WO2021061823A1

WO2021061823A1 - Chemical compounds

Info

Publication number: WO2021061823A1
Application number: PCT/US2020/052284
Authority: WO
Inventors: Yong-Kang Zhang; Yasheen Zhou; Chunliang Liu; Chun Yu Liu; Marissa AUBREY
Original assignee: Boragen, Inc.
Priority date: 2019-09-23
Filing date: 2020-09-23
Publication date: 2021-04-01

Abstract

The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.

Description

CHEMICAL COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to each of US Provisional Application Serial No. 62/904,450 filed 23 September 2019 and US Provisional Application Serial No.62/949,278 filed 17 December 2019, each of which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present disclosure describes novel boron-containing compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound of the disclosure. BACKGROUND [0003] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys- regulation, or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases. Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2) play a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression, which stimulates biologic responses such as an itch signal. Activation of the JAK-STAT pathway also results in several other ancillary biologic activities that contribute to the inflammation and pruritic processes that contribute to acute allergy in animals but can also exacerbate clinical signs and contribute to chronic allergy. [0004] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease, affecting approximately 20% of children and up to 10% of adults and it imposes a significant financial and societal burden because of the direct medical costs and decreased productivity of individuals with AD. The burden of AD appears to be related mainly to the limited methods of treatment. Furthermore, according to the AD treatment guidelines, there is no standard of care and treatment may be tailored to an individual’s needs. Topical interventions are the mainstay of AD therapy. Until now, topical corticosteroids have been the first-line treatment. Their use, however, may be limited by potential local and systemic adverse effects. Topical calcineurin inhibitors are classified as second-line anti-inflammatory therapy for AD, with advantages in long-term maintenance and application to special sites. Topical calcineurin inhibitors inhibit calcineurin-dependent T-cell activation; however, a black box warning about a potential for developing malignant neoplasms with the use of topical calcineurin inhibitors reduces patients’ adherence to treatment. [0005] Psoriasis and psoriatic arthritis are associated with aberrant inflammation and the production of proinflammatory mediators. Psoriasis and psoriatic arthritis are inflammatory diseases with overlapping features and shared immunologic mechanisms. Psoriasis is a systemic disease in that it primarily affects the skin but up to 40% of individuals with psoriasis may go on to develop psoriatic arthritis. Psoriatic arthritis typically affects the peripheral joints and may occasionally affect the spine and sacroiliac area. Enthesitis, dactylitis, and nail changes such as pitting and discoloration are also common manifestations of psoriatic disease in patients with joint involvement. [0006] 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, Sjogren’s syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, artherosclerosis, and cancer. Reference is made to Schwartz et al., JAK inhibition as a therapeutic strategy for immune and inflammatory diseases, Nat Rev Drug Discov., 2017 Dec 28., 17(1):78, herein incorporated by reference with regard to the rationale for targeting JAKs. SUMMARY [0007] One embodiment of the present disclosure includes a compound of formula (I):

wherein: X is (CR^a2)g, wherein g is 1, 2, or 3; Z is (CR^a2)j, wherein j is 1, 2, or 3; each R^a is independently selected from the group consisting of: hydrogen, halogen, and C₁-C₆ hydrocarbyl; R¹ is selected from the group consisting of: H, (CH₂)nC(O)O(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)O(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₃-C⁶ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted aryl), (CH₂)nSO₂(substituted or unsubstituted heteroaryl), (CH₂)nSO₂(substituted or unsubstituted heterocyclyl), (CH₂)nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted aryl), (CH₂)nSO₂NH(substituted or unsubstituted heteroaryl), (CH₂)nSO₂NH(substituted or unsubstituted heterocyclyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted aryl), (CH₂)_nC(O)(substituted or unsubstituted heteroaryl), (CH₂)_nC(O)(substituted or unsubstituted heterocyclyl), C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl), substituted or unsubstituted aryl, substituted or unsubstituted C₃-C₆ cyclohydrocarbyl, and substituted or unsubstituted C₁-C₆ hydrocarbyl; and each n independently is 0, 1, 2, or 3, such that when n is 0, the group is absent, or a stereoisomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. [0008] In one aspect, the present disclosure provides a compound of formula (Ia):

[0009] One embodiment of the present disclosure includes a compound of formula (II),

wherein: R¹ is selected from the group consisting of: H, (CH₂)nC(O)O(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)O(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted aryl), (CH₂)nSO₂(substituted or unsubstituted heteroaryl), (CH₂)nSO₂(substituted or unsubstituted heterocyclyl), (CH₂)nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted aryl), (CH₂)nSO₂NH(substituted or unsubstituted heteroaryl), (CH₂)nSO₂NH(substituted or unsubstituted heterocyclyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)-substituted or unsubstituted aryl, (CH₂)nC(O)(substituted or unsubstituted heteroaryl), (CH₂)nC(O)(substituted or unsubstituted heterocyclyl), C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl), substituted or unsubstituted aryl, substituted or unsubstituted C₃-C₆ cyclohydrocarbyl, and substituted or unsubstituted C₁-C₆ hydrocarbyl; each n independently is 0, 1, 2, or 3, such that when n is 0, the group is absent; X is (CR^a2)g, wherein g is 1, 2, or 3, Z is a bond or (CR^a2)j, wherein j is 1, 2, or 3; each R^a, where present, is independently selected from the group consisting of: hydrogen, halogen, and C₁-C₆ hydrocarbyl, and a) E is a bond or (CH₂)k, where k is 1, 2, or 3, wherein: R² is selected from the group consisting of hydrogen, C₁-C₆ hydrocarbyl, and C₁-C₆ halohydrocarbyl; and A is hydrogen, C₁-C₆ hydrocarbyl, or C₁-C₆ halohydrocarbyl; or b) E is a bond or (CH₂)_k, where k is 1, 2, or 3, wherein: R² is absent; and A is (CH₂)_m where m is 1, 2, or 3, and A is taken together with the depicted nitrogen atom to form a 3 to 8 membered ring, or a stereoisomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. [0010] With regard to the embodiments when E is a bond, R² is absent, and A is taken together with the depicted nitrogen bound to R¹, namely the atom circled below:

. [0011] In one aspect, the present disclosure provides a compound selected from a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) and (IIf):

[0012] In one aspect, the present disclosure provides a compound of formula (IIa). [0013] In one aspect, the present disclosure provides wherein R¹ is other than hydrogen and is substituted with one or more halogen, haloalkyl, R', OR', OH, SH, SR', NO₂, CN, C(O)R', C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO₂H, NHCO₂R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO₂R', CO₂H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO₂NH2, S(O)H, S(O)R', SO₂NHR', SO₂NR’(CH₂)_1-3SO₂NHR’, SO₂N(R')₂, NHS(O)₂H, NR'S(O)₂H, NHS(O)2R', NR'S(O)2R', Si(R')3, =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO₂R', =NNHCO₂H, =NNHSO₂R', =NNHSO₂H, =N-CN, =NH, and =NR', wherein each R’ is the same or different and is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. [0014] In one aspect, the present disclosure provides R’ is further substituted with at least one halogen, C₁-C₆ hydrocarbyl, C_3-6 cyclohydrocarbyl, or CN. [0015] In one aspect, the present disclosure provides R¹ is substituted with at least one fluorine or CN. [0016] In one aspect, the present disclosure provides R¹ is selected from H, (CH₂)_nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)_nSO₂(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)_n SO₂(substituted or unsubstituted aryl), (CH₂)_nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)_nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)_nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)_nC(O)(substituted or unsubstituted aryl), and C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl). [0017] In one aspect, the present disclosure provides R¹ is selected from the group consisting of:

. [0018] In one aspect, n is 0, such that the alkylene linker is absent. [0019] In one aspect, each occurrence of aryl is phenyl. [0020] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

[0021] or a stereoisomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. [0022] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically accetpable salt thereof selected from the group consisting of:

[0023] or a stereoisomer thereof. [0024] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

[0025] or a stereoisomer thereof. [0026] One embodiment of the present disclosure includes a method for treating a patient having a disease or disorder susceptible to modulation of JAK 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, psoriasis, psoriatic arthritis, Bechet’s disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren’s syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, artherosclerosis, and cancer. In one aspect, the disease or disorder is one or more of atopic dermatitis, psoriasis, and rheumatoid arthritis. In one aspect, the compound is administered in an amount to perturb an immune regulatory pathway in a cell. In one aspect, the perturbation results in an effect on the JAK- STAT pathway. [0027] One embodiment of the present disclosure includes a method of inhibiting JAK in a mammalian cell 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. [0028] One embodiment of the present disclosure includes acomposition comprising a compound of the present disclosure and a pharmaceutically or veterinary acceptable carrier. [0029] One embodiment of the present disclosure includes acombination comprising a compound of of the present disclosure, and one or more other pharmaceutical or veterinary active substances. [0030] One embodiment of the present disclosure includes a method for treating one or more diseases or disorders of inflammation, auto-immune dysfunction, and cancer comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis. In one aspect, the subject is a mammal. In one aspect, the mammal is selected from humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, livestock mammals, domestic mammals, or companion mammals. [0031] One embodiment of the present disclosure includes a compound of the present disclosure for use in medicine. [0032] 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 disorder of inflammation, auto-immune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis. [0033] One embodiment of the present disclosure includes use of a compound of the present disclosure for the treatment of one or more diseases or disorders of inflammation, auto-immune dysfunction, and cancer. In one aspect, the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis. [0029] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

[0030] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of one or more of the following compounds:

PCT Application 81826-323777 BOR-117-WO

PCT Application 81826-323777 BOR-117-WO O _{2 O} ^O H S ³ OH N H B O O H_O ^B O S N ^N H N O BN102923 O H_O ^B O N N H N S O BN102934 O O ^B N ^N H BN102922

[0031] One embodiment of the present disclosure includes a compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of one or more of the following compounds: 59

60

61

a

[0032] One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments may be combined in any way or combination. BRIEF DESCRIPTION OF THE DRAWINGS [0033] The foregoing and other aspects of the embodiments disclosed herein may be further understood from the following detailed description when read in connection with the accompanying drawings. For the purposes of illustrating the embodiments disclosed herein, there is shown in the drawings embodiments that are presently preferred, it being understood, however, that the embodiments disclosed herein are not limited to the specific instrumentalities disclosed. Included in the drawings are the following figures. [0034] Figure 1, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 1 are intended as general and do not necessarily align with the variable designations otherwise herein described. [0035] Figure 2, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 2 are intended as general and do not necessarily align with the variable designations otherwise herein described. [0036] Figure 3, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 3 are intended as general and do not necessarily align with the variable designations otherwise herein described. [0037] Figure 4, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 4 are intended as general and do not necessarily align with the variable designations otherwise herein described. [0038] Figures 5 and 6 represent tables of examples of biological activity of the compounds of the present disclosure. [0039] Figure 7, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 7 are intended as general and do not necessarily align with the variable designations otherwise herein described. [0040] Figures 8a and 8b, in accordance with embodimetns of the present disclosure, illustrate a schematic representation of a synthetic scheme for making the compounds of the present disclosure. The variable designations in Figures 8a and 8b are intended as general and do not necessarily align with the variable desginations otherwise herein described. Figure 8a provides structures of pyrrolopyridine spirooxaborole piperidine compounds of the present disclosure. Figure 8b provides a scheme for preparation of the compounds of the present disclosure, including but not limited to those decpited in Figure 8a. The compound numbering and variable designation of Figure 8a relates to Figure 8b but is indepdent of the remainder of the present disclosure. [0041] While embodiments of the present disclosure are described herein by way of example using several illustrative drawings, those skilled in the art will recognize the present disclosure is not limited to the embodiments or drawings described. It should be understood the drawings and the detailed description thereto are not intended to limit the present disclosure to the form disclosed, but to the contrary, the present disclosure is to cover all modification, equivalents and alternatives falling within the spirit and scope of embodiments of the present disclosure as recited by the appended claims. DETAILED DESCRIPTION Definitions [0042] Any reference in the specification to “one embodiment” or “an embodiment” or “another embodiment” or a similar phrase means that a particular feature, structure, characteristic, operation, or function being described is included in at least one embodiment. Thus, any appearance of the phrases “in one embodiment” or “in an embodiment” in the specification is not necessarily referring to the same embodiment. Further, the particular features, structures, characteristics, operations, or functions may be combined in any suitable manner in one or more embodiments, and it is intended that embodiments of the described subject matter can and do cover modifications and variations of the described embodiments. Particular aspects, as used herein, should be treated in a similar manner. [0043] The phrases “at least one”, “one or more”, and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B, and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together. [0044] The term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” may be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” may be used interchangeably. [0045] A compound of this disclosure includes those described generally, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, “Handbook of Chemistry and Physics”, 75th Ed., CRC Press, New York, NY (1995). Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, CA (1999), and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York, NY (2001), “Plant Pathology”, 5^th Ed., Gore N Agrios, Elsevier Academic Press, Cambridge, MA (2005), the entire contents of which are hereby incorporated by reference. [0046] The term “hydrocarbyl” refers to a monovalent moiety formed by removing a hydrogen atom from a hydrocarbon. The term ‘hydrocarbyl’ includes alkyl groups, alkenyl groups, and alkynyl groups. A preferred “hydrocarbyl” group is an “alkyl” group. Representative hydrocarbyl groups are alkyl groups having 1 to 25 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, decyl, dodecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, and tricosyl, and the isomeric forms thereof such as iso-propyl, t-butyl, iso- butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethyl-butyl; alkenyl groups having 2 to 25 carbon atoms, such as methenyl, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl and the isomeric forms thereof; alkynyl groups having 2 to 25 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, and octynyl, and the isomeric forms thereof. A hydrocarbyl group may also be substituted with a “cyclohydrocarbyl” group. Accordingly, groups such as 2-(cyclopropyl)-ethyl, cyclohexylmethyl, cyclopropylethyl, and cyclopropylmethyl, are contemplated hydrocarbyl groups. [0047] In some embodiments, a “hydrocarbyl” contains 1 to 6 members (C₁-C₆), or for alkenyl or alkynyl groups 2 to 6 members (C₂-C₆). In other embodiments, the hydrocarbyl contains 1 to 3 members (C1-C3), or for alkenyl or alkynyl groups 2 to 3 members (C2-C3). In yet other embodiments, the hydrocarbyl may contain from 1 to 17 substitutions, or in another embodiment from 1 to 5 substitutions. The hydrocarbyl may also contain one or more substitutions. When a hydrocarbyl is substituted with one or more halogen, including up to per-halogenation, the resulting group may be referred to as a “halohydrocarbyl.” [0048] In some embodiments, a hydrocarbyl may be attached through an oxygen atom and be referred to as a hydrocarbyloxy, or, in certain aspects, as alkoxy. [0049] The term “cyclohydrocarbyl”, by itself or part of another substituent, unless otherwise stated, refers to a cyclic hydrocarbyl group which may be fully saturated, monounsaturated, or polyunsaturated but not aromatic, and includes C₃-C₁₅ hydrocarbons in a ring system. The cyclohydrocarbyl group may contain one or more substitutions. In one embodiment, the ring contains 3 to 6 members (C₃-C₆). [0050] In another embodiment, a cyclohydrocarbyl group may have from 1 to 11 substitutions, or in another embodiment from 2 to 6 substitutions. Examples of cyclohydrocarbyl groups include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, cyclohex-1-enyl, cyclohex-3- enyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamant-1-yl, adamant-2-yl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]-hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo-[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl, and the like. [0051] Similarly, a “heterocyclyl,” refers to a cyclohydrocarbyl where one or more ring atom is replaced with a heteroatom. Thus, the term “heterocyclyl” refers to a substituted or unsubstituted, unsaturated or partially saturated hydrocarbon ring, containing from 3 to 15 ring atoms, wherein one or more carbon atom is replaced with a heteroatom selected from O, N, S, or Si, where each N, S, or Si may be oxidized, and where each N may be quarternized. A heterocyclyl group may be attached to the remainder of the molecule through a heteroatom. [0052] The term "aryl", unless otherwise stated, used alone or as part of a larger moiety as in “arylalkyl”, is an aromatic cyclohydrocarbyl group that is monocyclic or polycyclic containing up to three fused rings, preferably up to two fused rings, and more preferably, monocyclic. Examples of aryl groups include, but are not limited to unsubstituted phenyl, naphthyl, anthracenyl, and phenanthryl and substituted phenyl, naphthyl, anthracenyl, and phenanthryl groups. [0053] Unsubstituted phenyl, unsubstitued naphthyl, substituted phenyl, and substituted naphthyl groups are preferred aryl groups, with unsubstituted phenyl and substituted phenyl groups being more preferred. In one embodiment, the ring system may have 1 to about 5 substitutions, or in another embodiment 2 to 3 substitutions are present on the ring system. In one embodiment, the ring system has 1 substitution. [0054] The term “phenyl” as used herein is a C₆H₅ group. The term “phenyl” may be abbreviated herein as “Ph”. “Phenyl” groups may be substituted. Similarly, the term “naphthyl” as used herein is a C₁₀H₇ group. “Naphthyl” groups may be substituted. [0055] The term "heteroaryl", unless otherwise stated, used alone or as part of a larger or smaller moiety as in “aryl”, contain from one to four heteroatoms selected from nitrogen, oxygen, and sulfur, where the nitrogen and sulfur atoms are optionally oxidized, and one or several nitrogen atoms are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. [0056] A heteroaryl group may contain one ring or two fused rings. Non-limiting examples of heteroaryl groups include, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 1-imidizoyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzo-thiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Non-limiting examples of heteroaryl groups include pyridine, thiophene, thiazole, imidazole, benzimidazole, pyrazole, and oxazole. [0057] The terms "arylalkyl" and "heteroarylalkyl" is meant to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth- 1-yloxy)propyl, and the like). The term “benzyl” as used herein referes to a group in which a phenyl group is attached to a CH₂ group (i.e. a CH₂Ph group). The term substituted benzyl refers to a group in which either the CH₂ linker or the phenyl group contains one or more substitutions. In one embodiment, the substituted phenyl group may have 1 to 5 substitutions, or in another embodiment 2 to 3 substitutions. [0058] Each of the above terms "hydrocarbyl", "cyclohydrocarbyl", “heterocyclyl”, "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl" may be present in substituted and unsubstituted forms of the indicated radical unless otherwise stated. The "hydrocarbyl", "cyclohydrocarbyl", “heterocyclyl”, "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl" groups are optionally substituted by one or more groups that may be the same or different and which are, independently, selected from halogen, haloalkyl, R', OR', OH, SH, SR', NO₂, CN, C(O)R', C(O)OR', OC(O)R', CON(R')₂, OC(O)N(R')₂, NH₂, NHR', N(R')₂, NHCOR', NHCOH, NHCONH₂, NHCONHR', NHCON(R')₂, NRCOR', NRCOH, NHCO₂H, NHCO₂R', NHC(S)NH₂, NHC(S)NHR', NHC(S)N(R')₂, CO₂R', CO₂H, CHO, CONH₂, CONHR', CON(R')₂, S(O)₂H, S(O)₂R', SO₂NH₂, S(O)H, S(O)R', SO₂NHR', SO₂NR’(CH₂)_1-3SO₂NHR’, SO₂N(R')₂, NHS(O)₂H, NR'S(O)₂H, NHS(O)₂R', NR'S(O)₂R', Si(R')₃, =O, =S, =NNHR', =NNH₂, =NN(R')₂, =N-OR', =N- OH, =NNHCOR', =NNHCOH, =NNHCO₂R', =NNHCO₂H, =NNHSO₂R', =NNHSO₂H, =N-CN, =NH, and =NR', wherein each R’ is the same or different and is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. In one aspect, R¹ is further substituted with at least one halogen, C₁-C₆ hydrocarbyl, C_3-6 cyclohydrocarbyl, or CN. A saturated carbon atom of any such "hydrocarbyl", "cyclohydrocarbyl", “heterocyclyl”, "alkoxy", "aryl", "heteroaryl", "arylalkyl", or "heteroarylalkyl" groups may be optionally substituted as long as valency allows. Thus, in embodiments where a saturated carbon atom is optionally substituted with one or more substituent groups, the substituents may be the same or different and 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 the foregoing, each occurrence of R' is, independently, selected from "hydrocarbyl", "cyclohydrocarbyl", “heterocyclyl”, "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl”. [0059] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S). The heteroatoms oxygen and nitrogen are preferred. [0060] As used herein, the phrase veterinary or veterinarily, or pharmaceutical or pharmaceutically acceptable salt refers to any salt of a compound disclosed herein which retains its biological properties and which is not toxic or otherwise undesirable for veterinary or pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter- ions known in the art. Such salts include acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4- chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and like acids. [0061] Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as halides, such as, chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane- disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like. [0062] Examples of inorganic bases that 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. [0063] Examples of organic bases that may be used to form base addition salts include, but are not limited to, metal alkoxides, such as lithium, sodium, and potassium alkoxides including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium hydroxides, such as choline hydroxide; and amines including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines. [0064] According to embodiments of the present disclosure, the base may be a quaternary ammonium hydroxide, wherein one or more of the alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that may be used in accordance with the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide, and is preferably choline hydroxide. According to embodiments of the present disclosure, an alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that may be used in accordance with the present disclosure include methylamine, ethylamine, diethylamine, and triethylamine. A substituted alkylamine base is preferably substituted with one or more hydroxyl groups, and preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that may be used in accordance with the present disclosure include 2-(diethylamino)ethanol, Ν,Ν-dimethylethanolamine (deanol), tromethamine, ethanolamine, and diolamine. [0065] In certain cases, the depicted substituents may contribute to optical isomers and/or stereoisomerism. Compounds having the same molecular formula but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “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 with at least one stereocenter may 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 may be characterized by the manner in which the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (namely, as (+)- or (-)-isomers, respectively). A chiral compound may exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture”. [0066] In certain embodiments, the compounds disclosed herein may possess one or more asymmetric centers, and such compounds may therefore be produced as a racemic mixture, an enantiomerically enriched mixture, or as an individual enantiomer. In certain embodiments, the compounds disclosed herein may be tautomers. Tautomers occur when each of two or more isomers of a compound exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule. Moreover, in certain embodiments, the compounds disclosed herein may possess axial chirality. Atropisomers are an example of stereoisomers that exhibit axial chirality. Unless indicated otherwise, for example by designation of stereochemistry at any position of a formula, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures, racemic or otherwise, thereof. Methods for determination of stereochemistry and separation of stereoisomers are well-known in the art. [0067] 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 those of skill in the art. Of course, this level of purity may be less than 100%. In certain embodiments, “stereochemically pure” designates a compound that is substantially free, i.e. at least about 85% or more, of alternate isomers. In particular embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free of other isomers. [0068] 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 cat. In a further embodiment, the subject is an animal such as a sheep, cow, horse, goat, fish, pig, or domestic fowl (such as a chicken, turkey, duck, or goose). In another embodiment, the subject is a primate such as a monkey such as a cynomolgous monkey or a chimpanzee. [0069] In addition, a pharmaceutically acceptable prodrug of the compound represented by the formula (I) and (II) is also included in the present disclosure. The pharmaceutically acceptable prodrug refers to a compound having a group which may be converted into an amino group, a hydroxyl group, a carboxyl group, or the like, by solvolysis or under a physiological condition. Examples of the groups forming the prodrug include those as described in Prog. Med., 5, 2157- 2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol.7, Drug Design, 163-198. The term prodrug is used throughout the specification to describe any pharmaceutically acceptable form of a compound which, upon administration to a patient, provides the active compound. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present disclosure. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that may be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. [0070] The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the disclosure wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certain isotopically-labelled compounds of the disclosure, such as those incorporating a radioactive isotope, may be useful in drug or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the disclosure may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Compositions and Methods of Administration [0071] The compounds of formula (I) and (II) used in the methods disclosed herein may be administered in certain embodiments using veterinary or pharmaceutical compositions including at least one compound of formula (I) and (II), if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and veterinary or pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent. There are provided compositions which comprise a derivative of formula (I) and (II) or a salt thereof, and an acceptable excipient, carrier or diluent. The composition may also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal, or subdermal formulations. [0072] The composition may be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of veterinary or pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide elegant and palatable preparations. [0073] Lozenges are solid compositions containing one or more active ingredients intended to dissolve or disintegrate slowly in the oral cavity by passive incubation in the oral cavity, or actively by sucking or chewing. They may be used for systemic effect if the drug is absorbed through the buccal or esophageal lining or is swallowed. In particular, soft lozenges may be chewed or allowed to dissolve slowly in the mouth. These dosage forms have the advantage of being flavored and thus easy to administer to both human and animal patients; have formulas that are easy to change and may be patient specific; may deliver accurate amounts of the active ingredient to the oral cavity and digestive system; and allow for the drug to remain in contact with the oral or esophageal cavity for an extended period of time. [0074] Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. [0075] Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. [0076] The compositions may also be in the form of oil-in-water or water-in-oil emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, bittering agents, flavoring agents, and preservatives. [0077] In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids. Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously. In one embodiment of the oily phase, the oily phase may be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oily phase, the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C8-C10 caprylic/capric triglyceride. In another embodiment, the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion. The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion. Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, the cosurfactants include short-chain alcohols, such as ethanol and propanol. Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment for the amount of surfactant/cosurfactant, the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. [0078] In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion. [0079] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives. [0080] Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occuring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above. [0081] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring and coloring agents, may also be present. [0082] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and coloring agent(s). [0083] The compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. Preservatives, such as phenol or benzyl alcohol, may be used. [0084] In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0085] Topical, dermal and subdermal formulations may include emulsions, creams, ointments, gels or pastes. [0086] Organic solvents that may be used in the disclosure include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents. [0087] As vehicle or diluent, compositions of the present disclosure may include plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8- C12) triglycerides. [0088] Dosage forms may contain from about 0.5 mg to about 5 g of an active agent. [0089] In one embodiment of the disclosure, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume. [0090] A compound according to one or more of formula (I) and (II) may be employed as such or in the form of their preparations or formulations as combinations. [0091] A compound according to one of more of formula (I) and (II) according to the disclosure may be combined with one or more agents having the same sphere of activity, for example, to increase activity, or with substances having another sphere of activity, for example, to broaden the range of activity. As an example, a combination of a compound of formula (I) and (II) with one or more of an additional JAK inhibitor or a JAK/Signal Transducer and Activator of Transcription (JAK/STAT) modulator may offer therapeutic advantage. Examples of JAK inhibitors that may be useful as combination agents include Baricitinib, Ruxolitinib, Filgotinib, CYT387, Upadacitinib, Fedratinib, Peficitinib, Lestaurtinib, Pacritinib, Oclacitinib, Cerdulatinib, and Tofacitinib. [0092] The compounds according to one or more of formula (I) and (II) according to the disclosure may be combined with one or more additional active agents. Further additional active agents which may be used in the methods provided herein in combination with a compound of formula (I) and (II) include, but are not limited to, disease-modifying anti-rheumatic drugs (DMARDs such as cyclosporine A and methotrexate), anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), immnunosuppressants, mycophenolate mofetil, biologic agents, TNF-a inhibitors (such as etanercept), Cox-2 inhibitors, and analgesics. These agents may include but are not limited to cyclosporin A, e.g. Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate, e.g., Cellcept®, azathioprine, e.g. Imuran®, daclizumab, e.g. Zenapax®, OKT3, e.g. Orthocolone®, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids, e.g. prednisolone or dexamethasone. [0093] In some embodiments, the second active agents may include, but are not limited to, anti- inflammatories such as NSAIDs including, but not limited to, diclofenac (e.g., ARTHROTEC®), diflunisal (e.g., DOLOBID^®), etodolac (e.g., LODINE®), fenoprofen (e.g., NALFON®), ibuprofen (e.g., ADVIL®, CHILDREN'S ADVIL/MOTRIN®, MEDIPREN®, MOTRIN®, NUPRIN®, or PEDIACARE FEVER®), indomethacin (e.g., ARTHREXIN®), ketoprofen (e.g., ORUVAIL®), ketorolac (e.g., TORADOL®), fosfomycin tromethamine (e.g., MONURAL®), meclofenamate (e.g. , MECLOMEN^®), nabumetone (e.g., RELAFEN®), naproxen (e.g. , ANAPROX^®, ANAPROX^® DS, EC-NAPROSYN®, NAPRELAN^® or NAPROSYN®), oxaprozin (e.g., DAY PRO® ), piroxicam (e.g., FELDENE®), sulindac (e.g., CLINORIL®), and tolmetin (e.g., TOLECTIN® DS or TOLECTIN®). [0094] In other embodiments, the second active agents may include, but are not limited to, disease-modifying antirheumatic drugs (DMARDs) or immnunosuppressants such as, but not limited to, methotrexate (RHEUMATREX®), sulfasalazine (AZULFIDINE®), and cyclosporine (SANDIMMUNE^® or NEROAL®; and including cyclosporine A). [0095] In other embodiments, the second active agents may include, but are not limited to, mycophenolate mofetil (CellCept^®), an immunosuppressive agent widely used in organ transplantation and gaining favor in treating autoimmune and inflammatory skin disorders. [0096] In further embodiments, the second active agents may include, but are not limited to, biologic agents such as etanercept (ENBREL®), infliximab (REMICADE^®) and adalimumab (HUMIRA®). [0097] In further embodiments of interest, the second active agents may include, but are not limited to Cox-2 inhibitors such as celecoxib (CELEBREX®), valdecoxib (BEXTRA®) and meloxicam (MOBIC^®). [0098] These one or more additional active agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. [0099] The pharmaceutical preparation comprising the compounds of formula (I) and (II), for delivery to a human or other mammal, is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component. The unit dosage form may be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet or lozenge itself, or it may be an appropriate number of any of these in packaged form. [0100] The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component. The composition may, if desired, also contain other compatible therapeutic agents. [0101] In therapeutic use for the treatment or alleviation of inflammation, auto-immune diseases, and cancer in a human or other mammal, the compounds utilized in the method of treatment 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 may be daily, weekly, monthly, quarterly, semi- annually, or annually. The dosages may be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound(s) being used. Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner. Generally, the treatment will be initiated with smaller dosages, which are less than the optimum dose of the compound, which may be increased in small increments until the optimum effect under the particular circumstances of the condition is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. [0102] In therapeutic use, the compounds of formula (I) and (II) are useful in manufacture of a medicament for a method of the treating any indication where inhibition of JAK would be desirable, including but not limited to cancer, neuroinflammation, inflammatory airway diseases, ankylosing spondylitis, inflammatory bowel diseases, rheumatoid arthritis, psoriasis, and atopic dermatitis. In one or more embodiment, a compound of formula (I) and (II) is useful in the treatment of one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet’s disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren’s syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, artherosclerosis, and cancer. [0103] The present disclosure explicitly encompasses those compounds presented below including salt forms thereof. A composition comprising a therapeutically acceptable amount of any of these compounds is also within the scope of the disclosure. The composition may further comprise a pharmaceutically or veterinary acceptable excipient, diluent, carrier, or mixture thereof. Such a composition may be administered to a subject in need thereof to treat or control a disease or disorder mediated, in whole or in part, directly or indirectly, by JAK. The composition may further comprise an additional active agent, as described herein. [0104] Compound Lists [0105] The present disclosure includes the following compounds, as well as stereoisomers thereof. As one example, compounds of the present disclosure may contain one or more chiral center. As another example, compounds of the present disclosure may exhibit axial chirality, such as, for example, the following isomers:

