )- Selected from the group consisting of, X 2 X 1 and X 3 Includes a union between, X 3 -C(R 6 )(R 7 )- and, however, X 1 and X 2 Both cannot be -O-. R 1 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. R 2 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 2 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 3 These are, independently, hydrogen and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 3 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen, -C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 6 and R 7 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, R 6 and R 7 They may be connected to form a ring. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 Selected from the group consisting of alkyl groups, Each R 13 These are independently hydrogen, halogen, cyano, and 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 Selected from the group consisting of -alkyl and 4- to 7-membered heterocycloalkyl groups, the above R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 1.

4. R 1 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 2 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, Each R 3 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 The alkyl group may optionally be substituted with one or more halogens. R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and 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 Selected from the group consisting of -alkyl and 4- to 7-membered heterocycloalkyl groups, the above R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 1.

5. R 1 , R 2 , and R 3 It is hydrogen, R 4 is halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 The alkyl group may optionally be substituted with one or more halogens. Each R 11 These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two substituents may optionally be independently substituted with one or more halogens. Each R 11a These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two substituents may optionally be independently substituted with one or more halogens. R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and C 1～6 Alkyl, C 3～7 Cycloalkyl, and C 1～6 Selected from the group consisting of alkyl(oxy), the above R 13 The last three members of the group may be optionally substituted with one or more halogens, independently of each other. The compound according to claim 1.

6. Compounds of formula (Ia) or (Ib): 【Transformation 3】 [In the formula, X 1 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, X 2 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 )- Selected from the group consisting of, X 2 X 1 and X 3 Includes a union between, X 3 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, where X 1 and X 2 Both cannot be -O-, X 2 and X 3 Both cannot be -O-. R 1 is hydrogen, halogen (X 3 -C(R 7 )(R 8 )- if), hydroxy, C 1 ~ 6 Alkyl, C 3 ~ 7 Cycloalkyl, C 1 ~ 6 Alkyl (oxy), and C 3 ~ 7 Selected from the group consisting of cycloalkyl(oxy), the above R 1 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. R 2 is hydrogen, C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 2 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 3 These are, independently, hydrogen, halogen (X 1 -C(R 7 )(R 8 ) if C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 3 The last four members of the group may be optionally substituted with one or more halogens, independently of each other. R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkinyl, -CHO, Cyclopropyl, C 1 ~C 3 Haloalkyl, C 2 ~C 3 Haloalkenil, C 2 ~C 3 Selected from the group consisting of haloalkynyls and partially or completely halogenated cyclopropyls, A is benzo[c][1,2]oxabolol-1(3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxabolinin-1-ol, and 2H-benzo[e][1,2]oxabolinin-2-ol, or 7,8-dihydro-2H-1,6,9-trioxa-9-borabenzo[cd]azulene, or derivatives thereof, for example, A 1 ~A 7 : 【Chemistry 4】 A group consisting of parts selected from any one of the following, R 5 is 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 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 A selection from the group consisting of -alkyl)-(heteroaryl), with R other than hydrogen. 5 The above members of the group are C 1～6 The heteroatom may be optionally substituted independently with one or more substituents selected from the group consisting of alkyls and halogens, provided that the halogens are not adjacent to the heteroatom. R 6 and R 7 These are independently hydrogen, halogen, hydroxyl, and -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 member heterocycloalkyl, -(C 1～3- Alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 Selected from the group consisting of -alkyl)-(heteroaryl), the above R 6 and R 7 The last 15 members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, R 6 and R 7 They may be connected to form a ring. R 8 and R 9 These are, independently, hydrogen and 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)-(C 2～6 -alkyl), -(C 2～3 -alkyl(oxy)-(C 3～6 -Cycloalkyl), 4-7 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 Selected from the group consisting of -alkyl)-(heteroaryl), the above R 8 and R 9 The last 14 members of the group may be optionally substituted with one or more halogens independently of each other, or R 8 and R 9 They may be connected to form a ring. R 10 is 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 -alkyl)-(C 2～6 -alkyl), -(C 2～3 -alkyl(oxy)-(C 3～6 -Cycloalkyl), 4-7 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -heteroaryl, and -(C 1～3 Selected from the group consisting of -alkyl)-(heteroaryl), the above R 10 The last 13 members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that such substitutions do not have to be geminal. Each R 11 These are, independently, hydrogen, halogen, and C 1～6 Alkyl, C 3～7 Cycloalkyl, 4-7 member heterocycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 11 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that R 11 If adjacent to oxygen, R 11 It is not a halogen, but two adjacent R 11 They may be connected to provide a condensed cycloalkyl, such as cyclopropyl. Each R 11a These are, independently, hydrogen, halogen, and C 1～6 Alkyl, C 3～7 Cycloalkyl, 4-7 member heterocycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 11 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, provided that R 11 If adjacent to oxygen, R 11 It is not a halogen, but two adjacent R 11 They may be connected to provide a condensed cycloalkyl, such as cyclopropyl. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl groups, Each R 13 These are independently hydrogen, halogen, cyano, and 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 member heterocycloalkyl, -(C 1～3 -alkyl)-(4-7 member heterocycloalkyl), -N-(R 5 )(R 5 ), -SO 2 -(R 5 ), -SO 2 -(R 5 )(R 5 ), -S(O)-(R 5 ), and -S-(R 5 Selected from the group consisting of the above R 13 The last 14 members of this group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. or its pharmaceutically acceptable salts, stereoisomers, or tautomers.