, where a depiction of one isomer is intended to include the alternative isomer, unless particular specificity is indicated, such as upon separation and testing of the individual compounds. The dfferent stereoisomers may have substantially different biological effects, which is not capable of prediction. [0106] Compound List [0107] Embodiments of the present disclosure are provided in the following list, where an aspect of compound activity is noted. For each list, this disclosure includes any isomer of each compound, as well as a veterinary or pharmaceutically acceptable salt thereof. The (*) symbols indicate preferential activity, where the greater number identifies the most preferred compounds.

EXAMPLES Experimental Procedures: [0108] The following examples provide a more detailed description of the process conditions for preparing compounds of the present disclosure. It is to be understood, however, that the disclosure, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation. In the examples, certain abbreviations may be used. Those skilled in the art will appreciate the abbreviated terms. SYNTHETIC EXAMPLES [0109] Procedure – Pyrrolopyridine Oxaborole Dispiro Compounds [0110] 1-(Propylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0111] The title compound was prepared by the scheme and procedures shown below:

[0112] To a stirring solution of PPh3CH3Br (96.5 g, 270 mmol) in Et2O (1000 mL) was added t- BuOK (30.3 g, 270 mmol) and the mixture was stirred at rt for 1h before being treated with a solution of N-Boc-3-pyrrolidinone (50.0 g, 270 mmol) in Et₂O (500 mL). The resulting mixture was stirred at room temperature overnight, and then it was poured into water and extracted with EtOAc. The organic layer was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1) to give the desired compound tert-butyl 3- methylenepyrrolidine-1-carboxylate (29.0 g, yield 58%) as a light oil.¹H NMR (300 MHz, CDCl₃): δ 4.96 (s, 2H), 3.91 (s, 2H), 3.45 (s, 2H), 2.66-2.42 (m, 2H), 1.46 (s, 9H) ppm. To a suspension of the obtained tert-butyl 3-methylenepyrrolidine-1-carboxylate (10.0 g, 54.6 mmol) in Et₂O (75 ml) was added Zn-Cu (28.1 g, 21.8 mmol) at 10^oC under N2 atmosphere. A solution of CCl3CCOCl (19.8 g, 109 mmol) in dimethoxyethane (DME, 75 mL) was added. The mixture was stirred at room temperature overnight, and then it was quenched with aqueous NaHCO3 and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel chromatography to give tert-butyl 1,1-dichloro-2-oxo-6-azaspiro[3.4]octane-6-carboxylate (7.5 g, yield 47%) as a light-yellow oil.¹H NMR (300 MHz, CDCl₃): δ 4.00-3.80 (m, 1H), 3.75-3.29 (m, 4H), 3.29-3.12 (m, 1H), 2.57-2.39 (m, 1H), 2.02-1.88 (m, 1H), 1.48 (s, 9H) ppm. To a solution of tert-butyl 1,1-dichloro-2-oxo-6-azaspiro[3.4]octane-6-carboxylate (7.5 g, 25.6 mmol) in MeOH (80 mL) were added Zn (16.6 g, 256 mmol) and saturated NH4Cl (30 mL). The reaction mixture was stirred at room temperature for 3h. It was filtered and the filtrate was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl 2-oxo- 6-azaspiro[3.4]octane-6-carboxylate (5.2 g, yield 90%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 3.61-3.34 (m, 4H), 3.20-2.87 (m, 4H), 2.11-1.98 (m, 2H), 1.46 (s, 9H) ppm. MS: m/z =248.2 (M+Na)⁺. A solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 10.5 mmol) in THF (100 mL) was added i-PrMgCl-LiCl (10.5 mL, 13.7 mmol) at -20^oC under N₂. The reaction was stirred at -20^oC for 1h. To it was added slowly a solution of tert-butyl 2- oxo-6-azaspiro[3.4]octane-6-carboxylate (2.4 g, 10.5 mmol) in THF (50 mL). The reaction mixture was warmed to room temperature for 2h, then quenched with H₂O and extracted with EtOAc. The organic layer was concentrated and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl 2-(5-bromo-1-(triisopropylsilyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, yield 17%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, 1H), 7.30 (s, 1H), 6.59 (d, J = 3.5 Hz, 1H), 3.81-3.61 (m, 2H), 3.45-3.25 (m, 2H), 2.96-2.71 (m, 4H), 1.86-1.78 (m, 5H), 1.48 (s, 9H), 1.10 (d, J = 6.8 Hz, 18H) ppm. MS: m/z =578.2 and 580.2 (M+H)⁺. To a solution of tert-butyl 2- (5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-6-azaspiro[3.4]octane-6- carboxylate (360 mg, 0.62 mmol) in THF (15 mL) were added (BPin)2 (304 mg, 1.2 mmol), KOAc (176 mg, 1.8 mmol) and Pd(dppf)Cl2 (196 mg, 0.24 mmol) under N2 atmosphere. The reaction was stirred at 75^oC overnight, and then it was filtered, and the filtrate was concentrated. The residue was dissolved in THF (10 mL), and 6N HCl (2 mL) was added. The mixture was stirred for 30 min and extracted with EtOAc. The organic layer was concentrated to give a black solid (450 mg). It was mixed with DCM (5 mL) and TFA (1 mL), and the mixture was stirred for 2h. The solution was concentrated under reduce pressure to give the crude dispiro[pyrrolidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (400 mg) as a black solid. To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (400 mg, crude) in DCM (10 mL) were added Et3N (101 mg, 1.0 mmol) and propane-1-sulfonyl chloride (142 mg, 1.0 mmol) at 0^oC. The reaction mixture was stirred at 0^oC for 2h, and then it was poured to water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by pre-HPLC (NH₄OH in CH3CN and H2O) to give the desired product 1-(propylsulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (12 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 7.61 (t, J = 2.8 Hz, 1H), 6.72 (dd, J = 3.4, 1.6 Hz, 1H), 3.63 (s, 2H), 3.40-3.35 (m, 2H), 3.16-3.03 (m, 2H), 2.87-2.83 (m, 2H), 2.34-2.30 (m, 2H), 2.20 (t, J = 7.0 Hz, 2H), 1.76-1.70 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 95.60 % at 210 nm. MS: m/z =376.1 (M+H)⁺. [0113] 3''-Hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0114] The title compound was prepared by the scheme and procedures shown below:

[0115] To a solution of 2,2,2-trifluoroethanamine (99 mg, 1.0 mmol) in DCM (10 mL) was added CDI (162 mg, 1.0 mmol) and the reaction was stirred at room temperature for 30 min. A solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (400 mg, crude) in DCM (2 mL) was added, and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified by pre-HPLC (NH4OH in ACN and H2O) to give the desired product 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''- dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxamide (11.7 mg, yield 5% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 9.28 (s, 1H), 8.50 (s, 1H), 7.61 (t, J = 3.0 Hz, 1H), 6.87 (t, J = 5.6 Hz, 1H), 6.71 (dd, J = 3.4, 1.6 Hz, 1H), 3.88-3.75 (m, 2H), 3.66 (s, 2H), 3.40-3.34 (m, 2H), 2.82 (d, J = 13.5 Hz, 2H), 2.33- 2.26 (m, 2H), 2.19-2.10 (m, 2H) ppm. HPLC purity: 98.61% at 210 nm and 97.29% at 254 nm. MS: m/z =395.1 (M+H)⁺. [0116] 1-(isobutylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0117] The title compound was prepared by the scheme and procedures shown below:

[0118] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (300 mg, crude) in Et2O (10 mL) were added aqueous NaOH (0.4 mL, 20%) and 2-methylpropane-1-sulfonyl chloride (156 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1h, then it was poured into water and extracted with DCM/MeOH (10:1). The organic layer was concentrated and the residue was purified by pre-HPLC to give the desired product 1- (isobutylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (34.9 mg, yield 9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 9.30 (s, 1H), 8.49 (s, 1H), 7.61 (s, 1H), 6.71 (d, J = 2.4Hz, 1H), 3.62 (s, 2H), 3.00 (d, J = 6.5 Hz, 2H), 2.85 (d, J = 13.8 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 2.24-2.08 (m, 3H), 1.06 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 97.49 % at 210 nm. MS (ESI+): m/z =390.2 (M+H)⁺. [0119] 1-tosyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol

[0120] The title compound was prepared by the scheme and procedures shown below:

[0121] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (300 mg, crude) in Et2O (10 mL) were added aq. NaOH (0.4 mL, 20%) and 4-methylbenzene-1-sulfonyl chloride (190 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1h, and then it was poured into water and extracted with DCM/MeOH (10:1). The organic layer was concentrated and the residue was purified by pre-HPLC to give the desired product 1-tosyldispiro[pyrrolidine-3,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (31.0 mg, yield 7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.58 (t, J = 2.8 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 1.6 Hz, 1H), 3.50 (s, 2H), 3.29-3.23 (m, 2H), 2.70 (d, J = 13.8 Hz, 2H), 2.38 (s, 3H), 2.11-1.91 (m, 4H) ppm. HPLC purity: 96.75 % at 210 nm. MS (ESI+): m/z =424.1 (M+H)⁺. [0122] 3-(3''-hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile

[0123] The title compound was prepared by the scheme and procedures shown below:

[0124] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (250 mg, crude) in DMF (5 mL) were added DIPEA (258 mg, 2.0 mmol) and HATU (418 mg, 1.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2h, and then it was poured into water and extracted with DCM/MeOH (10:1). The organic layer was washed with brine, water and concentrated. The residue was purified by pre-HPLC (NH4HCO3 in CH3CN and H2O) to give the desired product 3-(3''-hydroxy- 3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 1-yl)-3-oxopropanenitrile (11.8 mg, yield 4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.29 (d, J = 13.1 Hz, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 6.77-6.65 (m, 1H), 4.01 (s, 1H), 3.96 (s, 1H), 3.74 (d, J = 6.7 Hz, 2H), 3.48 (t, J = 6.8 Hz, 1H), 3.41 (t, J = 7.0 Hz, 1H), 2.90-2.76 (m, 2H), 2.41-2.08 (m, 4H) ppm. HPLC purity: 93.85 % at 210 nm. MS (ESI+): m/z =337.1 (M+H)⁺. [0125] 1-(Butylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0126] The title compound was prepared by the scheme and procedures shown below:

[0127] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (150 mg, crude) in Et2O (5 mL) were added aq. NaOH (0.2 mL, 20%) and butane-1-sulfonyl chloride (80 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 1h, then it was poured into water and extracted with DCM/MeOH (10:1). The organic was concentrated and the residue was purified by pre-HPLC (NH4HCO3 in CH3CN and H2O) to give the product 1-(butylsulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (16.5 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 9.28 (br s, 1H), 8.49 (s, 1H), 7.62 (t, J = 2.6 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 3.63 (s, 2H), 3.36 (s, 2H), 3.18-3.05 (m, 2H), 2.85 (d, J = 13.7 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 2.20 (t, J = 6.9 Hz, 2H), 1.77-1.59 (m, 2H), 1.50-1.36 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 96.99 % at 210 nm. MS (ESI⁺): m/z = 390.2 (M+1)⁺. [0128] 1-(Ethylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0129] The title compound was prepared by the scheme and procedures shown below:

[0130] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (150 mg, crude) in Et2O (5 mL) were added aq. NaOH (0.2 mL, 20%) and ethanesulfonyl chloride (65 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 1h, and then it was poured into water and extracted with DCM/MeOH (10:1). The organic was concentrated and the residue was purified by pre-HPLC (NH4HCO3 in CH3CN and H2O) to give the product 1-(ethylsulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (2.1 mg, yield 1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.28 (s, 1H), 8.49 (s, 1H), 7.61 (t, J = 2.8 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 3.64 (s, 2H), 3.42-3.34 (m, 2H), 3.14 (q, J = 7.3 Hz, 2H), 2.85 (d, J = 13.7 Hz, 2H), 2.39-2.27 (m, 2H), 2.20 (t, J = 6.9 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 92.31 % at 210 nm. MS (ESI⁺): m/z =362.2 (M+H)⁺. [0131] 1-(Methylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo [2,3-b]pyridin]-3''(6''H)-ol

[0132] The title compound was prepared by the scheme and procedures shown below:

[0133] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (150 mg, crude) in Et2O (5 mL) were added aq. NaOH (0.2 mL, 20%) and methanesulfonyl chloride (58 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 1h, and then poured into water and extracted with DCM/MeOH (10:1). The organic was concentrated and the residue was purified by pre-HPLC (NH4HCO3 in CH3CN and H2O) to give the product 1-(methylsulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (7.4 mg, yield 4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.30 (br s, 1H), 8.50 (s, 1H), 7.63 (s, 1H), 6.74 (s, 1H), 3.60 (s, 2H), 3.33 (t, J = 7.0 Hz, 2H), 2.95 (s, 2H), 2.86 (d, J = 13.7 Hz, 2H), 2.34 (d, J = 13.6 Hz, 2H), 2.20 (t, J = 7.0 Hz, 2H) ppm. HPLC purity: 98.10% at 210 nm. MS (ESI⁺): m/z =348.1 (M+H)⁺. [0134] 1-(Cyclohexylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0135] The title compound was prepared by the scheme and procedures shown below:

[0136] To a solution of compound dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (150 mg, crude) in Et2O (5 mL) were added aq. NaOH (0.2 mL, 20%) and cyclohexanesulfonyl chloride (90 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 1h, and then poured into water and extracted with DCM/MeOH (10:1). The organic was concentrated and the residue was purified by pre-HPLC (NH4HCO3 in CH3CN and H2O) to give the product 1-(cyclohexylsulfonyl)dispiro[pyrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (2.5 mg, yield 1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.28 (s, 1H), 8.49 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 3.67 (s, 2H), 3.39 (t, J = 6.9 Hz, 2H), 3.21-3.12 (m, 1H), 2.84 (d, J = 13.6 Hz, 2H), 2.37-2.24 (m, 2H), 2.21 (t, J = 7.0 Hz, 2H), 2.03 (d, J = 11.0 Hz, 2H), 1.79 (d, J = 12.6 Hz, 2H), 1.63 (d, J = 11.1 Hz, 1H), 1.50-1.07 (m, 5H) ppm. HPLC purity: 98.51 % at 210 nm. MS (ESI⁺): m/z =416.2 (M+H)⁺. [0137] 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborole [4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0138] The title compound was prepared by the scheme and procedures shown below:

[0139] To a solution of propan-1-amine (118 mg, 2 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction mixture was stirred at room temperature for 30 min. Then the solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol (300 mg, crude) in DCM (5 mL) was added. It was stirred at room temperature overnight, and then it was concentrated. The residue was purified by prep-HPLC (NH₄HCO₃ in CH₃CN and H₂O) to give the product 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (1.3 mg, yield 1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 9.26 (s, 1H), 8.50 (s, 1H), 7.61 (s, 1H), 6.71 (s, 1H), 6.13-6.11 (m, 1H), 3.61 (s, 2H), 3.00-2.95 (m, 4H), 2.81 (d, J = 13.8 Hz, 2H), 2.67 (s, 2H), 2.37-2.19 (m, 2H), 2.17-2.05 (m, 2H), 1.51-1.35 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 96.08 % at 210 nm. MS (ESI⁺): m/z =355.2 (M+H)⁺. [0140] 1-(phenylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0141] The title compound was prepared by the scheme and procedures shown below:

[0142] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (150 mg, crude) in Et2O (5 mL) were added aq. NaOH (0.2 mL, 20%) and benzenesulfonyl chloride (88 mg, 0.5 mmol) at room temperature. It was stirred at room temperature for 1 h, poured into water and extracted with DCM/MeOH (10:1). The organic was concentrated and the residue was purified by prep-HPLC (NH4HCO3 in CH3CN and H2O) to give the product 1-(phenylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (5.8 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 9.27 (br s, 1H), 8.45 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.69-7.61 (m, 3H), 7.57 (s, 1H), 6.63 (s, 1H), 3.51 (s, 2H), 3.27 (t, J = 7.0 Hz, 2H), 2.67 (d, J = 10.4 Hz, 2H), 2.04-1.94 (m, 4H) ppm. HPLC purity: 99.06 % at 210 nm. MS (ESI⁺): m/z =410.3 (M+H)⁺. [0143] N-Ethyl-3''-hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborole [4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0144] The title compound was prepared by the scheme and procedures shown below:

[0145] To a solution of ethanamine (2 mL, 2 N in THF) in DCM (10 mL) was added CDI (628 mg, 4 mmol) and the reaction was stirred at room temperature for 30 min. And then dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (800 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by prep- HPLC (0.1% TFA in CH3CN and H2O) to give the product N-ethyl-3''-hydroxy-3'',6''- dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxamide (15.1 mg, yield 2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.22 (s, 1H), 9.35 (br s, 1H), 8.53 (s, 1H), 7.67 (s, 1H), 6.78 (s, 1H), 6.13 (br s, 1H), 3.61 (s, 2H), 3.29 (t, J = 6.7 Hz, 2H), 3.06 (dd, J = 14.1, 7.1 Hz, 2H), 2.82 (d, J = 13.7 Hz, 2H), 2.28 (d, J = 13.9 Hz, 2H), 2.12 (t, J = 6.8 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 99.85 % at both 210 nm and 254 nm. MS (ESI+): m/z =341.2 (M+H)⁺. [0146] 3''-Hydroxy-N-isobutyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborole[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0147] The title compound was prepared by the scheme and procedures shown below:

[0148] To a solution of 2-methylpropan-1-amine (292 mg, 4 mmol) in DCM (10 mL) was added CDI (648 mg, 4 mmol) and the reaction was stirred at room temperature for 30 min. And then dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (800 mg, crude) and Et₃N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (0.1% TFA in CH₃CN and H₂O) to give the product 3''-hydroxy-N-isobutyl-3'',6''-dihydrodispiro- [pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (21.9 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H), 9.32 (br s, 1H), 8.52 (s, 1H), 7.67 (s, 1H), 6.77 (s, 1H), 6.15 (br s, 1H), 3.61 (s, 2H), 3.28 (s, 2H), 2.95-2.74 (m, 4H), 2.29 (d, J = 13.8 Hz, 2H), 2.13 (t, J = 6.8 Hz, 2H), 1.71-1.66 (m, 1H), 0.81 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 99.28 % at 210 nm and 96.85 % at 254 nm. MS (ESI+): m/z = 368.9 (M+H)⁺. [0149] Cyclohexyl(3''-hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborole[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0150] The title compound was prepared by the scheme and procedures shown below:

[0151] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (800 mg, crude) in DMF (10 mL) were added cyclohexanecarboxylic acid (256 mg, 2 mmol), DIPEA (516 mg, 4 mmol) and HATU (760 mg, 2 mmol). The reaction was stirred at room temperature for 2h, poured into water and extracted with EtOAc. The organic was washed with brine, water and concentrated. The residue was purified by prep-HPLC (0.1% TFA in CH₃CN and H₂O) to give the product cyclohexyl(3''- hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-1-yl)methanone (72 mg, yield 10%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 9.37 (br s, 1H), 8.53 (s, 1H), 7.68 (s, 1H), 6.79 (s, 1H), 3.81 (s, 1H), 3.69 (s, 1H), 3.55 (t, J = 6.8 Hz, 1H), 3.36 (t, J = 6.9 Hz, 1H), 2.95-2.77 (m, 2H), 2.45-2.02 (m, 5H), 1.84-1.55 (m, 5H), 1.44-1.07 (m, 5H) ppm. HPLC purity: 98.93 % at 210 nm. MS (ESI⁺): m/z =380.2 (M+H)⁺. [0152] (3''-Hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone

[0153] The title compound was prepared by the scheme and procedures shown below:

[0154] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (800 mg, crude) in DMF (10 mL) were added benzoic acid (244 mg, 2 mmol), DIPEA (516 mg, 4 mmol) and HATU (760 mg, 2 mmol). The reaction was stirred at room temperature for 2h, poured into water and extracted with EtOAc. The organic was washed with brine, water and concentrated. The residue was purified by prep-HPLC (TFA in CH₃CN and H₂O) to give the product (3''-hydroxy-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone (65.8 mg, yield 9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.30 (br s, 1H), 8.60- 8.46 (m, 1H), 7.65-7.44 (m, 6H), 6.76 (s, 1H), 3.96-3.67 (m, 2H), 3.65-3.41 (m, 2H), 2.96-2.75 (m, 2H), 2.43-2.09 (m, 4H) ppm. HPLC purity: 98.53 % at 210 nm. MS (ESI⁺): m/z =374.2 (M+H)⁺. [0155] 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborole [4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0156] The title compound was prepared by the scheme and procedures shown below:

[0157] To a solution of methanamine (2 mL, 2 N in THF) in DCM (10 mL) was added CDI (648 mg, 4 mmol) and the reaction mixture was stirred at room temperature for 30 min. Dispiro[pyro- lidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (800 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. It was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (TFA in CH3CN and H2O) to give the product 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (15 mg, yield 2%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.27 (br s, 1H), 9.36 (br s, 1H), 8.54 (s, 1H), 7.69 (s, 1H), 6.80 (s, 1H), 6.11 (br s, 1H), 3.61 (s, 2H), 3.43-3.12 (m, 2H), 2.82 (d, J = 13.6 Hz, 2H), 2.57 (s, 3H), 2.28 (d, J = 13.4 Hz, 2H), 2.19-2.02 (m, 2H) ppm. HPLC purity: 99.77 % at 210 nm and 99.67 % at 254 nm. MS (ESI⁺): m/z =327.2 (M+H)⁺. [0158] 1-((4-ethylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0159] The title compound was prepared by the scheme and procedures shown below:

[0160] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and 4-ethylbenzene-1-sulfonyl chloride (204 mg, 1.0 mmol) at 0^oC. The reaction mixture was stirred at room temperature for 30 min and it was concentrated. The residue was purified by prep-HPLC (0.1% TFA in ACN and H2O) to give the product 1-((4- ethylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (13.1 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.35 (br s, 1H), 8.48 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.60 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 6.67 (s, 1H), 3.51 (s, 2H), 3.31-3.19 (m, 2H), 2.76-2.57 (m, 4H), 2.12-1.93 (m, 4H), 1.15 (t, J = 7.6 Hz, 3H) ppm. HPLC purity: 92.3% at 210 nm. MS (ESI⁺): m/z =437.7 (M+H)⁺. [0161] 1-((4-propylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0162] The title compound was prepared by the scheme and procedures shown below:

[0163] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 4-propylbenzene-1-sulfonyl chloride (218 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H₂O) to give the product 1-((4-propylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (6.1 mg, yield 2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.29 (s, 1H), 8.46 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 2.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 1.9 Hz, 1H), 3.50 (s, 2H), 3.26 (t, J = 6.9 Hz, 2H), 2.73-2.57 (m, 4H), 2.03 (t, J = 6.9 Hz, 2H), 1.99-1.86 (m, 2H), 1.60- 1.50 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 93.62% at 210 nm. MS (ESI⁺): m/z =452.2 (M+H)⁺. [0164] 1-(m-tolylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0165] The title compound was prepared by the scheme and procedures shown below:

[0166] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 3-methylbenzene-1-sulfonyl chloride (190 mg, 1.0 mmol) at 0^oC. It was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H₂O) to give the product 1-(m-tolylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (13.1 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 7.73-7.41 (m, 5H), 6.63 (d, J = 3.2 Hz, 1H), 3.53 (s, 2H), 3.30-3.24 (m, 2H), 2.73-2.58 (m, 2H), 2.42 (s, 3H), 2.03 (t, J = 6.9 Hz, 2H), 1.96-1.83 (m, 2H) ppm. HPLC purity: 92.93% at 210 nm. MS (ESI⁺): m/z =424.2 (M+H)⁺. [0167] 1-((4-isopropylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0168] The title compound was prepared by the scheme and procedures shown below:

[0169] To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and 4-isopropylbenzene-1-sulfonyl chloride (218 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product 1-((4-isopropylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (20.6 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 9.27 (s, 1H), 8.46 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.62-7.45 (m, 3H), 6.63 (d, J = 1.7 Hz, 1H), 3.51 (s, 2H), 3.26 (t, J = 7.0 Hz, 2H), 3.00-2.90 (m, 1H), 2.76-2.61 (m, 2H), 2.11-1.89 (m, 4H), 1.17 (d, J = 6.9 Hz, 6H) ppm. HPLC purity: 90.02% at 210 nm. MS (ESI⁺): m/z =452.2 (M+H)⁺. [0170] 1-((4-isobutylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol [ d was prepared by the scheme and procedures shown below:

[0172] To a solution of isobutylbenzene (1.34 g, 10.0 mmol) in DME (50 mL) were added PCl₅ (2.4 g, 12.0 mmol) and ClSO₃H (1.3 mL, 20.0 mmol) slowly at rt. The mixture was stirred at 80^oC overnight, poured into water and extracted with DCM. The organic was concentrated to give 4-isopropylbenzene-1-sulfonyl chloride (2.4 g, crude). To a solution of dispiro[pyrrolidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 4-isopropylbenzene-1-sulfonyl chloride (218 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H₂O) to give the product 1-((4-isobutyl- phenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (14.5 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.31 (br s, 1H), 8.46 (s, 1H), 7.77 (d, J = 6.6 Hz, 2H), 7.59 (s, 1H), 7.41 (d, J = 6.7 Hz, 2H), 6.65 (s, 1H), 3.51 (s, 2H), 3.36-3.18 (m, 2H), 2.63 (d, J = 12.1 Hz, 2H), 2.11-1.96 (m, 2H), 1.91-1.70 (m, 3H), 0.71 (d, J =6.8 Hz, 6H) ppm. HPLC purity: 98.48 % at 210 nm and 93.34% at 254 nm. MS (ESI⁺): m/z =466.2 (M+H)⁺. [0173] 1-(o-tolylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0174] The title compound was prepared by the scheme and procedures shown below:

[0175] To a solution of o-toluidine (4 g, 37.4 mmol) in ACN (80 mL) was added con. HCl (10 mL) and it was cooled to 0^oC. NaNO₂ (2.8 g, 41.1 mmol) in H₂O (20 mL) was added at 0^oC. The reaction was stirred at 0^oC for 30 min and AcOH (20 mL) was added. SO₂ gas was bubbled into the reaction over 5 min and then CuCl₂ (3.0 g, 22.4 mmol) and CuCl (50 mg) were added. The reaction was stirred at room temperature overnight, poured into water and extracted with EtOAc. The organic was washed with brine, water, dried and concentrated. The residue was purified by column chromatography to give 2-methylbenzenesulfonyl chloride (1.8 g, yield 25%) as a light oil.¹H NMR (300 MHz, CDCl₃): δ 8.07 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.52-7.33 (m, 2H), 2.80 (s, 3H) ppm. To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo- [4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and 2-methylbenzene-1-sulfonyl chloride (190 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (NH4HCO3 in ACN and H2O) to give the product 1-(o-tolylsulfonyl)dispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (44.3 mg, yield 10%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (s, 1H), 9.31 (br s, 1H), 8.51 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H), 7.50-7.36 (m, 2H), 6.75 (d, J = 1.7 Hz, 1H), 3.58 (s, 2H), 3.32 (t, J = 6.9 Hz, 2H), 2.82 (d, J = 13.7 Hz, 2H), 2.62 (s, 3H), 2.29-2.10 (m, 4H) ppm. HPLC purity: 99.50% at 210 nm and 95.70% at 254 nm. MS (ESI⁺): m/z =424.2 (M+H)⁺. [0176] 1-((4-(cyclopropylmethyl)phenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0177] The title compound was prepared by the scheme and procedures shown below:

[0178] To a solution of 1-bromo-4-iodobenzene (2.8 g, 10 mmol) in THF (20 mL) was added iPrMgCl-LiCl (1.3N in THF, 10 mL) at -20^oC under argon atmosphere. The reaction was stirred at -20^oC for 40 min, and then cyclopropanecarbaldehyde (700 mg, 10.0 mmol) in THF (10 mL) was added. The reaction was allowed to warm to room temperature for 2h, quenched with water and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography to give (4-bromophenyl)(cyclopropyl)methanol (1.6 g, yield 71%) as a light yellow oil.¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J = 7.9 Hz, 2H), 7.40-7.20 (m, 3H), 3.98 (d, J = 8.3 Hz, 1H), 2.05 (br s, 1H), 1.21-1.08 (m, 1H), 0.75-0.53 (m, 2H), 0.53-0.28 (m, 2H) ppm. To a solution of (4-bromophenyl)(cyclopropyl)methanol (1.6 g, 7.1 mmol) in DCM (80 mL) was added TFA (1.2 g, 10.7 mmol) and Et₃SiH (1.3 g, 10.7 mmol) at room temperature. The reaction was stirred for 30 min and concentrated. The residue was purified by column chromatography to give 1-bromo-4-(cyclopropylmethyl)benzene (1.3 g, yield 87%) as a light oil. ¹H NMR (300 MHz, CDCl₃): δ 7.42 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 2.51 (d, J = 6.8 Hz, 2H), 1.04 – 0.86 (m, 1H), 0.71 – 0.37 (m, 2H), 0.37 – 0.05 (m, 2H) ppm. To a solution of 1- bromo-4-(cyclopropyl-methyl)benzene (800 mg, 3.8 mmol) in THF (15 mL) was added n-BuLi (1.9 mL, 2.4 N) at -78^oC under N2 atmosphere. The reaction was stirred at -78^oC for 1 h, and then SO₂ gas was bubbled into the reaction for 5 min. It was warmed to rt, and then DCM (10 mL) and NCS (612 mg, 4.6 mmol) were added. The reaction was stirred at rt for 2h, poured into water, extracted with DCM, and concentrated. The residue was purified by column chromatography to give 4-(cyclopropylmethyl)benzenesulfonyl chloride (600 mg, yield 69%) as a lightly yellow oil.¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H), 1.00 (t, J = 7.5 Hz, 1H), 0.61 (d, J = 9.0 Hz, 2H), 0.25 (d, J = 6.0 Hz, 2H) ppm. To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 4-(cyclopropylmethyl)-benzenesulfonyl chloride (230 mg, 1.0 mmol) at 0^oC. The reaction mixture was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H₂O) to give the product 1-((4- (cyclopropylmethyl)phenyl)sulfonyl)-dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (12.6 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.31 (br s, 1H), 8.47 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 6.66 (t, J = 1.7 Hz, 1H), 3.51 (s, 2H), 3.27 (t, J = 6.9 Hz, 2H), 2.67 (d, J = 13.7 Hz, 2H), 2.57 (d, J = 6.9 Hz, 2H), 2.04 (t, J = 6.9 Hz, 2H), 1.96 (d, J = 13.7 Hz, 2H), 0.95- 0.82 (m, 1H), 0.45 -0.26 (m, 2H), 0.13 (d, J = 4.8 Hz, 2H) ppm. HPLC purity: 98.55 % at 210 nm and 93.99% at 254 nm. MS (ESI⁺): m/z =464.2 (M+H)⁺. [0179] 1-((4-cyclopropylphenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0180] The title compound was prepared by the scheme and procedures shown below:

[0181] To a solution of 4-iodoaniline (2.0 g, 9.1 mmol) in H₂O/PhMe=1:10 (20 mL) were added cyclopropylboronic acid (939 mg, 10.9 mmol), K₃PO₄ (5.8 g, 27.3 mmol), P(Cy)₃ (255 mg, 0.9 mmol) and Pd(OAc)₂ (101 mg, 0.45 mmol) under N₂ atmosphere. The reaction was stirred at 80^oC overnight and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give 4-cyclopropylaniline (380 mg, yield 31%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.48-7.28 (m, 2H), 7.08-6.83 (m, 2H), 2.03-1.78 (m, 1H), 1.15-0.92 (m, 2H), 0.84- 0.59 (m, 2H) ppm. To a solution of 4-cyclopropylaniline (380 mg, 2.9 mmol) in ACN (10 mL) was added con. HCl (2 mL) at 0°C. NaNO₂ (241 mg, 3.5 mmol) in H O (2 mL) was added. The reaction was stirred at 0°C for 30 min, and AcOH (5 mL) was added. SO gas was bubbled into the reaction over 5 min, and then CuCI₂2 (243 mg, 1.8 mmol) and CuCl (5 mg) were added. The reaction was stirred at room temperature overnight, poured into water and extracted with EtOAc. The organic was washed with brine, water, dried, and concentrated. The residue was purified by column chromatography to give 4-cyclopropylbenzenesulfonyl chloride (180 mg, yield 29%) as a light-yellow oil. MS (ESI): m/z =197.0 (M-Cl+OH). To a solution of dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and 4-cyclopropylbenzenesulfonyl chloride (180 mg, 0.8 mmol) at 0°C. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product 1-((4-cyclopropylphenyl)-sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (23 mg, yield 6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.35 (br s, 1H), 8.49 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 2.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 1.7 Hz, 1H), 3.49 (s, 2H), 3.24 (t, J = 6.9 Hz, 2H), 2.70 (d, J = 13.7 Hz, 2H), 2.14-1.88 (m, 5H), 1.08-0.91 (m, 2H), 0.77-0.65 (m, 2H) ppm. HPLC purity: 99.42 % at 210 nm and 98.50% at 254 nm. MS (ESI ): m/z =450.2 (M+H)⁺ . [0182] 1-((4-(pentan-3-yl)phenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0183] The title compound was prepared by the scheme and procedures shown below:

[0184] To a solution of 1-bromo-4-iodobenzene (2.8 g, 10 mmol) in THF (20 mL) was added i- PrMgCl-LiCl (1.3N in THF, 10 mL) at -20^oC under argon atmosphere. The reaction was stirred at -20^oC for 1 h, and then pentan-3-one (860 mg, 10.0 mmol) in THF (10 mL) was added. The reaction was warmed to room temperature for 2h, quenched with water and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography to give a mixture of 3-(4-bromophenyl)pentan-3-ol (main component, 87% by ¹HNMR) and (E)- 1-bromo-4-(pent-2-en-3-yl)benzene (minor, 13% by ¹HNMR) as a light-yellow oil (1.8 g, yield 75%).¹H NMR (400 MHz, CDCl₃) of the main component: δ 7.96 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 1.82-1.67 (m, 2H), 1.63-1.53 (m, 2H), 0.78 (t, J = 7.4 Hz, 6H) ppm. To a solution of the mixture obtained above (1.8 g, 7.4 mmol) in DCM (80 mL) were added TFA (1.3 g, 11.1 mmol) and Et3SiH (1.4 g, 11.1 mmol) at room temperature. The reaction was stirred for 30 min. It was washed with water, dried, and concentrated. The residue was purified by column chromatography to give a mixture of 1-bromo-4-(pentan-3-yl)benzene (main component, 84% by ¹HNMR) and (E)-1-bromo-4-(pent-2-en-3-yl)benzene (minor, 16% by ¹HNMR) as a light oil (1.6 g, yield 94%).¹H NMR (300 MHz, CDCl₃) of the main component: δ 7.41 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 2.38-2.16 (m, 1H), 1.75-1.60 (m, 2H), 1.60-1.45 (m, 2H), 0.76 (t, J = 7.3 Hz, 6H) ppm. To a solution of the mixture obtained above (400 mg, 1.8 mmol) in toluene (10 mL) was added PtO₂ (50 mg) and it was backfilled with

three times. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated to give 1- bromo-4-(pentan-3-yl)benzene (400 mg, yield 100%) as a light oil.¹H NMR (300 MHz, CDCl₃): δ 7.42 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 7.7 Hz, 2H), 2.34-2.20 (m, 1H), 1.75-1.60 (m, 2H), 1.60- 1.45 (m, 2H), 0.77 (t, J = 7.2 Hz, 6H) ppm. To a solution of 1-bromo-4-(pentan-3-yl)benzene (400 mg, 1.8 mmol) in THF (10 mL) was added n-BuLi (0.9 mL, 2.4 N) at -78^oC under N2 atmosphere. The reaction was stirred at -78^oC for 1h, and then SO₂ gas was bubbled into the reaction for 5 min. It was warmed to rt, and then NCS (294 mg, 2.2 mmol) in DCM (10 mL) was added. The reaction mixture was stirred at rt for 2h, poured into water, extracted with DCM, and concentrated. The residue was purified by column chromatography to give 4-(pentan-3- yl)benzenesulfonyl chloride (280 mg, yield 64%) as a light oil.¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 2.59-2.37 (m, 1H), 1.88-1.67 (m, 2H), 1.67- 1.51 (m, 2H), 0.80 (t, J = 7.3 Hz, 6H) ppm. To a solution of dispiro[pyrrolidine-3,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 4-(pentan-3-yl)benzenesulfonyl chloride (280 mg, 1.1 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (NH₄HCO₃ in ACN and H₂O) to give the product 1-((4-(pentan-3- yl)phenyl)sulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (4.9 mg, yield 1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.95 (s, 1H), 9.22 (s, 1H), 8.43 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 2.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.60 (d, J = 2.0 Hz, 1H), 3.51 (s, 2H), 3.30-3.22 (m, 2H), 2.63-2.55 (m, 2H), 2.42 - 2.29 (m, 1H), 2.03 (t, J = 6.7 Hz, 2H), 1.74 (d, J = 13.5 Hz, 2H), 1.68-1.53 (m, 2H), 1.53-1.35 (m, 2H), 0.52 (t, J = 7.3 Hz, 6H) ppm. HPLC purity: 96.88 % at 210 nm and 94.70% at 254 nm. MS (ESI⁺): m/z =480.2 (M+H)⁺. [0185] N-(3'-hydroxy-3',6'-dihydrospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3-yl)propane-1-sulfonamide

[0186] The title compound was prepared by the scheme and procedures shown below:

[0187] To a stirring ice-cold solution of tert-butyl (3-oxocyclobutyl)carbamate (17.2 g, 93 mmol) in EtOH (250 mL) was slowly added NaBH₄ (4.2 g, 112 mmol). The reaction mixture was stirred at 0^oC for 1.5 h. TLC showed no starting material left. The reaction mixture was quenched with 1N HCl to pH = 6-7 and extracted with DCM. The DCM solution was washed with sat. NaHCO₃, and brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give tert-butyl (3-hydroxy- cyclobutyl)carbamate (16.0 g, yield 92%, isomers) as a colorless oil, it was used to the next step without further purification. To a solution of tert-butyl (3-hydroxy-cyclobutyl)carbamate (16.0 g, 85.6 mmol) in DMF (250 mL) was added NaH (5.1 g, 128 mmol, 60%) in portions at 0^oC under N2 atmosphere. It was then stirred at rt for 30 min and re-cooled to 0^oC. BNBr (14.5 g, 85.6 mmol) was added dropwise and the reaction mixture was stirred at rt for another 2 h. It was quenched with H₂O (200 mL) at 0^oC, and stirred at rt for 30 min. The solid formed was collected by filtration and dried in vacuo to give tert-butyl (3-(benzyloxy)cyclobutyl)carbamate (14.0 g, yield 59%) as a white solid. To a solution of tert-butyl (3-(benzyloxy)cyclobutyl)carbamate (14.0 g, 51 mmol) in 1,4-dioxane (100 mL) was added 4N HCl in 1,4-dioxane (100 mL). The reaction mixture was stirred at rt overnight. The solid participate was collected by filtration and dried in vacuo to give 3-(benzyloxy)cyclobutan-1-amine HCl salt (10.0 g, yield 93%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): ^ 8.35 (s, 3H), 7.39 – 7.28 (m, 5H), 4.40 – 4.35 (m, 2H), 3.88 – 3.67 (m, 1H), 3.35 – 3.19 (m, 1H), 2.60 – 2.51 (m, 2H), 2.39 – 2.23 (m, 1H), 2.07 – 1.99 (m, 1H) ppm. To a solution of 3-(benzyloxy)cyclobutan-1-amine HCl salt (10.0 g, 46.9 mmol) and triethylamine (13.0 mL, 94.0 mmol) in dichloromethane (250 mL) at 0^oC was gradually added propane-1-sulfonyl chloride (6.6 g, 46.9 mmol). The mixture was stirred at room temperature for 3 h, added with water (50 ml), and extracted with dichloromethane (2 × 250 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluted with PE/EtOAc (30:1 to 10:1) to give N- (3-(benzyloxy)cyclobutyl)propane-1-sulfonamide (9.8 g, yield 74%) as a yellow oil. The mixture of N-(3-(benzyloxy)cyclobutyl)propane-1-sulfonamide (9.8 g, 34.6 mmol), Et₃N (9.7 mL, 69.2 mmol) and DMAP (80 mg) in CH₂Cl₂ (180 mL) was added to a solution of (Boc)₂O (9.0 g, 41.5 mmol) in CH₂Cl₂ (30 mL) at 0°C under a N₂ atmosphere. It was stirred at rt for 2 h and quenched with saturated NaHCO₃ water (10 mL). The organic layer was separated and dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a crude product, which was purified by flash chromatography using 10% EtOAc in petroleum to afford tert-butyl (3- (benzyloxy)cyclobutyl)(propylsulfonyl)carbamate (10 g, yield 75%) as a colorless oil. To a solution of tert-butyl (3-(benzyloxy)cyclobutyl)(propylsulfonyl)carbamate (10 g, 26 mmol) and 0.2 mL of 6N HCl in MeOH (150 mL) was added Pd-C (10%, 1 g) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ balloon at rt overnight and then filtered through a pad of Celite. The filtrate was diluted with EtOAc and washed with sat. NaHCO₃ and H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography (PE/EtOAc = 10/1) to afford tert-butyl (3-hydroxycyclobutyl)(propylsulfonyl)carbamate (6.8 g, yield 89%) as a colorless oil. The solution of tert-butyl (3- hydroxycyclobutyl)(propylsulfonyl)carbamate (6.8 g, 23.2 mmol) and 2-Iodoxybenzoic acid (IBX, 19.5 g, 70 mmol) in EtOAc (150 mL) was refluxed overnight. The reaction mixture was cooled to rt and filtered through a pad of Celite. The filtrate was concentrated to dryness and the residue was purified by column chromatography (PE/EtOAc = 30/1) to afford tert-butyl (3- oxocyclobutyl)(propylsulfonyl)carbamate (4.5 g, yield 67%) as a white solid.¹HNMR (400 MHz, DMSO-d₆): δ 5.05 – 4.93 (m, 1H), 3.60 – 3.50 (m, 2H), 3.39 (s, 4H), 1.75-1.64 (m, 2H), 1.48 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H- pyrrolo[2,3-b]pyridine (5.1 g, 10.6 mmol) in THF (30 mL) was added i-PrMgCl-LiCl (8.0 mL, 10.6 mmol, 1.3 M in THF) at -35 °C under N2 atmosphere, and the mixture was stirred at -35^oC for 1 h. A solution of tert-butyl (3-oxocyclobutyl)-(propylsulfonyl)carbamate (3.1 g, 10.6 mmol) in THF (5 mL) was added to the mixture. The resulting mixture was stirred at -35^oC for another 1 h, allowed to warm to 0^oC, quenched with H2O, and extracted with EtOAc. The organic was washed with bine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (30%-50% EtOAc in petroleum) to give tert-butyl (3-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-hydroxycyclobutyl)(propylsulfonyl)carbamate (1.9 g, yield 28%, isomers) as a yellow solid.¹HNMR (400 MHz, DMSO-d₆): δ 8.30 (s, 1H), 7.56 (s, 1H), 6.79 (d, J = 3.3 Hz, 1H), 5.93 (s, 1H), 3.98 – 3.86 (m, 1H), 3.55-3.45 (m, 4H), 2.90-2.80 (m, 2H), 1.94 – 1.68 (m, 5H), 1.51 (s, 9H), 1.13 – 0.99 (m, 21H) ppm. To a solution of tert-butyl (3-(5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3- hydroxycyclobutyl)(propylsulfonyl)carbamate (800 mg, 1.24 mmol) in THF (15.0 mL) under N₂ were added KOAc (706 mg, 3.0 mmol), Pin₂B₂ (363 mg, 0.5 mmol) and Pd(dppf)Cl₂ (175 mg, 0.24 mmol). The mixture was refluxed for 15 h, cooled to room temperature and filtered. The filtrate was mixed with 2N HCl (2 mL) and the mixture was stirred at rt for 30 min. The solvent was removed and the residue was purified by column chromatography (10% EtOAc in petroleum) to afford tert-butyl (3'-hydroxy-3',6'-dihydrospiro-[cyclobutane-1,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3-yl)(propylsulfonyl)carbamate (410 mg, crude). This material was dissolved in 4N HCl 1,4-dioxane solution (10 mL) in a sealed-tube and it was stirred at 30^oC for 3h. LC-MS indicated the reaction was complete. It was concentrated in vacuo to dryness and the residue was purified by prep-HPLC (0.1% TFA in MeCN and H₂O) to afford the desired product N-(3'-hydroxy-3',6'-dihydrospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3-yl)propane-1-sulfonamide (177 mg, yield 42%).¹HNMR (400 MHz, DMSO-d₆): δ 12.43 (two s, 1H), 10.80 (br s, 1H), 8.56 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 6.75 (s, 1H), 4.38-4.20 (m, 1H), 3.13-2.92 (m, 4H), 2.87-2.68 (m, 2H), 1.85-1.61 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 99.02% at 210 nm. MS (ESI⁺): m/z =336.2 (M+H)⁺. [0188] 1-(3'-hydroxy-3',6'-dihydrospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3-yl)-3-(2,2,2-trifluoroethyl)urea

[0189] The title compound was prepared by the scheme and procedures shown below:

[0190] To a solution of tert-butyl (3-oxocyclobutyl)carbamate (2.5 g, 13.5 mmol) and (HCHO)n (0.5 g, 16.7 mmol) in DCM (25 mL) was added TMSCl (5.1 mL, 40.0 mmol) at 0^oC under N2 atmosphere. After the addition was complete, the mixture was warmed to rt and stirred at rt for 1.5 h. It was re-cooled to 0^oC and a solution of Et3N (9.6 mL) in MeOH (45 mL) was added in one portion. The internal mixture temperature was reached to about 20^oC, and the mixture was stirred at rt for 2 h. It was poured into sat. NaHCO₃ (20 mL) and separated. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (eluting by PE/EtOAc = 10/1) to give tert-butyl (methoxymethyl)(3- oxocyclobutyl)carbamate (2.3 g, yield 74%) as a yellow oil.¹H NMR (400 MHz, CDCl₃): δ 4.78 (s, 2H), 4.41-4.25 (m, 1H), 3.45-3.35 (m, 2H), 3.29 (s, 3H), 3.28-3.21 (m, 2H), 1.48 (s, 9H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-indole (4.7 g, 10.0 mmol) in THF (25 mL) was added iPrMgCl-LiCl (7.7 mL, 10.0 mmol) at -20^oC under N₂. The reaction was stirred at - 20^oC for 1 h, and then tert-butyl (methoxymethyl)(3-oxocyclobutyl)carbamate (2.3 g, 10.0 mmol) in THF (10 mL) was added slowly. The reaction was warmed to room temperature for 2 h, quenched with H₂O and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl (3-(5- bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3- hydroxycyclobutyl)(methoxymethyl)carbamate (678 mg, yield 12%) as a white solid. MS (ESI⁺): m/z =582.2 (M+H)⁺. To a solution of tert-butyl (3-(5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)-3-hydroxycyclobutyl)(methoxymethyl)-carbamate (500 mg, 0.76 mmol) in THF (25 mL) were added (PinB)2 (230 mg, 0.90 mmol), KOAc (200 mg, 2.20 mmol) and Pd(dppf)Cl2 (222 mg, 0.30 mmol) under N2 atmosphere. The reaction was stirred at 75^oC overnight, filtered and concentrated to give tert-butyl (3-hydroxy-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)cyclobutyl)(methoxymethyl)carbamate (220 mg, crude) as a yellow oil. To a solution of this material (220 mg, crude) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirred at rt for 2 h. The solvent was removed under reduce pressure to give 3-aminospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol TFA salt (200 mg, crude) as a yellow oil. MS (ESI⁺): m/z =230.1 (M+H)⁺. To a solution of 2,2,2-trifluoroethanamine (99 mg, 1.0 mmol) in DCM (10 mL) was added CDI (162 mg, 1.0 mmol) and the reaction was stirred at room temperature for 30 min. A solution of 3- aminospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol TFA salt (200 mg, crude) in DCM (2 mL) was added. The reaction was stirred at room temperature overnight, and then the solvent was removed. The residue was purified by pre-HPLC (NH₄OH in ACN and H₂O) to give the product 1-(3'-hydroxy-3',6'-dihydrospiro[cyclobutane-1,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3-yl)-3-(2,2,2-trifluoroethyl)urea (12.1 mg) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.29 (br s, 2H), 8.50 (s, 1H), 7.63 (s, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.71 (s, 1H), 6.54 (t, 1H), 4.63-4.53 (m, 1H), 3.86-3.74 (m, 4H), 2.99-2.89 (m, 2H) ppm. HPLC purity: 98.29% at 210 nm and 98.96% at 254 nm. MS (ESI⁺): m/z =355.1 (M+H)⁺. [0191] 1-(propylsulfonyl)dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0192] The title compound was prepared by the scheme and procedures shown below:

[0193] To a solution of PPh3CH3Br (41.8 g, 117 mmol) in Et2O (200 mL) was added t-BuOK (13.1 g, 117 mmol) and the mixture was stirred at rt for 1 h before being treated with a solution of tert-butyl 3-oxoazetidine-1-carboxylate ( 20.0 g, 117 mmol) in Et2O (100 mL). The resulting mixture was stirred at rt overnight, poured into water and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1) to give tert-butyl 3-methyleneazetidine-1-carboxylate (12.0 g, yield 60%) as a light oil. ¹H NMR (300 MHz, CDCl₃): δ 5.08-4.88 (m, 2H), 4.49 (t, J = 2.3 Hz, 4H), 1.46 (s, 9H) ppm. To a solution of tert-butyl 3-methyleneazetidine-1-carboxylate (12.0 g, 71.0 mmol) in Et₂O (100 ml) was added Zn-Cu (36.6 g, 284.0 mmol) at 10^oC under N2 atmosphere. And then CCl3CCOCl (25.8 g, 0.142 mol) in DME (100 mL) was added. The mixture was stirred at room temperature overnight, quenched with aq. NaHCO₃ and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel chromatography to give tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]- heptane-2-carboxylate (11.0 g) as a yellow oil. To a solution of tert-butyl 5,5-dichloro-6-oxo-2- azaspiro[3.3]-heptane-2-carboxylate (11 g) in MeOH (100 mL) were added Zn (25.4 g, 0.39 mol) and sat. NH₄Cl (40 mL). The reaction was stirred at room temperature for 3 h, filtered and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromate- graphy to give tert-butyl 6-oxo-2-azaspiro[3.3]-heptane-2-carboxylate (6.1 g, yield 41%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 4.14 (s, 4H), 3.30 (s, 4H), 1.46 (s, 9H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (12.0 g, 25.1 mmol) in THF (100 mL) was added i-PrMgCl-LiCl (25.0 mL, 32.5 mmol) at -20 ^oC under N2. The reaction was stirred at -20^oC for 1 h, and then tert-butyl 6-oxo-2-azaspiro[3.3]-heptane-2-carboxylate (5.3 g, 25.1 mmol) in THF (50 mL) was added slowly. The reaction was stirred at room temperature for 3 h, quenched with H2O and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl 6- (5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (9.0 g, yield 64%) as a light-yellow solid.¹H NMR (300 MHz, CDCl₃): δ 8.28 (s, 1H), 7.32-7.30 (m, 1H), 6.59 (d, J = 2.9 Hz, 1H), 4.24 (s, 2H), 3.87 (s, 2H), 3.08-2.85 (m, 4H), 1.89- 1.73 (m, 3H), 1.45 (s, 9H), 1.09 (d, J = 7.4 Hz, 18H) ppm. To a solution of tert-butyl 6-(5-bromo- 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (2.8 g, 5.0 mmol) in THF (50 mL) were added (PinB)₂ (2.5 g, 10.0 mmol), KOAc (1.5 g, 15.0 mmol) and Pd(dppf)Cl₂ (1.6 g, 2.0 mmol) under N₂ atmosphere. The reaction was stirred at 75^oC overnight, filtered and concentrated. The residue was dissolved in THF (40 mL) and 6N HCl (5 mL) was added. The reaction was stirred for 30 min and extracted with EtOAc. The organic was concentrated to give a residue (3.4 g) as a black solid, which was dissolved in DCM (30 mL) and then TFA (10 mL) was added. The reaction was stirred for 1h, poured into water and extracted with DCM. The aqueous solution was concentrated to give dispiro[azetidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (2.0 g, crude) as a yellow solid. MS (ESI⁺): m/z =256.2 (M+1)⁺. To a solution of this amine TFA salt (500 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and propane-1-sulfonyl chloride (142 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product (28.3 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.32 (br s, 1H), 8.50 (s, 1H), 7.63 (t, J = 2.8 Hz, 1H), 6.65 (t, J = 1.7 Hz, 1H), 4.14 (d, J = 14.4 Hz, 4H), 3.13 (t, J = 7.6 Hz, 2H), 3.03 (d, J = 14.3 Hz, 2H), 2.60 (d, J = 14.3 Hz, 2H), 1.81-1.63 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 99.27 % at 210 nm. MS (ESI+): m/z = 362.1 (M+1)⁺. [0194] 1-(isobutylsulfonyl)dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0195] The title compound was prepared by the scheme and procedures shown below:

[0196] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol TFA salt (500 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and 2- methylpropane-1-sulfonyl chloride (156 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H₂O) to give the product 1-(isobutylsulfonyl)dispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (26.9 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.36 (br s, 1H), 8.51 (s, 1H), 7.64 (t, J = 2.8 Hz, 1H), 6.66 (d, J = 1.7 Hz, 1H), 4.13 (d, J = 13.5 Hz, 4H), 3.10-2.91 (m, 4H), 2.60 (d, J = 14.3 Hz, 2H), 2.22-2.05 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 98.96 % at 210 nm. MS (ESI⁺): m/z =376.2 (M+H)⁺. [0197] (3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone

[0198] The title compound was prepared by the scheme and procedures shown below:

[0199] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol TFA salt (400 mg, crude) in DMF (10 mL) were added benzoic acid (122 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at room temperature for 1h and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product (3''-hydroxy-3'',6''-dihydrodispiro[azetidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone (20.3 mg, yield 6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.30 (br s, 1H), 8.50 (s, 1H), 7.77-7.58 (m, 3H), 7.59-7.40 (m, 3H), 6.72 & 6.63 (s & s, 1H), 4.63 (s, 1H), 4.57 (s, 1H), 4.36 (s, 1H), 4.30 (s, 1H), 3.16-2.96 (m, 2H), 2.72-2.56 (m, 2H) ppm. HPLC purity: 98.04 % at 210 nm and 94.32% at 254 nm. MS (ESI⁺): m/z =360.2 (M+H)⁺. [0200] N-ethyl-3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0201] The title compound was prepared by the scheme and procedures shown below:

[0202] To a solution of ethanamine (1 mL in THF, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at 25^oC for 30 min. And then dispiro[azetidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (500 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at 25 ^oC overnight and concentrated. The residue was purified by pre-HPLC (TFA in CH3CN and H2O) to give the product N-ethyl-3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (10.4 mg, yield 3%) as a white solid. 1H NMR (400 MHz, DMSO-d₆): δ 12.18 (s, 1H), 9.31 (br s, 1H), 8.51 (s, 1H), 7.65 (t, J = 2.6 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 6.31 (br s, 1H), 4.06 (s, 2H), 4.02 (s, 2H), 3.11-2.90 (m, 4H), 2.58 (d, J = 14.4 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 99.80% at 210 nm and 99.82% at 254 nm. MS (ESI⁺): m/z =327.2 (M+H)⁺. [0203] 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0204] The title compound was prepared by the scheme and procedures shown below:

[0205] To a solution of 2,2,2-trifluoroethanamine (198 mg, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol). The reaction was stirred at 25^oC for 30 min, and then dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (500 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at 25^oC overnight and concentrated. The residue was purified by pre-HPLC (TFA in CH3CN and H2O) to give the product 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''- dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxamide (13.7 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.18 (s, 1H), 9.36 (br s, 1H), 8.51 (s, 1H), 7.65 (t, J = 2.9 Hz, 1H), 7.05 (t, J = 6.3 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H), 4.14 (s, 2H), 4.10 (s, 2H), 3.87-3.69 (m, 2H), 3.01 (d, J = 14.3 Hz, 2H), 2.60 (d, J = 14.3 Hz, 2H) ppm. HPLC purity: 98.42% at 210 nm and 93.92% at 254 nm. MS (ESI⁺): m/z =381.2 (M+H)⁺. [0206] Cyclohexyl (3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0207] The title compound was prepared by the scheme and procedures shown below:

[0208] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in DMF (10 mL) were added cyclohexanecarboxylic acid (128 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol)) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at room temperature for 1h and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product cyclohexyl(3''-hydroxy-3'',6''-dihydro- dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1- yl)methanone (27 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.28 (br s, 1H), 8.50 (d, J = 3.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.65 (d, J = 10.0 Hz, 1H), 4.44 (s, 1H), 4.41 (s, 1H), 4.11 (s, 1H), 4.05 (s, 1H), 3.09-2.89 (m, 2H), 2.66-2.54 (m, 2H), 2.28- 2.13 (m, 1H), 1.78-1.48 (m, 4H), 1.39-1.04 (m, 6H) ppm. HPLC purity: 99.34 % at 210 nm and 97.35% at 254 nm. MS (ESI⁺): m/z =366.2 (M+H)⁺. [0209] Ethyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate

[0210] The title compound was prepared by the scheme and procedures shown below:

[0211] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (500 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and ethyl carbonochloridate (109 mg, 1.0 mmol) at 0^oC. The reaction was stirred at 0 ^oC for 1 h and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product ethyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxylate (16 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.32 (br s, 1H), 8.50 (s, 1H), 7.64 (s, 1H), 6.64 (s, 1H), 4.19 (s, 2H), 4.15 (s, 2H), 4.08-3.93 (m, 2H), 3.02 (d, J = 12.6 Hz, 2H), 2.60 (d, J = 12.6 Hz, 2H), 1.18 (t, J = 6.6 Hz, 3H) ppm. HPLC purity: 95.99 % at 210 nm. MS (ESI⁺): m/z =328.2 (M+H)⁺. [0212] 3-(3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile

[0213] The title compound was prepared by the scheme and procedures shown below:

[0214] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (500 mg, crude) in THF (10 mL) were added 2-cyanoacetic acid (85 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at room temperature for 1h and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product (30.7 mg, yield 10%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 9.37 (br s, 1H), 8.51 (s, 1H), 7.66 (s, 1H), 6.73 & 6.68 (two s, 1H), 4.46 (s, 1H), 4.41 (s, 1H), 4.21 (s, 1H), 4.14 (s, 1H), 3.77 (d, J = 5.4 Hz, 2H), 3.10-2.95 (m, 2H), 2.66-2.53 (m, 2H) ppm. HPLC purity: 95.49 % at 210 nm. MS (ESI⁺): m/z =323.2 (M+H)⁺. [0215] 1-tosyldispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol

[0216] The title compound was prepared by the scheme and procedures shown below:

[0217] To a solution of dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (500 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and 4- methylbenzene-1-sulfonyl chloride (190 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 1h and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product 1-tosyldispiro[azetidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (62.8 mg, yield 15%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (s, 1H), 9.45 (br s, 1H), 8.48 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.50 (d, J = 8.1 Hz, 2H), 6.64 (s, 1H), 4.00 (s, 2H), 3.95 (s, 2H), 2.82 (d, J = 14.0 Hz, 2H), 2.40 (s, 3H), 2.25 (d, J = 14.1 Hz, 2H) ppm. HPLC purity: 98.71 % at 210 nm. MS (ESI⁺): m/z = 410.2. (M+H)⁺. [0218] 1-(Propylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0219] The title compound was prepared by the scheme and procedures shown below:

[0220] To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (9.6 g, 20.0 mmol) in THF (100 mL) was added iPrMgCl-LiCl (20.0 mL, 26.0 mmol) at -20^oC under N₂. The reaction was stirred at -20^oC for 1h, and then a solution of tert-butyl 2-oxo-7- azaspiro[3.5]nonane-7-carboxylate (4.8 g, 20.0 mmol) in THF (50 mL) was added slowly. The reaction mixture was warmed to room temperature for 3 h, then quenched with H₂O and extracted with EtOAc. The organic was concentrated and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give the product tert-butyl 2-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (7.3 g, yield 62%) as a light yellow solid.¹H NMR (300 MHz, CDCl₃): δ 8.31 (s, 1H), 7.31 (d, J = 3.1 Hz, 1H), 6.65 (d, J = 3.1 Hz, 1H), 3.61-3.39 (m, 2H), 3.39-3.20 (m, 2H), 2.87-2.40 (m, 6H), 2.05-1.92 (m, 2H), 1.90-1.75 (m, 3H), 1.48 (s, 9H), 1.12 (d, J = 7.4 Hz, 18H) ppm. MS (ESI⁺): m/z =592.2 and 594.2 (M+H)⁺. To a solution of tert-butyl 2-(5-bromo-1-(triisopropylsilyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.8 g, 3.0 mmol) in THF (40 mL) were added (BPin)2 (1.5 g, 6.0 mmol), KOAc (880 mg, 9.0 mmol) and (dppf)PdCl2 (880 mg, 1.2 mmol) under N2 atmosphere. The reaction mixture was stirred at 75^oC for 2 d and then filtered. The filtrate was concentrated, and the residue was dissolved in THF (40 mL).6N HCl (5 mL) was added and the mixture was stirred for 30 min. It was extracted with EtOAc, and the organic was concentrated to give the crude product tert-butyl 3''-hydroxy-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxylate (2.7 g, crude) as a black solid. MS (ESI⁺): m/z =384.2 (M+H)⁺. To a solution of tert- butyl 3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxylate (2.7 g, crude) in DCM (20 mL) was added TFA (10 mL) and the reaction mixture was stirred for 1h. It was poured into water and extracted with DCM to remove organic impurity. The aqueous solution was concentrated to give the crude product dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (1.5 g, crude) as a yellow solid. MS (ESI⁺): m/z = 284.2 (M+H)⁺. To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (400 mg, crude) in Et2O (10 mL) were added aq. NaOH (20%, 0.2 mL) and propane-1- sulfonyl chloride (142 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 30 min and it was poured into water. It was acidified by 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (NH₄HCO₃ in ACN and H₂O) to give the product 1-(propylsulfonyl)dispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (4.0 mg, yield 1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s, 1H), 9.23 (br s, 1H), 8.48 (s, 1H), 7.60 (d, J = 3.3 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H), 3.28-3.21 (m, 2H), 3.21-3.10 (m, 2H), 3.06-2.93 (m, 2H), 2.63-2.55 (m, 2H), 2.28-2.18 (m, 2H), 2.08-1.98 (m, 2H), 1.93-1.79 (m, 2H), 1.77-1.63 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 97.82% at 210 nm and 96.18% at 254 nm. MS (ESI⁺): m/z = 389.8 (M+H)⁺. [0221] 1-(Ethylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0222] The title compound was prepared by the scheme and procedures shown below:

[0223] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (450 mg, crude) in Et2O (10 mL) were added aq. NaOH (20%, 0.2 mL) and ethanesulfonyl chloride (128 mg, 1.0 mmol) at room temperature. It was stirred at room temperature for 30 min, poured into water, acidified with 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (NH4HCO3 in ACN and H₂O) to give the product 1-(ethylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (1.7 mg, yield 0.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.25 (br s, 1H), 8.49 (s, 1H), 7.62 (s, 1H), 6.70 (s, 1H), 3.26 (s, 2H), 3.18 (s, 2H), 3.10-2.98 (m, 2H), 2.59 (d, J = 13.5 Hz, 2H), 2.24 (d, J = 13.8 Hz, 2H), 2.03 (s, 2H), 1.86 (s, 2H), 1.22 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 99.70% at 210 nm and 95.66% at 254 nm. MS (ESI⁺): m/z =376.2 (M+H)⁺. [0224] Cyclohexyl(3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0225] The title compound was prepared by the scheme and procedures shown below:

[0226] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (500 mg, crude) in DMF (10 mL) were added cyclohexanecarboxylic acid (128 mg, 1.0 mmol), DIPEA (0.4 mL) and HATU (380 mg, 1.0 mmol). The reaction was stirred at room temperature for 1h, poured into water and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product cyclohexyl(3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone (23.4 mg, yield 6%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.27 (br s, 1H), 8.50 (s, 1H), 7.63 (s, 1H), 6.71 (s, 1H), 3.67-3.30 (m, 4H), 2.68-2.55 (m, 4H), 2.33-2.15 (m, 2H), 2.05-1.84 (m, 2H), 1.84-1.50 (m, 7H), 1.44-1.05 (m, 4H) ppm. HPLC purity: 94.41% at 210 nm. MS (ESI⁺): m/z =394.4 (M+H)⁺. [0227] (3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone

[0228] The title compound was prepared by the scheme and procedures shown below:

[0229] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (500 mg, crude) in DMF (10 mL) were added benzoic acid (122 mg, 1.0 mmol), DIPEA (0.4 mL) and HATU (380 mg, 1.0 mmol). The reaction was stirred at room temperature for 1h, poured into water and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product (32.4 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.21 (s, 1H), 9.35 (br s, 1H), 8.51 (s, 1H), 7.65 (s, 1H), 7.55-7.30 (m, 5H), 6.71 (s, 1H), 3.90-3.10 (m, 4H), 2.74-2.56 (m, 2H), 2.36-2.20 (m, 2H), 2.12-1.62 (m, 4H) ppm. HPLC purity: 95.85% at 210 nm. MS (ESI⁺): m/z =388.2 (M+H)⁺. [0230] 3''-Hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0231] The title compound was prepared by the scheme and procedures shown below:

[0232] To a solution of 2,2,2-trifluoroethanamine (200 mg, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at room temperature for 30 min. Then dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) and Et₃N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight. It was concentrated and the residue was purified by prep-HPLC (TFA in CH₃CN and H₂O) to give the product 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxamide (7.9 mg, yield 2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (br s, 1H), 9.29 (br s, 1H), 8.51 (s, 1H), 7.64 (s, 1H), 7.20-7.08 (m, 1H), 6.73 (s, 1H), 3.90-3.75 (m, 2H), 3.51-3.25 (m, 4H), 2.59 (d, J = 13.7 Hz, 2H), 2.24 (d, J = 13.6 Hz, 2H), 1.91 (s, 2H), 1.74 (s, 2H) ppm. HPLC purity: 98.40 % at 210 nm and 91.00 % at 254 nm. MS (ESI⁺): m/z = 408.8 (M+H)⁺. [0233] 3-(3''-Hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile

[0234] The title compound was prepared by the scheme and procedures shown below:

[0235] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (200 mg, crude) in DMF (5 mL) were added 2-cyanoacetic acid (85 mg, 1.0 mmol), DIPEA (0.2 mL) and HATU (190 mg, 0.5 mmol). The reaction was stirred at room temperature for 1h and it was poured into water. It was extracted with EtOAc and the organic was concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 3-(3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborole-[4,3- d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile (8.8 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.13 (br s, 1H), 9.29 (br s, 1H), 8.51 (s, 1H), 7.64 (s, 1H), 6.73 (s, 1H), 4.07 (s, 2H), 3.63-3.22 (m, 4H), 2.61 (d, J = 11.4 Hz, 2H), 2.25 (d, J = 13.8 Hz, 2H), 2.05-1.88 (m, 2H), 1.88-1.68 (m, 2H) ppm. HPLC purity: 96.19% at 210 nm. MS (ESI⁺): m/z = 350.9 (M+H)⁺. [0236] 1-tosyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol

[0237] The title compound was prepared by the scheme and procedures shown below:

[0238] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in Et₂O (10 mL) were added aq. NaOH (20%, 0.2 mL) and 4-methylbenzene-1-sulfonyl chloride (190 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 30 min and it was poured into water. It was acidified with 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep- HPLC (NH4HCO3 in ACN and H2O) to give the product 1-tosyldispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (27.1 mg, yield 6% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.96 (s, 1H), 9.19 (s, 1H), 8.45 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 1.6 Hz, 1H), 3.10- 2.96 (m, 2H), 2.96-2.83 (m, 2H), 2.49-2.44 (m, 2H), 2.38 (s, 3H), 2.16-1.95 (m, 4H), 1.92-1.79 (m, 2H) ppm. HPLC purity: 99.08% at 210 nm and 92.06% at 254 nm. MS (ESI⁺): m/z =438.2 (M+H)⁺. [0239] N-ethyl-3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo-[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0240] The title compound was prepared by the scheme and procedures shown below:

[0241] To a solution of ethyl amine (1 mL in THF, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at room temperature for 30 min. Then dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (NH4HCO3 in CH3CN and H2O) to give the product N-ethyl-3''-hydroxy-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxamide (35.6 mg, yield 9%) as a white solid.¹H NMR (300 MHz, DMSO-d₆): δ 11.98 (s, 1H), 9.20 (s, 1H), 8.48 (s, 1H), 7.59 (d, J = 2.6 Hz, 1H), 6.68 (s, 1H), 6.45 (t, J = 5.1 Hz, 1H), 3.40-3.33 (m, 2H), 3.31-3.20 (m, 2H), 3.10-3.00 (m, 2H), 2.57 (d, J = 13.6 Hz, 2H), 2.22 (d, J = 13.7 Hz, 2H), 1.96-1.82 (m, 2H), 1.81-1.61 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 98.01 % at 210 nm. MS (ESI⁺): m/z =355.2 (M+H)⁺. [0242] ethyl 3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate

[0243] The title compound was prepared by the scheme and procedures shown below:

[0244] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in DCM (10 mL) were added Et₃N (0.4 mL) and ethyl carbonochloridate (108 mg, 1.0 mmol) at 0^oC. The reaction was stirred at 0^oC for 1h, poured into water and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in CH₃CN and H₂O) to give the product ethyl 3''-hydroxy-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxylate (8 mg, yield 2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 9.22 (s, 1H), 8.48 (s, 1H), 7.60 (d, J = 3.4 Hz, 1H), 6.67 (d, J = 3.4 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.52-3.41 (m, 2H), 3.41-3.33 (m, 2H), 2.58 (d, J = 13.8 Hz, 2H), 2.23 (d, J = 13.8 Hz, 2H), 2.00-1.84 (m, 2H), 1.83-1.65 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 97.26 % at 210 nm. MS (ESI⁺): m/z =356.2 (M+H)⁺ [0245] 1-(methylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0246] The title compound was prepared by the scheme and procedures shown below:

[0247] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and methanesulfonyl chloride (114 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 30 min, poured into water, acidified with 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product 1-(methylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (11.7 mg, yield 3% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.35 (br s, 1H), 8.51 (s, 1H), 7.64 (t, J = 2.7 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 3.29-3.15 (m, 2H), 3.15-3.02 (m, 2H), 2.85 (s, 3H), 2.60 (d, J = 13.8 Hz, 2H), 2.25 (d, J = 13.8 Hz, 2H), 2.14-1.98 (m, 2H), 1.97-1.80 (m, 2H) ppm. HPLC purity: 97.72% at 210 nm. MS (ESI⁺): m/z =362.2 (M+H)⁺. [0248] 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0249] The title compound was prepared by the scheme and procedures shown below:

[0250] To a solution of methanamine (1 mL in THF, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at room temperature for 30 min. Then dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (TFA in CH3CN and H2O) to give the product 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (32.8 mg, yield 9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.17 (s, 1H), 9.30 (br s, 1H), 8.51 (s, 1H), 7.65 (s, 1H), 6.74 (s, 1H), 6.41 (br s, 1H), 3.43-3.17 (m, 4H), 2.65-2.53 (m, 5H), 2.29-2.13 (m, 2H), 1.99-1.81 (m, 2H), 1.81-1.62 (m, 2H) ppm. HPLC purity: 98.70% at 210 nm and 91.79% at 254 nm. MS (ESI⁺): m/z = 341.2 (M+H)⁺. [0251] 1-(isopropylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0252] The title compound was prepared by the scheme and procedures shown below:

[0253] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (450 mg, crude) in Et2O (10 mL) were added aq. NaOH (20%, 0.2 mL) and propane-2-sulfonyl chloride (142 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 30 min, poured into water, acidified with 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1-(isopropylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (12.0 mg, yield 3% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.30 (br s, 1H), 8.50 (s, 1H), 7.63 (s, 1H), 6.71 (s, 1H), 3.40-3.15 (m, 4H), 2.64-2.54 (m, 2H), 2.30-2.17 (m, 2H), 2.08-1.93 (m, 2H), 1.92-1.74 (m, 2H), 1.23 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 96.92% at 210 nm. MS (ESI⁺): m/z =390.2 (M+H)⁺. [0254] 1-(isobutylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0255] The title compound was prepared by the scheme and procedures shown below:

[0256] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in Et2O (10 mL) were added aq. NaOH (20%, 0.2 mL) and 2-methylpropane-1-sulfonyl chloride (156 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 30 min, poured into water, acidified with 6N HCl and extracted with EtOAc. The organic was concentrated and the residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1-(isobutylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (15.5 mg, yield 4% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (s, 1H), 9.33 (br s, 1H), 8.50 (s, 1H), 7.63 (s, 1H), 6.70 (s, 1H), 3.33-3.03 (m, 4H), 2.89 (d, J = 6.5 Hz, 2H), 2.70-2.60 (m, 2H), 2.30-2.20 (m, 2H), 2.20-2.10 (m, 1H), 2.09-1.97 (m, 2H), 1.95-1.78 (m, 2H), 1.04 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 94.59% at 210 nm. MS (ESI⁺): m/z =404.2 (M+H)⁺. [0257] 3''-hydroxy-N-isopropyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0258] The title compound was prepared by the scheme and procedures shown below:

[0259] To a solution of propan-2-amine (1 mL in THF, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at room temperature for 30 min. Then dispiro-[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (TFA in CH3CN and H2O) to give the product 3''-hydroxy-N-isopropyl-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (22 mg, yield 6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (s, 1H), 9.28 (br s, 1H), 8.51 (s, 1H), 7.66 (s, 1H), 6.73 (s, 1H), 6.16 (br s, 1H), 3.87-3.67 (m, 1H), 3.44-3.19 (m, 4H), 2.66-2.54 (m, 2H), 2.30-2.14 (m, 2H), 1.96-1.79 (m, 2H), 1.79-1.61 (m, 2H), 1.06 (d, J = 6.5 Hz, 6H) ppm. HPLC purity: 99.22% at 210 nm. MS (ESI⁺): m/z =369.2 (M+H)⁺. [0260] 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0261] The title compound was prepared by the scheme and procedures shown below:

[0262] To a solution of propan-1-amine (118 mg, 2.0 mmol) in DCM (10 mL) was added CDI (324 mg, 2 mmol) and the reaction was stirred at room temperature for 30 min. Then dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) and Et3N (0.4 mL) in DCM (10 mL) were added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by prep-HPLC (TFA in CH₃CN and H₂O) to give the product 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (12.4 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.31 (br s, 1H), 8.51 (s, 1H), 7.64 (s, 1H), 6.72 (s, 1H), 6.48 (s, 1H), 3.45-3.18 (m, 4H), 3.05-2.89 (m, 2H), 2.64-2.53 (m, 2H), 2.29-2.16 (m, 2H), 1.98-1.80 (m, 2H), 1.80-1.63 (m, 2H), 1.52-1.32 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 98.73% at 210 nm. MS (ESI⁺): m/z =369.2 (M+H)⁺. [0263] Propyl 3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate [

[0265] To a solution of dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in DCM (10 mL) were added Et3N (0.4 mL) and propyl carbonochloridate (122 mg, 1.0 mmol) at 0^oC. The reaction was stirred at 0^oC for 30 min and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product propyl 3''-hydroxy-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (33.9 mg, yield 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (s, 1H), 9.43 (br s, 1H), 8.53 (s, 1H), 7.68 (s, 1H), 6.76 (s, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.60-3.15 (m, 4H), 2.68-2.53 (m, 2H), 2.35-2.16 (m, 2H), 2.01- 1.85 (m, 2H), 1.85-1.68 (m, 2H), 1.68-1.47 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 97.89 % at 210 nm and 96.70% at 254 nm. MS (ESI⁺): m/z =370.2 (M+H)⁺. [0266] propyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate

[0267] The title compound was prepared by the scheme and procedures shown below:

[0268] To a solution of ethyl 4-oxocyclohexanecarboxylate (120 g, 0.71 mol) in toluene (600 mL) were added ethane-1,2-diol (48 g, 0.78 mol) and p-TsOH (2.4 g, 12.6 mmol) at rt. The reaction was stirred at 110^oC overnight, cooled to rt, poured into water and separated. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 20/1) to give ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (94 g, yield 62%) as a light oil.¹H NMR (300 MHz, CDCl₃): δ 4.12 (q, J = 7.5 Hz, 2H), 3.94 (s, 4H), 2.43-2.22 (m, 1H), 2.02-1.66 (m, 6H), 1.65-1.45 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H) ppm. To a solution of diisopropylamine (51.5 g, 0.51 mol) in THF (500 mL) was added n-BuLi (213 mL, 2.4 N) slowly at -30^oC under N2 atmosphere. It was stirred at -30^oC for 30 min. Then ethyl 1,4- dioxaspiro[4.5]decane-8-carboxylate (105 g, 0.49 mol) in THF (500 mL) was added at -78^oC and stirred at this temperature for 1h. Ethyl carbonochloridate (64.0 g, 0.59 mol) in THF (250 mL) was added dropwise. The reaction was stirred at -78^oC for 1 h, quenched by water and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give diethyl 1,4-dioxaspiro[4.5]decane-8,8- dicarboxylate (94.0 g, yield 67%) as a light oil.¹H NMR (400 MHz, CDCl₃): δ 4.19 (q, J = 7.1 Hz, 4H), 3.94 (s, 4H), 2.24-2.08 (m, 4H), 1.73-1.63 (m, 4H), 1.25 (t, J = 7.1 Hz, 6H) ppm. To a solution of LiAlH₄ (31.5 g, 0.83 mol) in THF (750 mL) was added diethyl 1,4-dioxaspiro[4.5]- decane-8,8-dicarboxylate (94.0 g, 0.33 mol) in THF (750 mL) dropwise at 0^oC under N₂ atmosphere. The reaction was stirred at 0^oC for 1 h, quenched with H₂O (31.5 mL), dried with Na₂SO₄, diluted with EtOAc and filtered. The cake was washed with EtOAc, THF, and DCM/MeOH (10:1). The organic was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 100/1 to 10/1) to give (1,4-dioxaspiro[4.5]decane-8,8- diyl)dimethanol (38.0 g, yield 57%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 3.95 (s, 4H), 3.65 (s, 4H), 2.43 (br s, 2H), 1.65-1.60 (m, 4H), 1.58-1.53 (m, 4H) ppm. To a solution of this dimethanol compound (30 g, 0.15 mol) in MeCN (300 mL) were added DIPEA (58 g, 0.45 mol) and trifluoromethanesulfonic anhydride (93.0 g, 0.33 mol) at -30^oC under N₂ atmosphere. The reaction was stirred at -30^oC for 1h, and then (2,4-dimethoxy-phenyl)-methanamine (30.0 g, 0.18 mol) and DIPEA (58.0 g, 0.45 mol) were added. It was stirred at 80^oC overnight, poured into water and extracted with DCM. The organic was concentrated and the residue was purified by column chromatography (DCM/MeOH = 100/1 to 10/1) to give 2-(2,4-dimethoxybenzyl)-8,11- dioxa-2-azadispiro[3.2.47.24]tridecane (25.0 g, yield 50%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆): δ 7.36-7.19 (m, 1H), 6.67-6.41 (m, 2H), 3.92-3.75 (m, 12H), 3.20-3.15 (m, 4H), 1.86- 1.66 (m, 4H), 1.61-1.42 (m, 4H) ppm. In a high-pressure autoclave, 2-(2,4-dimethoxybenzyl)- 8,11-dioxa-2-azadispiro[3.2.47.24]-tridecane (25.0 g, 75.0 mmol), Pd/C (10%, 5.0 g), Et3N (23.0 g, 225 mmol) and Boc2O (20.0 g, 90.0 mmol) were mixed in MeOH (300 mL). It was purged with H2 three times and stirred at 80^oC overnight. The reaction was cooled and filtered, and the cake was washed with MeOH. The filtrate was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl 8,11-dioxa-2- azadispiro[3.2.47.24]tridecane-2-carboxylate (16.0 g, yield 75%) as a white solid.¹H NMR (300 MHz, CDCl₃): δ 3.93 (s, 4H), 3.61 (s, 4H), 1.84-1.74 (m, 4H), 1.64-1.55 (m, 4H), 1.44 (s, 9H) ppm. This intermediate (3.0 g, 10.6 mmol) was dissolved in acetone/H2O (10:1, 60 mL) and then p-TsOH (400 mg, 2.1 mmol) was added. The reaction was stirred at 45^oC for 4 h and concentrated. The residue was purified by column chromatography (PE/EtOAc = 20/1 to 10/1) to give tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.3 g, yield 52%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 3.80 (s, 4H), 2.45-2.27 (m, 4H), 2.14-1.98 (m, 4H), 1.48 (s, 9H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4.8 g, 10.0 mmol) in THF (50 mL) was added i-PrMgCl-LiCl (7.7 mL, 10.0 mmol) at -30^oC under N₂. The reaction was stirred at -30^oC for 1 h, and then tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2- carboxylate (2.4 g, 10.0 mmol) in THF (25 mL) was added dropwise. The reaction was stirred at room temperature for 2 h, quenched with H₂O and extracted with EtOAc. The organic was concentrated and the residue was purified by column chromatography (PE/EtOAc = 50/1 to 10/1) to give tert-butyl 7-(5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-hydroxy-2- azaspiro[3.5]nonane-2-carboxylate (1.7 g, yield 29%) as a light yellow solid.¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 7.19-7.17 (m, 1H), 7.02 (d, J = 3.4 Hz, 1H), 3.75 (s, 2H), 3.57 (s, 2H), 2.83-2.61 (m, 2H), 2.07-1.85 (m, 2H), 1.86-1.62 (m, 7H), 1.40 (s, 9H), 1.03 (d, J = 7.5 Hz, 18H) ppm. To a solution of this intermediate (1.7 g, 2.9 mmol) in THF (40 mL) were added (PinB)₂ (1.1 g, 4.4 mmol), KOAc (852 mg, 8.7 mmol) and Pd(dppf)Cl₂ (810 mg, 1.1 mmol) under N₂ atmosphere. The reaction was stirred at 70^oC overnight, cooled to rt and filtered. The filtrate was concentrated, and the residue was dissolved in THF (40 mL).6N HCl (5 mL) was added and the reaction was stirred for 30 min and extracted with EtOAc. The organic was concentrated to give tert-butyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxa-borolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxylate (3.0 g, crude) as a black solid. MS (ESI⁺): m/z =384.2 (M+1)⁺. To a solution of this intermediate (3.0 g, crude) in DCM (30 mL) was added TFA (10 mL). The reaction was stirred for 1h, poured into water and extracted with DCM. The aqueous solution was concentrated to give dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (2.1 g, crude) as a yellow solid. MS (ESI⁺): m/z = 284.2 (M+1)⁺. To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (300 mg, crude) in THF (5 mL) were added Et3N (0.2 mL) and propyl carbonochloridate (61 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 30 min and it was concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product propyl 3''-hydroxy-3'',6''- dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxylate (8.0 mg, yield 4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.91 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 7.52 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 4.03-3.78 (m, 4H), 3.71-3.48 (m, 2H), 2.21-2.03 (m, 2H), 2.03-1.81 (m, 4H), 1.65-1.49 (m, 2H), 1.49-1.32 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 95.60% at 210 nm and 95.44% at 254 nm. MS (ESI⁺): m/z = 370.2. [0269] 1-(propylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0270] The title compound was prepared by the scheme and procedures shown below:

[0271] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol TFA salt (300 mg, crude) in THF (5 mL) were added Et₃N (0.2 mL) and propane-1-sulfonyl chloride (71 mg, 0.5 mmol) at room temperature. The reaction was stirred at room temperature for 1h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product 1-(propylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (5.8 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.91 (s, 1H), 9.13 (s, 1H), 8.50 (s, 1H), 7.53 (t, J = 2.9 Hz, 1H), 6.51 (d, J = 1.9 Hz, 1H), 3.91 (s, 2H), 3.63 (s, 2H), 3.19-3.06 (m, 2H), 2.20-2.04 (m, 2H), 2.03- 1.82 (m, 4H), 1.81-1.66 (m, 2H), 1.41 (d, J = 13.1 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 95.76% at 210 nm and 94.13% at 254 nm. MS (ESI⁺): m/z =390.2 (M+H)⁺. [0272] 1-(isobutylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0273] The title compound was prepared by the scheme and procedures shown below:

[0274] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (300 mg, crude) in THF (5 mL) were added Et3N (0.2 mL) and 2- methylpropane-1-sulfonyl chloride (78 mg, 0.5 mmol) at room temperature. It was stirred at rt for 1h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product 1-(isobutylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (11.3 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.92 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 7.53 (t, J = 2.9 Hz, 1H), 6.51 (d, J = 1.9 Hz, 1H), 3.91 (s, 2H), 3.63 (s, 2H), 3.06 (d, J = 6.5 Hz, 2H), 2.23-2.02 (m, 3H), 1.93 (d, J = 7.2 Hz, 4H), 1.41 (d, J = 13.0 Hz, 2H), 1.06 (d, J = 6.7 Hz, 6H) ppm. HPLC purity: 93.35 % at 210 nm. MS (ESI⁺): m/z =404.2 (M+H)⁺. [0275] 1-tosyldispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol

[0276] The title compound was prepared by the scheme and procedures shown below:

[0277] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (300 mg, crude) in THF (5 mL) were added Et₃N (0.2 mL) and 4- methylbenzene-1-sulfonyl chloride (95 mg, 0.5 mmol) at room temperature. It was stirred at rt for 1h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product 1-tosyldispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (7.4 mg, yield 3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.18 (br s, 1H), 8.50 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 6.59 (s, 1H), 3.75 (s, 2H), 3.44 (s, 2H), 2.43 (s, 3H), 2.01 (t, J = 12.1 Hz, 2H), 1.78 (t, J = 11.8 Hz, 2H), 1.45 (d, J = 12.8 Hz, 2H), 1.30 (d, J = 13.2 Hz, 2H) ppm. HPLC purity: 97.71 % at 210 nm. MS (ESI⁺): m/z = 438.2 (M+H)⁺. [0278] Ethyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate

[0279] The title compound was prepared by the scheme and procedures shown below:

[0280] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (600 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and ethyl carbonochloridate (108 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred at rt for 1h and concentrated. The residue was purified by prep-HPLC (FA in ACN and H2O) to give the product ethyl 3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxa- borolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (41 mg, yield 12%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.91 (s, 1H), 9.13 (s, 1H), 8.50 (s, 1H), 7.53 (d, J = 2.7 Hz, 1H), 6.52 (d, J = 1.8 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.90 (s, 2H), 3.63 (s, 2H), 2.21-2.02 (m, 2H), 2.02- 1.84 (m, 4H), 1.40 (d, J = 13.1 Hz, 2H), 1.18 (t, J = 7.0 Hz, 3H) ppm. HPLC purity: 98.78% at 210 nm and 95.49% at 254 nm. MS (ESI⁺): m/z =356.2 (M+H)⁺. [0281] (3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone

[0282] The title compound was prepared by the scheme and procedures shown below:

[0283] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (600 mg, crude) in THF (10 mL) were added benzoic acid (122 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at rt for 1h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product (3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone (25.1 mg, yield 6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.43 (s, 1H), 9.35 (br s, 1H), 8.58 (s, 1H), 7.80- 7.59 (m, 3H), 7.59-7.39 (m, 3H), 6.74 (d, J = 22.7 Hz, 1H), 4.33 (s, 1H), 4.07 (s, 1H), 4.04 (s, 1H), 3.80 (s, 1H), 2.26-2.06 (m, 2H), 2.06-1.83 (m, 4H), 1.55-1.39 (m, 2H) ppm. HPLC purity: 98.84% at 210 nm and 96.95% at 254 nm. MS (ESI+): m/z =388.2 (M+H)⁺. [0284] 1-(isopropylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0285] The title compound was prepared by the scheme and procedures shown below:

[0286] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (600 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and propane-2- sulfonyl chloride (142 mg, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 0.5h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1-(isopropylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (21.2 mg, yield 5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.92 (s, 1H), 9.14 (s, 1H), 8.50 (s, 1H), 7.53 (t, J = 2.7 Hz, 1H), 6.54 (d, J = 1.8 Hz, 1H), 3.91 (s, 2H), 3.63 (s, 2H), 3.29-3.17 (m, 1H), 2.19-2.07 (m, 2H), 2.01- 1.83 (m, 4H), 1.41 (d, J = 13.1 Hz, 2H), 1.26 (d, J = 6.8 Hz, 6H) ppm. HPLC purity: 98.23% at 210 nm and 87.25% at 254 nm. MS (ESI⁺): m/z =390.2 (M+H)⁺. [0287] 1-(ethylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0288] The title compound was prepared by the scheme and procedures shown below:

[0289] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (600 mg, crude) in THF (10 mL) were added Et3N (0.4 mL) and ethyl sulfonyl chloride (128 mg, 1.0 mmol) at room temperature. It was stirred at rt for 0.5h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1-(ethylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (32 mg, yield 9%) as a white solid.¹H NMR (400 MHz, DMSO- d6): δ 12.24 (s, 1H), 9.24 (br s, 1H), 8.56 (s, 1H), 7.62 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 3.93 (s, 2H), 3.64 (s, 2H), 3.16 (q, J = 7.3 Hz, 2H), 2.20-2.06 (m, 2H), 1.95 (d, J = 6.8 Hz, 4H), 1.44 (d, J = 13.0 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 97.11% at 210 nm and 94.31% at 254 nm. MS (ESI⁺): m/z =376.2 (M+H)⁺. [0290] 1-(methylsulfonyl)dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0291] The title compound was prepared by the scheme and procedures shown below:

[0292] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (600 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and methyl sulfonyl chloride (115 mg, 1.0 mmol) at rt. It was stirred at rt for 1 h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1- (methylsulfonyl)-dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (39.4 mg, yield 11%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.26 (s, 1H), 9.51 (br s, 1H), 8.57 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 3.94 (s, 2H), 3.65 (s, 2H), 3.04 (s, 3H), 2.19-2.10 (m, 2H), 1.96 (s, 4H), 1.45 (d, J = 14.2 Hz, 2H) ppm. HPLC purity: 98.48% at 210 nm and 98.30% at 254 nm. MS (ESI⁺): m/z =362.2 (M+H)⁺. [0293] 3-(3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile

[0294] The title compound was prepared by the scheme and procedures shown below:

[0295] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added 2-cyanoacetic acid (85 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at room temperature for 1 h and then concentrated. The residue was purified by pre- HPLC (NH4HCO3 in ACN and H2O) to give the product 3-(3''-hydroxy-3'',6''- dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)- 3-oxopropanenitrile (45.9 mg, yield 13%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.96 & 11.93 (2 s, 1H), 9.15 (s, 1H), 8.51 (s, 1H), 7.56 & 7.54 (2 s, 1H), 6.55 & 6.47 (2 s, 1H), 4.13 (s, 1H), 3.89 (d, J = 13.2 Hz, 2H), 3.77 (d, J = 5.5 Hz, 2H), 3.64 (s, 1H), 2.21-2.03 (m, 2H), 2.03-1.79 (m, 4H), 1.42 (t, J = 12.5 Hz, 2H) ppm. HPLC purity: 96.41% at 210 nm. MS (ESI⁺): m/z = 351.1 (M+H)⁺. [0296] Cyclohexyl(3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0297] The title compound was prepared by the scheme and procedures shown below:

[0298] To a solution of dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (10 mL) were added cyclohexanecarboxylic acid (128 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at rt. The reaction was stirred at rt for 1 h and then concentrated. The residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product cyclohexyl(3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'- cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone (116 mg, yield 30%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (s, 1H), 9.36 (s, 1H), 8.59 (s, 1H), 7.70 (s, 1H), 6.76-6.71 (m, 1H), 4.13 (s, 1H), 3.86 (s, 1H), 3.81 (s, 1H), 3.54 (s, 1H), 2.37-2.08 (m, 3H), 2.02-1.79 (m, 4H), 1.79-1.53 (m, 5H), 1.47 (d, J = 13.3 Hz, 2H), 1.40-1.05 (m, 5H) ppm. HPLC purity: 97.62% at 210 nm. MS (ESI⁺): m/z = 394.2 (M+H)⁺. [0299] 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0300] The title compound was prepared by the scheme and procedures shown below:

[0301] To a solution of methanamine (2 mL, 1N in THF) in DCM (5 mL) was added CDI (324 mg, 2.0 mmol) at 25^oC, and the reaction was stirred for 30 min. And then Et3N (0.4 mL) and dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (5 mL) were added. The reaction mixture was stirred at 25^oC for 4 h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 3''-hydroxy-N-methyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (108 mg, yield 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.72 (br s, 1H), 12.44 (s, 1H), 8.59 (s, 1H), 7.69 (s, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.17 (br s, 1H), 3.78 (s, 2H), 3.53 (s, 2H), 2.56 (s, 3H), 2.21-2.02 (m, 2H), 2.01-1.75 (m, 4H), 1.46 (d, J = 13.2 Hz, 2H) ppm. HPLC purity: 98.79% at 210 nm. MS (ESI⁺): m/z = 341.2 (M+H)⁺. [0302] 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[azetidine-3,1'- cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0303] The title compound was prepared by using the scheme and procedures shown below:

[0304] To a solution of 2,2,2-trifluoroethanamine (200 mg, 2.0 mmol) in DCM (5 mL) was added CDI (324 mg, 2.0 mmol) at 25^oC, and the mixture was stirred for 30 min. And then Et₃N (0.4 mL) and dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)- ol (400 mg, crude) in THF (5 mL) were added. The reaction mixture was stirred at 25^oC for 4 h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 3''-hydroxy-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (105 mg, yield 13%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (s, 1H), 9.44 (br s, 1H), 8.57 (s, 1H), 7.65 (s, 1H), 6.96 (t, J = 6.2 Hz, 1H), 6.56 (s, 1H), 3.85 (s, 2H), 3.81-3.70 (m, 2H), 3.60 (s, 2H), 2.21-2.04 (m, 2H), 2.02-1.75 (m, 4H), 1.45 (d, J = 13.2 Hz, 2H) ppm. HPLC purity: 98.84% at 210 nm and 97.25% at 254 nm. MS (ESI⁺): m/z = 409.2 (M+H)⁺. [0305] N-ethyl-3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0306] The title compound was prepared by using the scheme and procedures shown below:

[0307] To a solution of ethanamine (2 mL, 1N in THF) in DCM (5 mL) was added CDI (324 mg, 2.0 mmol) at 25^oC, and the reaction mixture was stirred for 30 min. And then Et₃N (0.4 mL) and dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (400 mg, crude) in THF (5 mL) were added. The reaction was stirred at 25^oC for 4 h and concentrated. The residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product N-ethyl-3''-hydroxy-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (50.5 mg, yield 11%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.31 (s, 1H), 9.44 (br s, 1H), 8.57 (s, 1H), 7.66 (s, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.21 (s, 1H), 3.77 (s, 2H), 3.53 (s, 2H), 3.02 (q, J = 7.0 Hz, 2H), 2.22- 2.03 (m, 2H), 2.01-1.76 (m, 4H), 1.45 (d, J = 13.3 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 98.39% at 210 nm. MS (ESI⁺): m/z = 355.2 (M+H)⁺. [0308] 3''-hydroxy-N-isopropyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0309] The title compound was prepared by using the scheme and procedures shown below:

[0310] To a solution of propan-2-amine (118 mg, 2.0 mmol) in DCM (5 mL) was added CDI (324 mg, 2.0 mmol) at 25^oC, and the reaction mixture was stirred for 30 min. And then Et3N (0.4 mL) and dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol (400 mg, crude) in THF (5 mL) were added. It was stirred at 25^oC for 4 h and concentrated. The residue was purified by prep-HPLC (NH4HCO3 in ACN and H2O) to give the product 3''-hydroxy-N-isopropyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (11.7 mg, yield 2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.95 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 7.55 (s, 1H), 6.43 (s, 1H), 5.95 (d, J = 8.0 Hz, 1H), 3.76 (s, 2H), 3.75-3.63 (m, 1H), 3.51 (s, 2H), 2.19-2.05 (m, 2H), 1.99-1.79 (m, 4H), 1.41 (d, J = 13.4 Hz, 2H), 1.06 (d, J = 6.5 Hz, 6H) ppm. HPLC purity: 97.28% at 210 nm. MS (ESI⁺): m/z = 369.2 (M+H)⁺. [0311] 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0312] The title compound was prepared by using the scheme and procedures shown below:

[0313] To a solution of propan-1-amine (118 mg, 2.0 mmol) in DCM (5 mL) was added CDI (324 mg, 2.0 mmol) at 25^oC, and the reaction mixture was stirred for 30 min. And then Et3N (0.4 mL) and dispiro[azetidine-3,1'-cyclohexane-4',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol (400 mg, crude) in THF (5 mL) were added. It was stirred at 25^oC for 4 h and concentrated. The residue was purified by prep-HPLC (NH4HCO3 in ACN and H2O) to give the product 3''-hydroxy-N-propyl-3'',6''-dihydrodispiro[azetidine-3,1'-cyclohexane-4',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (34 mg, yield 5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.94 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 7.55 (s, 1H), 6.42 (d, J = 2.8 Hz, 1H), 6.22 (t, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.52 (s, 2H), 3.03-2.85 (m, 2H), 2.20-2.01 (m, 2H), 2.00-1.75 (m, 4H), 1.47-1.31 (m, 4H), 0.84 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 96.30% at 210 nm and 94.94% at 254 nm. MS (ESI⁺): m/z =369.2 (M+H)⁺. [0314] 2'-methyl-1-(propylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (isomers)

[0315] The title compounds were prepared by using the scheme and procedures shown below:

[0316] To a solution of tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (26 g, 116 mmol) and propan-2-amine (35 mL, 406 mmol) in Et2O (500 mL) was added TiCl4 (9.3 mL, 70 mmol) dropwise at -20^oC. It was then slowly warmed to rt and stirred at rt overnight. It was filtered through a pad of Celite and the filtrate was concentrated to dryness to give tert-butyl 2- (isopropylimino)-6-azaspiro[3.4]octane-6-carboxylate (30.8 g, crude) as a yellow oil. It was used in the next step without further purification. To a solution of tert-butyl 2-(isopropylimino)-6- azaspiro[3.4]octane-6-carboxylate (30 g, 116 mmol) in dry THF (300 mL) was added LDA (61 mL, 2M in THF) dropwise at -78^oC. After the addition was completed, the reaction mixture was stirred at -78^oC for 30 min. MeI (10.8 mL, 174 mmol) was added dropwise at -78^oC. The reaction mixture was stirred at the same temperature for 1 h, then warmed to 0^oC slowly, quenched with saturated NH4Cl, and extracted by EtOAc. The organic layer was concentrated in vacuo (35^oC) to dryness to give the crude tert-butyl (E)-2-(isopropylimino)-1-methyl-6- azaspiro[3.4]-octane-6-carboxylate (caution: unstable if using column chromatography to purify). The resulting intermediate was dissolved in Et2O (250 mL) and mixed with a solution of oxalic acid (21 g, 232 mmol) in H2O (250 mL).The mixture was stirred at 50^oC for 30 min. TLC showed the reaction was completed. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 95: 5) to give tert-butyl 1-methyl-2-oxo-6-azaspiro[3.4]-octane- 6-carboxylate (12.0 g, yield 43% over three steps).¹HNMR (400 MHz, CDCl₃): δ 3.66 – 3.41 (m, 3H), 3.37 – 3.15 (m, 2H), 3.09 – 2.76 (m, 2H), 2.15 – 2.05 (m, 1H), 1.77 – 1.65 (m, 1H), 1.46 (s, 9H), 1.10 (d, J = 7.3 Hz, 3H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H- pyrrolo[2,3-b]pyridine (9.6 g, 20 mmol) in THF (100 mL) was added i-PrMgCl-LiCl (20 mL, 20 mmol) at -20^oC under N2. The reaction was stirred at -20^oC for 1 h, and then a solution of tert- butyl 1-methyl-2-oxo-6-azaspiro[3.4]-octane-6-carboxylate (4.68 g, 20 mmol) in THF (50 mL) was slowly added. The reaction was warmed to room temperature for 2 h, quenched with H2O and extracted with EtOAc. The organic was concentrated and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl 2-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-1-methyl-6-azaspiro[3.4]octane-6- carboxylate as two fractions (Peak 1: 3.4 g, @ low polarity; Peak 2: 4.3 g, @ larger polarity, total: 7.7 g, yield 65% ) as a white solid. To a solution of tert-butyl 2-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy-1-methyl-6-azaspiro[3.4]octane-6- carboxylate (Peak 1, 3.4 g, 5.75 mmol) in 1,4-dioxane (25 mL) were added Pd(MeCN)₂Cl₂ (441 mg, 1.15 mmol), S-Phos (945 mg, 2.3 mmol), E₃N (1.7 g, 17.3 mmol) and BHPin (1.5 g, 11.5 mmol). The reaction mixture was stirred at 60^oC under N₂ atmosphere for 2 h, and LCMS showed no starting materials were left. The reaction mixture was filtered through a pad of Celite and the filtrate was mixed with 2N HCl (10 mL). It was stirred at rt for 10 min and extracted with DCM/MeOH (v/v = 10/1), the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1, then ethyl acetate : methanol = 10:1) to give tert-butyl 3''-hydroxy-2'- methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo-[2,3- b]pyridine]-1-carboxylate (600 mg, crude). Another isomeric intermediate of tert-butyl 3''- hydroxy-2'-methyl-3'',6''-dihydrodispiro-[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxylate (2.4 g, yellow foam solid) was obtained in a similar approach from tert-butyl 2-(5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydroxy- 1-methyl-6-azaspiro[3.4]octane-6-carboxylate (Peak 2, 4.3 g, 7.27 mmol). MS (ESI+): m/z = 384.2 (M+H)⁺. To a solution of tert-butyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (600 mg, Peak 1 series) in DCM (5 mL) was added TFA (2 mL) dropwise. It was then stirred at rt for 1 h, LCMS showed the reaction was completed. The solvent was removed under reduce pressure to give 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol TFA salt (600 mg, crude) as a black oil. MS (ESI⁺): m/z = 284.1 (M+H)⁺. Another isomeric intermediate of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo-[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (2.4 g, yellow oil, Peak 2 series) was obtained in a similar approach from its Boc-protected precursor (2.4 g, 6.3 mmol). MS (ESI⁺): m/z = 284.1 (M+H)⁺. To a solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (200 mg, Peak 1 series) in DCM (5 mL) was added Et3N (162 mg, 1.0 mmol), and the reaction mixture was stirred at room temperature for 30 min. A solution of propane-1-sulfonyl chloride (0.52 mmol, 0.25 mmol/mL ) in DCM (2 mL) was added, and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 2'- methyl-1-(propylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo-[4,3- d]pyrrolo[2,3-b]-pyridin]-3''(6''H)-ol (18.7 mg, yield 9% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 9.34 (br s, 1H), 8.55 (s, 1H), 7.66 (s, 1H), 6.83 (s, 1H), 3.64 (d, J = 9.5 Hz, 1H), 3.48 (d, J = 9.5 Hz, 1H), 3.33 (t, J = 7.0 Hz, 2H), 3.15 – 3.02 (m, 3H), 2.81 (d, J = 12.6 Hz, 1H), 2.28 – 2.10 (m, 3H), 1.80 – 1.68 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H) ppm. HPLC purity: 96.62% at 210 nm. MS (ESI⁺): m/z = 390.2 (M+H)⁺. Another isomeric compound of 2'-methyl-1-(propylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo-[4,3-d]-pyrrolo[2,3-b]-pyridin]-3''(6''H)-ol (52.6 mg, gray powder, yield 26%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO-d₆): δ 12.27 (s, 1H), 9.36 (br s, 1H), 8.53 (s, 1H), 7.67 (s, 1H), 6.91 (d, J = 2.0 Hz, 1H), 3.58 (d, J = 10.1 Hz, 1H), 3.49 – 3.30 (m, 3H), 3.18 – 3.05 (m, 3H), 2.84 (d, J = 12.5 Hz, 1H), 2.28 – 2.10 (m, 3H), 1.79 – 1.63 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H) ppm. HPLC purity: 98.14% at 210 nm and 97.85% at 254 nm. MS (ESI⁺): m/z = 390.2 (M+H)⁺. [0317] 1-(butylsulfonyl)-2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (Isomers)

[0318] The title compounds were prepared by using the scheme and procedures shown below:

[0319] To a solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (Peak 1, synthesized as shown in Example above, 200 mg, crude) in DCM (5 mL) was added Et3N (162 mg, 1.0 mmol) and the reaction was stirred at room temperature for 30 min. A solution of butane-1-sulfonyl chloride (0.52 mmol, 0.25 mmol/mL ) in DCM (2 mL) was added, and the reaction was stirred at room temperature overnight. The solvent was removed, and the residue was purified by prep-HPLC (TFA in ACN and H2O) to give the product 1-(butylsulfonyl)-2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (21.5 mg, yield 10%, Peak 1 series) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H), 9.50 (br s, 1H), 8.52 (s, 1H), 7.67 (s, 1H), 6.83 (d, J = 1.9 Hz, 1H), 3.64 (d, J = 9.5 Hz, 1H), 3.48 (d, J = 9.5 Hz, 1H), 3.33 (t, J = 7.0 Hz, 2H), 3.15 – 3.05 (m, 3H), 2.81 (d, J = 12.6 Hz, 1H), 2.27 – 2.14 (m, 3H), 1.72 – 1.60 (m, 2H), 1.50-1.37 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H) ppm. HPLC purity: 96.12% at 210 nm and 95.15% at 254 nm. MS (ESI⁺): m/z = 404.2. Another isomeric compound of 1-(butylsulfonyl)-2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (75.5 mg, white solid, yield 36%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.34 (br s, 1H), 8.51 (s, 1H), 7.63 (s, 1H), 6.86 (s, 1H), 3.58 (d, J = 10.0 Hz, 1H), 3.51 – 3.34 (m, 3H), 3.21 – 3.07 (m, 3H), 2.82 (d, J = 12.5 Hz, 1H), 2.26 – 2.10 (m, 3H), 1.71 – 1.59 (m, 2H), 1.47 – 1.34 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H) ppm. HPLC purity: 96.97% at 210 nm and 97.26% at 254 nm. MS (ESI⁺): m/z = 404.2. [0320] propyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (Isomers:)

[0321] The title compounds were prepared by using the scheme and procedures shown below:

[0322] To a solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (Peak 1, synthesized as shown in Example above, 200 mg, crude) in THF (5 mL) was added Et₃N (162 mg, 1.0 mmol) and the reaction was stirred at room temperature for 30 min. A solution of propyl carbonochloridate (0.52 mmol, 0.25 mmol/mL ) in THF (2 mL) was added, and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product propyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (22.1 mg, yield 12%, Peak 1 series) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (s, 1H), 9.46 (br s, 1H), 8.52 (s, 1H), 7.67 (s, 1H), 6.83 (s, 1H), 4.08 – 3.94 (m, 2H), 3.77 (d, J = 10.6 Hz, 1H), 3.45 (d, J = 10.4 Hz, 1H), 3.41-3.29 (m, 2H), 3.10-3.04 (m, 1H), 2.79 (d, J = 12.6 Hz, 1H), 2.24-2.05 (m, 3H), 1.70-1.50 (m, 2H), 1.07-0.89 (m, 3H), 0.76 (d, J = 6.9 Hz, 3H) ppm. HPLC purity: 93.0% at 210 nm. MS (ESI⁺): m/z = 370.2 (M+1)⁺. Another isomeric compound of propyl 3''-hydroxy-2'- methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxylate (50.9 mg, white solid, yield 27%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO-d₆): δ 12.22 (s, 1H), 9.30 (br s, 1H), 8.52 (s, 1H), 7.65 (s, 1H), 6.83 (s, 1H), 3.98 – 3.94 (m, 2H), 3.58 (d, J = 10.6 Hz, 1H), 3.48-3.43 (m, 2H), 3.36- 3.34 (m, 1H), 3.15-3.12 (m, 1H), 2.78 (d, J = 12.6 Hz, 1H), 2.24-2.05 (m, 3H), 1.62-1.55 (m, 2H), 0.95-0.88 (m, 3H), 0.78 (d, J = 6.9 Hz, 3H) ppm. HPLC purity: 95.40% at 210 nm and 98.00% at 254 nm. MS (ESI⁺): m/z = 370.2 (M+1)⁺. [0323] 3''-hydroxy-2'-methyl-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (Isomers)