7. X 1 -C(R 6 )(R 7 )- and, X 2 -C(R 6 )(R 7 )- Select from or X 2 X 1 and X 3 Includes a union between, X 3 -C(R 6 )(R 7 )- and, R 1 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. R 2 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 2 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 3 These are, independently, hydrogen and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 3 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the above R 6 and R 7 The last four members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls, R 6 and R 7 They may be connected to form a ring. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 Selected from the group consisting of alkyl groups, Each R 13 These are independently hydrogen, halogen, cyano, and 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 Selected from the group consisting of -alkyl and 4- to 7-membered heterocycloalkyl groups, the above R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 6.

8. R 1 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 2 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, Each R 3 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 4 is hydrogen, halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 The alkyl group may optionally be substituted with one or more halogens. R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and 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 Selected from the group consisting of -alkyl and 4- to 7-membered heterocycloalkyl groups, the above R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 6.

9. R 1 , R 2 , and R 3 It is hydrogen, R 4 is halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 The alkyl group may optionally be substituted with one or more halogens. Each R 11 These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two substituents may optionally be independently substituted with one or more halogens. Each R 11a These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two substituents may optionally be independently substituted with one or more halogens. R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and C 1～6 Alkyl, C 3～7 Cycloalkyl, and C 1～6 Selected from the group consisting of alkyl(oxy), the above R 13 The last three members of the group may be optionally substituted with one or more halogens, independently of each other. The compound according to claim 6.

10. Compounds selected from the group shown in Table 1 below: Table 1

11. X 1 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, X 2 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 )- Selected from the group consisting of, X 2 X 1 and X 3 Includes a union between, X 3 -C(R 6 )(R 7 )- and, however, X 1 and X 2 Both cannot be -O-. R 1 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. R 2 is hydrogen, C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. Each R 3 These are, independently, hydrogen and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyls, the last two members of the above group may be optionally substituted with one or more halogens independently of each other. R 4 is halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Alkyl, C 3～7 Cycloalkyl, C 1～6 Alkyl (oxy), and C 3～7 Selected from the group consisting of cycloalkyl(oxy), the last four members of the above group may be optionally independently substituted with one or more substituents selected from the group consisting of halogens and hydroxyls, R 6 and R 7 They may be connected to form a ring. Each R 12 These are, independently, hydrogen, halogen, and C 1～6 A compound according to claim 6, selected from the group consisting of alkyl groups.

12. X 1 is -O-, -N(R 5 )-, and -C(R 6 )(R 7 Selected from the group consisting of )-, X 2 -O- and -C(R 6 )(R 7 Selected from the group consisting of )-, where X 1 and X 2 Both cannot be -O-, or X 2 X 1 and X 3 Includes a union between, X 3 -C(R 6 )(R 7 )- and, R 1 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 2 is hydrogen and C 1～6 Selected from the group consisting of alkyl groups, Each R 3 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, R 4 is halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 Alkyl is sometimes substituted with one or more halogens. R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and 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 selected from the group consisting of 4- to 7-membered heterocycloalkyls, the R 13 The last seven members of the group may be optionally substituted independently of each other with one or more substituents selected from the group consisting of halogens and hydroxyls. The compound according to claim 6.

13. X 2 -C(R 6 )(R 7 )- and, X 3 -C(R 6 )(R 7 )- and, R 1 , R 2 , and R 3 It is hydrogen, R 4 is halogen, C 1 ~C 3 Alkyl and C 1 ~C 3 Selected from the group consisting of haloalkyls, R 6 and R 7 These are, independently, hydrogen and C 1～6 Selected from the group consisting of alkyl groups, C 1～6 Alkyl is sometimes substituted with one or more halogens. Each R 11 These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 11 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 11a These are, independently, hydrogen, halogen, and C 1～6 Alkyl and C 3～7 Selected from the group consisting of cycloalkyl, the above R 11 The last two members of the group may be optionally substituted with one or more halogens, independently of each other. Each R 12 It is hydrogen, Each R 13 These are independently hydrogen, halogen, cyano, and C 1～6 Alkyl, C 3～7 Cycloalkyl, and C 1～6 Selected from the group consisting of alkyl(oxy), the above R 13 The last three members of the group may be optionally substituted with one or more halogens, independently of each other. The compound according to claim 11.

14. Compounds selected from the group shown in Table 2 below: Table 2

15. Equations (Ia) and (Ib): 【Transformation 5】 The compound according to claim 10 or 14, which is a stereoisomer having the trans relative stereochemistry represented by .

16. The compound according to claim 10 or 14, wherein the compound is a single stereoisomer having trans relative stereochemistry.

17. The compound according to claim 16, wherein the compound has a trans stereochemistry represented by either formula (Ia) or formula (Ib).

18. A method for preparing the compound according to any one of claims 1, 6, 10, and 14.

19. A pharmaceutical composition for treating patients with diseases or disorders that are susceptible to JAK modulation, comprising a compound according to any one of claims 1, 6, 10, and 14.

20. The pharmaceutical composition according to claim 19, wherein the disease or disorder is a condition that can be improved by selective inhibition of Janus kinase JAK 1 compared to JAK 2.

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

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

23. The pharmaceutical composition according to claim 19, wherein the compound is administered in an amount that perturbs an immunomodulatory pathway in a cell.

24. The pharmaceutical composition according to claim 23, wherein the perturbation produces an effect on the JAK-STAT pathway.

25. A method for inhibiting JAK in mammalian cells, comprising contacting mammalian cells with a compound according to any one of claims 1, 6, 10, and 14 (excluding methods for treating humans).

26. The method according to claim 25, wherein the mammalian cells are cells from a subject having an inflammatory condition.

27. A composition comprising a compound according to any one of claims 1, 6, 10, and 14, and a pharmaceutically or veterinarily acceptable carrier.

28. A composition comprising a compound according to any one of claims 1, 6, 10, and 14, and one or more other pharmaceutically or veterinarily active substances in combination.

29. A pharmaceutical composition for treating one or more diseases or disorders among inflammation, autoimmune dysfunction, and cancer, comprising a compound according to any one of claims 1, 6, 10, and 14.

30. The pharmaceutical composition according to claim 29, wherein the disease or disorder is atopic dermatitis, flea allergy dermatitis, psoriasis, or rheumatoid arthritis.

31. The pharmaceutical composition according to claim 29, wherein the compound is administered orally, parenterally, or topically.

32. The pharmaceutical composition according to claim 29, wherein the target is a mammal.

33. The pharmaceutical composition according to claim 32, wherein the mammal is selected from one or more of domestic mammals, breeding mammals, and companion animals.

34. The pharmaceutical composition according to claim 32, wherein the mammal is selected from one or more of humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, and cats.

35. The pharmaceutical composition according to claim 32, wherein the mammal is a human, a dog, or a cat.

36. A pharmaceutical product comprising the compound described in any one of claims 1, 6, 10, and 14.

37. Use of the compound according to any one of claims 1, 6, 10, and 14 for the manufacture of a medicament for the treatment of one or more diseases or disorders among 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 a disease or disorder is improved by selective inhibition of Janus kinase JAK 1 compared to JAK 2.

40. Use of the compound according to any one of claims 1, 6, 10, and 14 and a second activator in the manufacture of a pharmaceutical for the treatment of a disease or disorder that can be improved by selective inhibition of Janus kinase JAK 1 compared to JAK 2.

41. Use of any one of the compounds according to claims 1, 6, 10, and 14 for the treatment of one or more diseases or disorders among inflammation, autoimmune dysfunction, and cancer (excluding use in humans).

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

Images