[0324] The title compounds were prepared by using the scheme and procedures shown below:

[0325] To a solution of 2,2,2-trifluoroethanamine (99 mg, 1.0 mmol) in DCM (5 mL) was added CDI (162 mg, 1.0 mmol) and the reaction was stirred at room temperature for 30 min. A solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol TFA salt (Peak 1, synthesized as shown in Example above, 200 mg, crude) in DCM (2 mL) was added, and then the reaction mixture was stirred at room temperature for 30 min. The solvent was removed, and the residue was purified by prep-HPLC (TFA in ACN and H₂O) to give the product 3''-hydroxy-2'-methyl-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[pyrrolidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide (57.6 mg, yield 27%, Peak 1 series) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.42 (two s, 1H), 9.57 (br s, 1H), 8.56 (s, 1H), 7.71 (s, 1H), 6.96 – 6.56 (m, 2H), 3.96 – 3.68 (m, 3H), 3.44 (d, J = 10.5 Hz, 1H), 3.32 (t, J = 6.7 Hz, 2H), 3.14 – 3.00 (m, 1H), 2.81 (d, J = 12.6 Hz, 1H), 2.26 – 1.98 (m, 3H), 0.74 (d, J = 6.9 Hz, 3H) ppm. HPLC purity: 98.10% at 210 nm and 98.48 at 254 nm. MS (ESI⁺): m/z = 409.2 (M+1)⁺. Another isomeric compound of 3''-hydroxy-2'-methyl-N-(2,2,2- trifluoroethyl)-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide (81.3 mg, white solid, yield 38%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO-d₆): δ 12.27 (s, 1H), 9.34 (br s, 1H), 8.53 (s, 1H), 7.69 (s, 1H), 6.86 – 6.75 (m, 2H), 3.92 – 3.74 (m, 2H), 3.61 (d, J = 10.4 Hz, 1H), 3.53 – 3.42 (m, 2H), 3.38 – 3.24 (m, 1H), 3.12 (q, J = 6.8 Hz, 1H), 2.77 (d, J = 12.6 Hz, 1H), 2.23 (d, J = 12.7 Hz, 1H), 2.18 – 2.02 (m, 2H), 0.80 (d, J = 7.0 Hz, 3H) ppm. HPLC purity: 99.57% at 210 nm and 99.44% at 254 nm. MS (ESI⁺): m/z = 409.2 (M+1)⁺. [0326] 3-(3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile (Isomers)

[0327] The title compounds were prepared by using the scheme and procedures shown below:

[0328] To a solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (Peak 1, synthesized as shown in Example above, 200 mg, crude) in THF (5 mL) were added 2-cyanoacetic acid (85 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and DIPEA (0.4 mL) at room temperature. The reaction was stirred at room temperature for 1h and then concentrated. The residue was purified by prep-HPLC (NH₄HCO₃ in ACN and H₂O) to give the product 3-(3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine- 3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile (103.6 mg, yield 57%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 9.28 (br s, 1H), 8.54 & 8.52 (two s, 1H), 7.69 (s, 1H), 6.87-6.84 (m, 1H), 4.02 (s, 1H), 3.95 (d, J = 4.3 Hz, 1H), 3.85 – 3.74 (m, 1H), 3.60 – 3.43 (m, 2H), 3.38 (t, J = 6.7 Hz, 1H), 3.14 – 3.02 (m, 1H), 2.80 (d, J = 12.7 Hz, 1H), 2.31 – 2.11 (m, 3H), 0.86 – 0.68 (m, 3H) ppm. HPLC purity: 97.03% at 210 nm. MS (ESI⁺): m/z =351.2 (M+H)⁺. Another isomeric compound of 3-(3''-hydroxy-2'-methyl-3'',6''- dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)- 3-oxopropanenitrile (81.3 mg, white solid, yield 44%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO-d₆): δ 12.36 (s, 1H), 9.39 (br s, 1H), 8.54 (s, 1H), 7.73- 7.70 (m, 1H), 6.91-6.88 (m, 1H), 4.06 – 3.91 (m, 2H), 3.78 – 3.65 (m, 1H), 3.61 – 3.47 (m, 2H), 3.42 – 3.31 (m, 1H), 3.23 – 3.08 (m, 1H), 2.81 (t, J = 12.1 Hz, 1H), 2.29 – 2.16 (m, 2H), 2.14 – 2.06 (m, 1H), 0.81-0.78 (m, 3H) ppm. HPLC purity: 96.70% at 210 nm. MS (ESI⁺): m/z = 351.2 (M+H)⁺. [0329] ethyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (Isomers)

[0330] The title compounds were prepared by using the scheme and procedures shown below:

[0331] To a solution of 2'-methyldispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (Peak 1, synthesized as shown in Example above, 200 mg, crude) in THF (5 mL) was added Et3N (162 mg, 1.0 mmol) and the reaction mixture was stirred at room temperature for 30 min. A solution of ethyl carbonochloridate (0.52 mmol, 0.25 mmol/mL ) in THF (2 mL) was added, and the reaction mixture was stirred at room temperature overnight. Then the solvent was removed, and the residue was purified by prep- HPLC (TFA in ACN and H2O) to give the product ethyl 3''-hydroxy-2'-methyl-3'',6''- dihydrodispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1- carboxylate (36.7 mg, yield 20% ) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.28 (s, 1H), 9.51 (br s, 1H), 8.52 (s, 1H), 7.68 (s, 1H), 6.84 (d, J = 2.0 Hz, 1H), 4.13 – 4.01 (m, 2H), 3.74 (d, J = 10.3 Hz, 1H), 3.46 (d, J = 10.4 Hz, 1H), 3.39 – 3.28 (m, 2H), 3.06 (q, J = 7.0 Hz, 1H), 2.79 (d, J = 12.6 Hz, 1H), 2.25 – 2.05 (m, 3H), 1.33 – 1.14 (m, 3H), 0.76 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 96.99% at 210 nm and 97.48% at 254 nm. MS (ESI⁺): m/z = 356.2 (M+H)⁺. Another isomeric compound of ethyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[pyrrolidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (14.5 mg, white solid, yield 4%, Peak 2 series) was obtained in a similar approach.¹H NMR (400 MHz, DMSO- d₆): δ 12.16 (s, 1H), 9.36 (br s, 1H), 8.51 (s, 1H), 7.64 (s, 1H), 6.80 (s, 1H), 4.12 – 3.96 (m, 2H), 3.57 (d, J = 10.8 Hz, 1H), 3.48 – 3.41 (m, 2H), 3.39 – 3.27 (m, 1H), 3.19 – 3.06 (m, 1H), 2.77 (d, J = 12.6 Hz, 1H), 2.20 (d, J = 12.6 Hz, 1H), 2.16 – 2.00 (m, 2H), 1.28 – 1.11 (m, 3H), 0.76 (d, J = 8.7 Hz, 3H) ppm. HPLC purity: 99.23% at 210 nm and 98.48% at 254 nm. MS (ESI⁺): m/z = 356.2 (M+H)⁺. [0332] 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol hydrogen chloride

[0333] The title compound was prepared by using the scheme and procedures shown below: Boc Boc H HCl

[0334] To a mixture of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.00 g, 20.89 mmol, 1 eq) in THF (160 mL) was added LiHMDS (1 M, 23.0 mL, 1.1 eq) at -65^oC dropwise over 0.5 h, and the mixture was stirred at -65°C for another 0.5 h under N₂. To the mixture was added iodomethane (14.83 g, 104.47 mmol, 6.50 mL, 5 eq) dropwise and it was stirred at -25°C for 9 h. The mixture was quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed by brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to get the residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 10% to 30% Ethyl acetate/Petroleum ether gradient @ 150 mL/min) to give tert-butyl 3-methyl- 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (20.0 g, 78.95 mmol, 94.46% yield) as colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 3.98-3.95 (m, 2H), 2.99 (q, J = 7.2 Hz, 1H), 2.94-2.85 (m, 2H), 2.81-2.71 (m, 2H), 1.90-1.83 (m, 1H), 1.67-1.60 (m, 2H), 1.48 (s, 9H), 1.44-1.40 (m, 1H), 1.07 (d, J = 7.2 Hz, 3H) ppm. The following step was conducted by 2 batches (2 x 10 g) in parallel. To a mixture of tert-butyl 3-methyl-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 39.47 mmol, 1 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 N, 69 mL, 7 eq) in one portion at 25°C. The mixture was stirred at 25°C for 1 h and then directly concentrated in vacuo to give the residue. The residue was triturated with EtOAc (20 mL) at 25°C and filtered to give 3-methyl-7- azaspiro[3.5]nonan-2-one HCl salt (13.0 g, 68.54 mmol, 86.81% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 9.28-9.12 (br m, 2H), 3.20-3.08 (m, 3H), 3.02-2.97 (m, 1H), 2.94-2.91 (m, 1H), 2.81 (dd, J = 17.2, 1.6 Hz, 1H), 2.08-2.00 (m, 1H), 1.91-1.79 (m, 3H), 1.57 (d, J = 14.0 Hz, 1H), 0.96 (d, J = 7.2 Hz, 3H) ppm. To a mixture of 3-methyl-7-azaspiro[3.5]nonan-2-one HCl salt (6.50 g, 34.27 mmol, 1 eq) in DCM (100 mL) was added TEA (3.47 g, 34.27 mmol, 4.80 mL, 1 eq) in one portion at 25°C, and the mixture was adjusted pH = 5 with AcOH. Then to the mixture were added benzaldehyde (4.36 g, 41.12 mmol, 4.20 mL, 1.2 eq) and NaBH(OAc)₃ (10.89 g, 51.40 mmol, 1.5 eq) in sequence. The resulting mixture was stirred at 25 °C for 3 h. The reaction was quenched with sat. aq. NaHCO₃ (50 mL) and it was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30%-50% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give 7-benzyl-3-methyl-7- azaspiro[3.5]nonan-2-one (4.60 g, 18.90 mmol, 27.58% yield) as yellow oil.¹H NMR (CDCl₃, 400 MHz): δ 7.39-7.32 (m, 5H), 3.51 (s, 2H), 3.02-2.97 (m, 1H), 2.86-2.79 (m, 2H), 2.75-2.65 (m, 2H), 2.10 (t, J = 10.4 Hz, 2H), 1.99 (td, J = 12.8, 3.6 Hz, 1H), 1.79-1.72 (m, 1H), 1.66-1.63 (m, 1H), 1.41 (d, J = 12.4 Hz, 1H), 1.05 (d, J = 7.2 Hz, 3H) ppm. To a mixture of 5-bromo-4- iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (22.65 g, 47.25 mmol, 2.5 eq) in THF (150 mL) was added i-PrMgCl (2 M, 23.70 mL, 2.5 eq) dropwise at -10°C, and the resulting mixture was stirred at -10°C for 1 h. To the mixture was added 7-benzyl-3-methyl-7-azaspiro[3.5]nonan- 2-one (4.60 g, 18.90 mmol, 1 eq) dropwise at -10°C and then it was stirred at 25°C for 1.5 h. The reaction was quenched with sat. aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 60%-80% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to generate 7-benzyl-2-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-methyl-7-azaspiro[3.5]nonan-2-ol (9.20 g, 12.33 mmol, 65.26% yield) as an yellow gum.¹H NMR (CDCl₃, 400 MHz): δ 8.31 (s, 1H), 7.38 (d, J = 4 Hz, 1H), 7.34-7.30 (m, 5H), 6.67 (d, J = 4 Hz, 1H), 4.71 (s, 1H), 3.51 (d, J = 12.8 Hz, 1H), 3.46 (d, J = 12.8 Hz, 1H), 3.09 (t, J = 7.2 Hz, 1H), 2.84-2.77 (m, 2H), 2.68-2.60 (m, 2H), 2.32 (d, J = 12.8 Hz, 1H), 2.19 (t, J = 11.6 Hz, 1H), 2.03-1.94 (m, 2H), 1.84-1.70 (m, 5H), 1.34 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 7.2 Hz, 18H) ppm. To a mixture of 7-benzyl-2-(5-bromo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-methyl-7-azaspiro[3.5]nonan-2-ol (1.30 g, 1.74 mmol, 80% purity, 1 eq) and 2-(5,5-dimethyl -1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2- dioxaborinane (2.36 g, 10.46 mmol, 6 eq) in 1,4-dioxane (20 mL) were added KOAc (428 mg, 4.36 mmol, 2.5 eq) and Pd(PPh₃)₂Cl₂ (245 mg, 349 umol, 0.2 eq) in one portion at 25°C under N₂. The mixture was stirred at 90°C for 20 h. The mixture was filtered and concentrated to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 5%-15% DCM/MeOH @ 160 mL/min) to give 1- benzyl-2'-methyl-6''-(triisopropylsilyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (3.00 g, 5.52 mmol, 45.23% yield) as yellow oil.¹H NMR (CDCl₃, 400 MHz): δ 8.52 (s, 1H), 7.39-7.29 (m, 6H), 6.73 (d, J = 3.6 Hz, 1H), 3.69-3.66 (m, 4H), 2.92-2.88 (m, 4H), 2.62-2.53 (m, 1H), 2.27-2.23 (m, 2H), 1.89-1.79 (m, 4H), 1.78-1.74 (m, 1H), 1.13 (d, J = 7.2 Hz, 18H), 0.94 (d, J = 6.8 Hz, 3H) ppm. To a solution of 1-benzyl-2'-methyl- 6''-(triisopropylsilyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol (1.50 g, 2.76 mmol, 1 eq) in i-PrOH (50 mL) was added Pd(OH)2 (0.3 g, 20% purity), and the suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25°C for 15 h. The reaction mixture was filtered and the filtrate was concentrated to give 2'-methyl-6''-(triisopropylsilyl)dispiro[piperidine- 4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (2.10 g, crude) as a yellow solid, which was used in the next step without further purification. To a mixture of 2'- methyl-6''-(triisopropylsilyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (100 mg, 221 umol, 1 eq) in THF (3 mL) was added aq. HCl (6 N, 478 uL, 13 eq) in one portion at 25°C under N2, and the mixture was stirred at 25°C for 2 h. The mixture was filtered to give the filter cake, which was then purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 um; mobile phase: [water (0.04%HCl)-ACN]; B%: 1%-20%, 7min) to give 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol hydrochloride (26.70 mg, 79.52 umol, 36.06% yield) as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 12.70 (s, 1H), 9.58 (br s, 1H), 9.03-8.94 (m, 1H), 8.85-8.73 (m, 1H), 8.65 (s, 1H), 7.26 (t, J = 6.8 Hz, 1H), 6.90 (s, 1H), 3.26-3.17 (m, 2H), 3.07-2.98 (m, 1H), 2.88 (q, J = 7.2 Hz, 2H), 2.64 (d, J = 12.8 Hz, 1H), 2.32 (d, J = 12.8 Hz, 1H), 2.17 (d, J = 12.8 Hz, 1H), 2.01-1.96 (m, 2H), 1.97-1.87 (m, 1H), 0.77 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.36% (220 nm) and 100% (254 nm). MS (ESI): m/z = 298.2 [M+H]⁺. [0335] 3-(3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile [ und was prepared by using the scheme and procedures shown below:

[0337] To a solution of 2-cyanoacetic acid (28 mg, 330 umol, 1.1 eq) in THF (2 mL) was added HATU (103 mg, 270 umol, 0.9 eq) and it was stirred for 10 min. Then to the mixture were added 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol HCl salt (100 mg, 300 umol, 1 eq) and TEA (91 mg, 899 umol, 125 uL, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min, quenched with H2O (1 mL) and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 10%-40%, 8min) to generate 3-(3''-hydroxy-2'-methyl-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)- 3-oxopropanenitrile (31.3 mg, 86 umol, 28.60% yield) as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.98 (s, 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 2.4 Hz, 1H), 6.72-6.69 (m, 1H), 4.23-4.17 (m, 1H), 4.14-4.05 (m, 2H), 3.64-3.53 (m, 1H), 3.22-3.17 (m, 0.5H), 3.15-3.08 (m, 0.5H), 2.91-2.85 (m, 0.5H) , 2.83-2.76 (m, 1.5H), 2.57 (d, J = 12.8 Hz, 1H), 2.25 (d, J = 12.8 Hz, 1H), 2.10-2.03 (m, 1H), 1.83-1.77 (m, 2H), 1.74-1.67 (m, 0.5H), 1.61-1.56 (m, 0.5H), 0.75 (d, J = 6 Hz, 3H) ppm. HPLC purity: 99.75% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 365.1 [M+H]⁺. [0338] Ethyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate und was prepared by using the scheme and procedures shown below:

[0340] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (200 mg, 599 umol, 1 eq) and TEA (243 mg, 2.40 mmol, 334 uL, 4 eq) in THF (4 mL) was added ethyl carbonochloridate (78 mg, 719 umol, 68 uL, 1.2 eq) in one portion at 0°C under N₂. The mixture was stirred at 25 °C for 20 min, added with H₂O (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were washed by brine (2 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to get the residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 25%-45%, 6min) to give ethyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo-[2,3-b]pyridine]-1-carboxylate (50.5 mg, 136 umol, 22.76% yield) as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.98 (s, 1H), 9.23 (s, 1H), 8.47 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.92-3.81 (m, 2H), 3.05-3.01 (m, 2H), 2.78 (q, J = 7.2 Hz, 1H), 2.54 (d, J = 12.4 Hz, 1H), 2.24 (d, J = 12.4 Hz, 1H), 2.03 (d, J = 12 Hz, 1H), 1.77-1.70 (m, 2H), 1.61-1.54 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H) ppm. HPLC: 99.76% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 370.2 [M+H]⁺. [0341] 3''-hydroxy-2'-methyl-N-(2,2,2-trifluoroethyl)-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0342] The title compound was prepared by using the scheme and procedures shown below:

[0343] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (100 mg, 299.74 umol, 1 eq) and 2,2,2- trifluoroethanamine HCl salt (122 mg, 899.23 umol, 96.71 uL, 3 eq) in THF (3 mL) was added TEA (152 mg, 1.50 mmol, 208.60 uL, 5 eq) in one portion, and the mixture was stirred at 0^oC for 5 min. Bis(trichloromethyl) carbonate (BTC, 142.32 mg, 479.59 umol, 1.6 eq) was added in one portion at 0°C and the mixture was stirred at 25°C for 15 min. The reaction was quenched with H2O (2 mL) and concentrated under reduced pressure to get the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 15%-45%, 6min) to give 3''-hydroxy-2'-methyl-N-(2,2,2- trifluoroethyl)-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide (44.2 mg, 104 umol, 17.42% yield, 99.78% purity) obtained as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.95 (s, 1H), 9.19 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 7.11 (t, J = 6 Hz, 1H), 6.71-6.69 (m, 1H), 3.87-3.81 (m, 4H), 3.02- 2.95 (m, 1H), 2.90-2.81 (m, 1H), 2.78 (q, J = 6.8 Hz, 1H), 2.54 (d, J = 12.8 Hz, 1H), 2.24 (d, J = 12.8 Hz, 1H), 2.02 (d, J = 12.4 Hz, 1H), 1.72-1.65 (m, 2H), 1.61-1.54 (m, 1H), 0.74 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.78% (220 nm). MS (ESI+): m/z = 423.2 [M+H]⁺. [0344] N-ethyl-3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0345] The title compound was prepared by using the scheme and procedures shown below:

[0346] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (100 mg, 300 umol, 1 eq) and TEA (121 mg, 1.20 mmol, 167 uL, 4 eq) in THF (3 mL) was added isocyanatoethane (42.6 mg, 599 umol, 47 uL, 2 eq) in one portion at 0°C. The mixture was stirred at 25 °C for 1 h. The mixture was added with H2O (0.5 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 10%-40%, 6min) to give N-ethyl-3''-hydroxy-2'-methyl- 3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (65 mg, 175 umol, 58.34% yield) as a white solid.¹H NMR (DMSO- d6, 400 MHz): δ 11.95 (s, 1H), 9.19 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.70-6.68 (m, 1H), 6.42 (t, J = 5.2 Hz, 1H), 3.81 (t, J = 13.2 Hz, 2H), 3.09-3.01 (m, 2H), 2.93-2.87 (m, 1H), 2.83-2.75 (m, 2H), 2.54 (d, J = 12.4 Hz, 1H), 2.22 (d, J = 12.4 Hz, 1H), 1.99 (d, J = 13.2 Hz, 1H), 1.70-1.67 (m, 2H), 1.59-1.52 (m, 1H), 1.01 (t, J = 7.2 Hz, 3H), 0.74 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.45% (220 nm). MS (ESI+): m/z = 369.2 [M+H]⁺. [0347] 3''-hydroxy-N-isopropyl-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide [ ound was prepared by using the scheme and procedures shown below:

[0349] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (150 mg, 450 umol, 1 eq) and TEA (182 mg, 1.80 mmol, 250 uL, 4 eq) in THF (2 mL) was added 2-isocyanatopropane (77 mg, 899 umol, 88 uL, 2 eq) in one portion at 0°C. The mixture was stirred at 25 °C for 1 h. The mixture was added with H2O (0.2 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 22%-52%, 6min) to give 3''-hydroxy-N-isopropyl-2'-methyl- 3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (59.2 mg, 155 umol, 34.42% yield) as a white solid.¹H NMR (DMSO- d₆, 400 MHz): δ 11.96 (s, 1H), 9.20 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.68 (d, J = 1.6 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 3.86-3.73 (m, 3H), 2.88 (t, J = 12 Hz, 1H), 2.81-2.75 (m, 2H), 2.53 (d, J = 12.4 Hz, 1H), 2.22 (d, J = 12.4 Hz, 1H), 1.98 (d, J = 13.2 Hz, 1H), 1.71-1.66 (m, 2H), 1.55 (t, J = 12 Hz, 1H), 1.06 (t, J = 6.4 Hz, 6H), 0.74 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.84% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 383.1 [M+H]⁺. [0350] 3''-hydroxy-2'-methyl-N-propyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide und was prepared by using the scheme and procedures shown below:

[0352] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (100 mg, 300 umol, 1 eq) and TEA (121 mg, 1.20 mmol, 167 uL, 4 eq) in THF (2 mL) was added 1-isocyanatopropane (51 mg, 599 umol, 57 uL, 2 eq) in one portion at 0°C. The mixture was stirred at 25°C for 1 h. The mixture was added with H2O (0.5 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 10%-40%, 6min) to give 3''-hydroxy-2'-methyl-N-propyl- 3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (65 mg, 168 umol, 56.20% yield) as a white solid.¹H NMR (DMSO- d6, 400 MHz): δ 11.95 (s, 1H), 9.19 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.69-6.68 (m, 1H), 6.44 (t, J = 5.6 Hz, 1H), 3.81 (t, J = 12.8 Hz, 2H), 2.98 (q, J = 6.4 Hz, 2H), 2.90 (t, J = 12.8 Hz, 1H), 2.83-2.76 (m, 2H), 2.53 (d, J = 12.8 Hz, 1H), 2.22 (d, J = 12.8 Hz, 1H), 1.98 (d, J = 12.8 Hz, 1H), 1.71-1.67 (m, 2H), 1.58 (t, J = 12.8 Hz, 1H), 1.41 (m, J = 7.2 Hz, 2H), 0.83 (t, J = 7.6 Hz, 3H), 0.74 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.07% (220 nm). MS (ESI+): m/z = 383.2 [M+H]⁺. [0353] 3''-hydroxy-N,2'-dimethyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0354] The title compound was prepared by using the scheme and procedures shown below:

[0355] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (100 mg, 300 umol, 1 eq, HCl) and TEA (121 mg, 1.20 mmol, 167 uL, 4 eq) in THF (2 mL) was added N-methylcarbamoyl chloride (34 mg, 360 umol, 66 uL, 1.2 eq) in one portion at 0°C under N2. The mixture was stirred at 25 °C for 20 min, added with H2O (0.3 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 10%-40%, 8min) to give 3''-hydroxy-N,2'- dimethyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (38.7 mg, 108 umol, 36.02% yield) as a white solid.¹H NMR (DMSO- d₆, 400 MHz): δ 11.96 (s, 1H), 9.20 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.40-6.38 (m, 1H), 3.80 (t, J = 13.2 Hz, 2H), 2.90 (t, J = 12.4 Hz, 1H), 2.83-2.75 (m, 2H), 2.57 (d, J = 4.4 Hz, 3H), 2.53 (d, J = 12.8 Hz, 1H), 2.22 (d, J = 12.8 Hz, 1H), 1.99 (d, J = 12.4 Hz, 1H), 1.69-1.67 (m, 2H), 1.55 (t, J = 12.4 Hz, 1H), 0.74 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 98.81% (220 nm) and 97.76% (254 nm). MS (ESI+): m/z = 355.2 [M+H]⁺. [0356] Propyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate

[0357] The title compound was prepared by using the scheme and procedures shown below:

[0358] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (110 mg, 330 umol, 1 eq) and TEA (133 mg, 1.32 mmol, 184 uL, 4 eq) in THF(2 mL) was added propyl carbonochloridate (48 mg, 396 umol, 44 uL, 1.2 eq) in one portion at 0°C under N2. The mixture was stirred at 25°C for 20 min. The mixture was added with H2O (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were washed by brine (2 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water(10mM NH₄HCO₃)-ACN]; B%: 25%-45%,6min) to give propyl 3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxa-borolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxylate (33.2 mg, 86 umol, 26.23% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 11.97 (s, 1H), 9.22 (s, 1H), 8.47 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.69-6.68 (m, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.91-3.83 (m, 2H), 3.05-3.04 (m, 2H), 2.79 (q, J = 7.2 Hz, 1H), 2.54 (d, J = 12.8 Hz, 1H), 2.24 (d, J = 12.8 Hz, 1H), 2.03 (d, J = 8 Hz, 1H), 1.78-1.68 (m, 2H), 1.63-1.54 (m, 3H), 0.90 (t, J = 7.2 Hz, 3H), 0.75 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.83% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 384.2 [M+H]⁺. [0359] cyclohexyl(3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0360] The title compound was prepared by using the scheme and procedures shown below:

[0361] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (150 mg, 450 umol, 1 eq) and TEA (182 mg, 1.80 mmol, 250 uL, 4 eq) in THF(2 mL) was added cyclohexanecarbonyl chloride (73 mg, 495 umol, 66 uL, 1.1 eq) in one portion at 0°C under N₂. The mixture was stirred at 25°C for 20 min, added with H₂O (0.1 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 30%-60%, 6min) to give cyclohexyl(3''- hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-1-yl)methanone (42.1 mg, 103 umol, 22.88% yield) as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.97 (s, 1H), 9.23-9.21 (m, 1H), 8.47 (s, 1H), 7.58 ( s, 1H), 6.69 (s, 1H), 4.27-4.18 (m, 1H), 3.88-3.77 (m, 1H), 3.26-3.07 (m, 1H), 2.80-2.66 (m, 2H), 2.63-2.54 (m, 2H), 2.26 (d, J = 12.8 Hz, 1H), 2.09-2.02 (m, 1H), 1.81-1.58 (m, 7H), 1.54-1.44 (m, 1H), 1.38-1.28 (m, 4H), 1.23-1.12 (m, 1H), 0.75 (d, J = 6.8 Hz, 3H) ppm. HPLC purity: 99.51% (220 nm). MS (ESI+): m/z = 408.2 [M+H]⁺. [0362] (3''-hydroxy-2'-methyl-3'',6''-dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)(phenyl)methanone

[0363] The title compound was prepared by using the scheme and procedures shown below:

[0364] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (100 mg, 300 umol, 1 eq) and TEA (121 mg, 1.20 mmol, 167 uL, 4 eq) in THF (4 mL) was added benzoyl chloride (46 mg, 330 umol, 38 uL, 1.1 eq) in one portion at 0°C under N2. The mixture was stirred at 25°C for 20 min, added with H2O (0.2 mL) and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH₄HCO₃)-ACN]; B%: 20%-50%, 6 min) to give (3''-hydroxy-2'-methyl-3'',6''- dihydrodispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1- yl)(phenyl)methanone (41.4 mg, 101 umol, 33.86% yield) as a white solid.¹H NMR (DMSO-d6, T=273+80K, 400 MHz): δ 11.73 (s, 1H), 8.95 (s, 1H), 8.48 (s, 1H), 7.52 (t, J = 2.8 Hz, 1H), 7.47- 7.44 (m, 3H), 7.42-7.38 (m, 2H), 6.68 (d, J = 2.4 Hz, 1H), 3.98-3.84 (m, 2H), 3.21 (t, J = 12 Hz, 1H), 3.15-3.12 (m, 1H), 2.85 (q, J = 6.8 Hz, 1H), 2.61 (d, J = 12.8 Hz, 1H), 2.29 (d, J = 12.8 Hz, 1H), 2.08 (d, J = 13.2 Hz, 1H), 1.88-1.69 (m, 3H), 0.81 (d, J = 7.2 Hz, 3H). HPLC purity: 98.36% (220 nm) and 98.11% (254 nm). MS (ESI+): m/z = 402.2 [M+H]⁺. [0365] 2'-methyl-1-(propylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0366] The title compound was prepared by using the scheme and procedures shown below:

[0367] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (120 mg, 360 umol, 1 eq) and TEA (182 mg, 1.80 mmol, 250 uL, 5 eq) in THF (2 mL) was added propane-1-sulfonyl chloride (77 mg, 540 umol, 61 uL, 1.5 eq) dropwise at 0°C. The mixture was stirred at 0 °C for 10 min, quenched with H2O (0.5mL) and concentrated to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water(10mM NH4HCO3)- ACN]; B%: 25%-55%, 8 min) to give 2'-methyl-1-(propylsulfonyl)dispiro[piperidine-4,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (65.4 mg, 162 umol, 44.99% yield) obtained as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.99 (s, 1H), 9.25 (s, 1H), 8.47 (s, 1H), 7.59-7.57 (m, 1H), 6.69 (t, J = 3.2 Hz, 1H), 3.56-3.46 (m, 2H), 3.02-2.95 (m, 3H), 2.88-2.78 (m, 2H), 2.53 (d, J = 12.8 Hz, 1H), 2.22 (d, J = 12.8 Hz, 1H), 2.13 (d, J = 12.8 Hz, 1H), 1.85-1.82 (m, 2H), 1.73-1.64 (m, 3H), 0.99 (t, J = 7.2 Hz, 3H), 0.76 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.8% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 404.1 [M+H]⁺. [0368] 1-(isopropylsulfonyl)-2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0369] The title compound was prepared by using the scheme and procedures shown below:

[0370] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (200 mg, 599 umol, 1 eq) in THF (3 mL) and H₂O (3 mL) were added Na₂CO₃ (318 mg, 3 mmol, 5 eq) in one portion at 0°C under N₂, and then propane-2-sulfonyl chloride (171 mg, 1.20 mmol, 134 uL, 2 eq) dropwise. It was stirred at 25°C for 0.5 h, added with 2N HCl (2 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water(10mM NH₄HCO₃)-ACN]; B%: 15%-45%, 8min) to give 1-(isopropylsulfonyl)-2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]-pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (49.6 mg, 123 umol, 20.47% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 11.97 (s, 1H), 9.25 (s, 1H), 8.47 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.69 (d, , J = 1.6 Hz, 1H), 3.59-3.53 (m, 2H), 3.25-3.28 (m, 1H), 3.08 (t, J = 12.8 Hz, 1H), 3.01-2.93 (m, 1H), 2.83-2.77 (m, 1H), 2.54 (d, J = 12.8 Hz, 1H), 2.24 (d, J = 12.8 Hz, 1H), 2.11 (d, J = 13.6 Hz, 1H), 1.85-1.78 (m, 2H), 1.69-1.63 (m, 1H), 1.22 (t, J = 6.8 Hz, 6H), 0.76 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.77% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 404.2 [M+H]⁺. [0371] 1-(isobutylsulfonyl)-2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0372] The title compound was prepared by using the scheme and procedures shown below:

[0373] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (150 mg, 505 umol, 1 eq) in H₂O (1 mL) and THF(1 mL) were added Na₂CO₃ (53.5 mg, 504.78 umol, 1 eq) in one portion at 0°C under N₂, and then 2-methylpropane-1-sulfonyl chloride (158 mg, 1.01 mmol, 2 eq) dropwise. It was stirred for 30 min at 25 °C, added with H2O (2 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed by brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 30%-60%, 10min) to give 1-(isobutylsulfonyl)-2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (69.5 mg, 166 umol, 32.87% yield) obtained as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.98 (s, 1H), 9.24 (s, 1H), 8.47 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.70-6.68 (m, 1H), 3.56-3.50 (m, 2H), 2.90-2.89 (m, 2H), 2.88-2.87 (m, 2H), 2.86-2.82 (m, 2H), 2.23 (d, J = 12.8 Hz, 1H), 2.14-2.10 (m, 2H), 1.87-1.80 (m, 2H), 1.74-1.67 (m, 1H), 1.04 (d, J = 6.8 Hz, 6H), 0.76 (d, J = 6.8 Hz, 3H) ppm. HPLC purity: 99.63% (220 nm) and 100% (254 nm). MS (ESI): m/z = 418.2 [M+H]⁺. [0374] 1-(ethylsulfonyl)-2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0375] The title compound was prepared by using the scheme and procedures shown below:

[0376] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (110 mg, 330 umol, 1 eq) and ethanesulfonyl chloride (85 mg, 659 umol, 62 uL, 2 eq) in THF (2 mL) and H₂O (2 mL) was added Na₂CO₃ (174.73 mg, 1.65 mmol, 5 eq) in one portion at 0°C under N₂. The mixture was stirred at 25 °C for 30 min, added with H2O (1 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with H2O (3 mL) to give 1-(ethylsulfonyl)-2'- methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3''(6''H)-ol (58.7 mg, 147 umol, 44.55% yield) as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 11.97 (s, 1H), 9.24 (s, 1H), 8.47 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.70-6.68 (m, 1H), 3.48-3.42 (m, 2H), 3.07-3.02 (m, 3H), 2.92-2.88 (m, 1H), 2.87-2.83 (m, 1H), 2.50 (d, J = 12.8 Hz, 1H), 2.23 (d, J = 12.8 Hz, 1H), 2.11 (d, J = 13.2 Hz, 1H), 1.88-1.81 (m, 2H), 1.74-1.67 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 0.76 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 97.41% (220 nm). MS (ESI+): m/z = 390.2 [M+H]⁺. [0377] 2'-methyl-1-(methylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0378] The title compound was prepared by using the scheme and procedures shown below:

[0379] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (110 mg, 330 umol, 1 eq) and TEA (133 mg, 1.32 mmol, 184 uL, 4 eq) in THF (4 mL) was added methylsulfonyl methanesulfonate (86 mg, 495 umol, 1.5 eq) in one portion at 0°C under N2. The mixture was stirred at 25°C for 20 min, added with H2O (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were washed with brine (2 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 15%-45%, 8min) to give 2'-methyl-1-(methylsulfonyl)dispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (76.7 mg, 204 umol, 31.00% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 11.98 (s, 1H), 9.25 (s, 1H), 8.47 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 3.53-3.43 (m, 2H), 2.92 (t, 1H), 2.86 (s, 3H), 2.85-2.79 (m, 2H), 2.52 (d, J = 12.8 Hz, 1H), 2.22 (d, J = 12.8 Hz, 1H), 2.15 (d, J = 13.2 Hz, 1H), 1.89-1.79 (m, 2H), 1.73 (t, J = 12.8 Hz, 1H), 0.76 (d, J = 7.2 Hz, 3H) ppm. HPLC purity: 99.38% (220 nm) and 100% (254 nm). MS (ESI+): m/z = 376.2 [M+H]⁺. [0380] 2'-methyl-1-tosyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

[0381] The title compound was prepared by using the scheme and procedures shown below:

[0382] To a mixture of 2'-methyldispiro[piperidine-4,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol HCl salt (50 mg, 168 umol, 1 eq) in THF (5 mL) were added TEA (34 mg, 337 umol, 47 uL, 2 eq) and 4-methylbenzenesulfonyl chloride (16 mg, 84 umol, 0.5 eq) at 25°C. The mixture was stirred at 25°C for 15 min, added with H2O (3 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO₂, PE: EtOAc = 1:10) to give 2'-methyl-1-tosyldispiro[piperidine-4,1'-cyclobutane- 3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol (13 mg, 27 umol, 15.88% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 11.95 (s, 1H), 9.21 (s, 1H), 8.44 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 3.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.64-6.62 (m, 1H), 3.55 (d, J = 12.4 Hz, 1H), 3.45 (d, J = 12 Hz, 1H), 3.20-3.17 (m, 1H), 2.77-2.73 (m, 1H), 2.48-2.45 (m, 1H), 2.42-2.37 (m, 1H), 2.38 (s, 3H), 2.12-2.08 (m, 1H), 1.97 (d, J = 12.8 Hz, 1H), 1.88-1.82 (m, 2H), 1.76-1.70 (m, 1H), 0.68 (d, J = 6.8 Hz, 3H). HPLC purity: 92.75% (220 nm) and 94.25% (254 nm). MS (ESI+): m/z = 452.3 [M+H]⁺. [0383] Procedure - Synthesis of Spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol and analogs [0384] 1-Benzylspiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol TFA salt

[0385] The title compound was prepared by the scheme and procedures shown below:

[0386] To a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (120 g, 609.04 mmol, 1 eq) in DCM (2.5 L) was added NMP (100 mL) dropwise. Then meta-chloroperoxybenzoic acid (197.06 g, 913.56 mmol, 1.5 eq) was added in portions at 25^oC during 10 min and the mixture was stirred at 25^oC for 16 h. The mixture was quenched with ice-water (1500 g/1500 g) and the resulting aqueous layer was adjusted to pH = 8 with solid Na2CO3 carefully. The resulting suspension was filtered, and the filter cake was washed with H2O (1500 mL). The collected gray solid was dried in vacuo to give 5-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (100 g, 469.41 mmol, 77.07% yield) as gray solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.65 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.48 (d, J = 3.2 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H) ppm. To a solution of 5-bromo- 1H-pyrrolo[2,3-b]pyridine 7-oxide (20 g, 93.88 mmol, 1 eq) in NMP (150 mL) was added POCl₃ (71.98 g, 469.41 mmol, 43.62 mL, 5 eq) dropwise at -20^oC, and the mixture was stirred at -20 to 20^oC for 1 h. The mixture was poured into H₂O (600 mL) and adjusted to pH=9 with saturated Na₂CO₃ (200 mL). The resulting gray suspension was filtered, and the filter cake was washed with H₂O (100 mL). The solid was collected and dried in vacuo to afford 5-bromo-4-chloro-1H- pyrrolo[2,3-b]pyridine (12 g, 51.84 mmol, 55.22% yield) as gray solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.65 (s, 1H), 8.38 (s, 1H), 7.63 (t, J = 2.8 Hz, 1H), 6.50 (t, J = 2.8 Hz, 1H) ppm. To a mixture of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (25 g, 108.00 mmol, 1 eq) in CH3CN (600 mL) were added NaI (80 g, 533.71 mmol, 4.94 eq) and acetyl chloride (25.43 g, 324.01 mmol, 23.12 mL, 3 eq) in one portion at 20°C under N2. The mixture was heated to 80°C and stirred for 10 h. Two batches were operated in parallel and worked up together. The reaction mixture was concentrated under reduced pressure to give a residue which was poured into ice-water (w/w = 1/1, 1000 mL) and the aqueous phase was adjusted pH to 7 with saturated aqueous NaHCO3. The aqueous phase was extracted with ethyl acetate (500 mL x 3). The combined organic phase was concentrated in vacuum and the residue was dissolved in THF (150 mL). An aqueous NaOH solution (50 mL, 1M) was added dropwise at 20°C under N₂. The mixture was stirred at 20°C for 2 h and then quenched with saturated NH₄Cl solution (500 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude product was recrystallized from MTBE (100 mL) at 25^oC to give 5-bromo-4-iodo-1H-pyrrolo[2,3-b]pyridine (66 g, 204.38 mmol, 94.62% yield) as a yellow solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.25 (s, 1H), 8.28 (s, 1H), 7.61 (d, J = 3.6 Hz, 1H), 6.28 (d, J = 3.6 Hz, 1H) ppm. To a mixture of 5-bromo-4-iodo-1H-pyrrolo[2,3-b]pyridine (16 g, 49.55 mmol, 1 eq) in THF (300 mL) was added NaH (4.95 g, 123.87 mmol, 60% purity, 2.5 eq) in portions at 0°C. The mixture was stirred at 0°C for 1h, and then TIPSCl (14.33 g, 74.32 mmol, 15.90 mL, 1.5 eq) was added dropwise at 0°C. The mixture was stirred at 0°C for additional 1 h and quenched with saturated NH₄Cl solution (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 2), and the combined organic phase was washed with brine (100 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 20/1) to give 5-bromo-4- iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (21 g, 43.82 mmol, 88.44% yield) as off-white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 8.31 (s, 1H), 7.61 (d, J = 3.6 Hz, 1H), 6.47 (d, J = 3.6 Hz, 1H), 1.85-1.81 (m, 3H), 1.04 (d, J = 7.6 Hz, 18H) ppm. To a solution of 5-bromo-4-iodo-1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (20 g, 41.73 mmol, 1 eq) in THF (220 mL) was added i-PrMgCl (2 M, 27.12 mL, 1.3 eq) dropwise at 0°C. After addition, the mixture was stirred at 0°C for 1 h, and then to this mixture was added 1-benzylpiperidin-4-one (13.26 g, 70.06 mmol, 13 mL, 1.68 eq) at 0°C. The mixture was stirred at 0°C for 1 h. The residue was poured into aqueous NH4Cl solution (300 mL) and it was stirred for 2 min. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=5/1 to 3/1) to give 1-benzyl-4-(5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol (5 g, 9.21 mmol, 22.08% yield) as a yellow solid.¹H NMR (DMSO-d₆, 400 MHz): δ 8.24 (s, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.36-7.31 (m, 4H), 7.29 (d, J = 3.6 Hz, 1H), 7.26-7.22 (m, 1H), 5.25 (s, 1H), 3.53 (s, 2H), 2.93-2.86 (m, 2H), 2.67-2.65 (m, 2H), 2.52-2.50 (m, 2H), 1.85-1.78 (m, 3H), 1.65 (d, J = 12.8 Hz, 2H), 1.04 (d, J = 7.6 Hz, 18H) ppm. To a mixture of 1-benzyl-4-(5-bromo-1- triisopropylsilyl-pyrrolo[2,3-b] pyridin-4-yl)piperidin-4-ol (4.5 g, 8.29 mmol) and 2-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (3.75 g, 16.59 mmol, 2 eq) in 1,4- dioxane (100 mL) were added KOAc (2.03 g, 20.73 mmol, 2.5 eq) and Pd(PPh₃)₂Cl₂ (291.04 mg, 414.65 umol, 0.05 eq) in one portion at 25°C under N₂. The mixture was heated to 80°C and stirred for 16 h. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C8250*50mm*10um; mobile phase: [water(10mM NH4HCO₃)-ACN]; B%: 70%-95%, 25min) to give 1'-benzyl-6- (triisopropylsilyl)spiro[[1,2]oxaborolo[4,3-d]pyrrolo [2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (5 g, crude) as a brown oil (MS (ESI⁺): m/z = 490.3 (M+1), fits the desired molecular mass) and 1'- benzylspiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine -1,4'-piperidin]-3(6H)-ol (2.5 g, crude) as a white solid (MS (ESI⁺): m/z = 334.1 (M+1), fits the desired molecular mass). If the reaction mixture was purified under TFA HPLC condition, deprotection of the triisopropylsilyl group happened extensively. The following experimental detail is an example. To a mixture of 1- benzyl-4-(5-bromo-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol (2.8 g, 5.16 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (2.33 g, 10.3 mmol, 2 eq) in 1,4-dioxane (50 mL) was added KOAc (1.27 g, 12.9 mmol, 2.5 eq) and Pd(PPh3)2Cl2 (181 mg, 258 umol, 0.05 eq) in one portion at 25°C under N2. The mixture was heated to 80°C and stirred for 16 h. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna c18 250mm*100mm*10um; mobile phase: [water(0.1%TFA)-ACN];B%: 20%-70%, 30min) to give 1'- benzylspiro[[1,2]oxaborolo [4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (710 mg, 1.56 mmol, 30.3% yield, 98.3% purity, TFA salt) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.07 (s, 1H), 9.88 (br s, 1H), 9.49 (bs, 1H), 8.58 (s, 1H), 7.63-7.61 (m, 3H), 7.55-7.52 (m, 3H), 6.61 (d, J = 1.6 Hz, 1H), 4.51 (d, J = 2.8 Hz, 2H), 3.54-3.51 (m, 2H), 3.39-3.30 (m, 2H), 2.65- 2.57 (m, 2H), 1.72 (d, J = 14.0 Hz, 2H) ppm. HPLC purity: 98.34% (220 nm) and 98.34% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI): m/z = 334.1 [M+H]⁺. [0387] Spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol and its TFA salt

[0388] The title compound was prepared by the scheme and procedures shown below:

[0389] To a solution of 1'-benzyl-spiro[[1,2]oxaborolo [4,3-d]pyrrolo[2,3-b]pyridine-1,4'- piperidin]-3(6H)-ol (1.2 g, 3.60 mmol) in i-PrOH (20 mL) was added Pd(OH)2 (1 g, 1.42 mmol, 20% purity, 0.395 eq) at 25°C. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25 °C for 30 h. The reaction mixture was filtered and concentrated under vacuum to give a key intermediate, spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (600 mg, 2.47 mmol, 68.54% yield) as a white solid and free base.¹HNMR and LS-MS data showed the material is good enough for use of further derivatization.¹H NMR (DMSO-d₆, 400 MHz): δ 12.13 (s, 1H), 8.88 (br s, 2H), 8.58 (s, 1H), 7.63 (t, J = 2.6 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 3.45 (d, J = 13.2 Hz, 2H), 3.30-3.15 (m, 2H), 2.58-2.50 (m, 2H), 1.62 (d, J = 14.0 Hz, 2H) ppm. LC purity: 86.5% (220 nm). MS (ESI⁺): m/z = 244.1. To obtain a material with better purity, its TFA salt was prepared and purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 1%-20%, 10min) to give spiro[[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol TFA salt in 34.6% yield as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.06 (s, 1H), 9.44 (br s, 1H), 8.66-8.59 (m, 2H), 8.57 (s, 1H), 7.61 (s, 1H), 6.47 (s, 1H), 3.45 (d, J = 13.2 Hz, 2H), 3.27-3.17 (m, 2H), 2.59-2.52 (m, 2H), 1.62 (d, J = 15.2 Hz, 2H) ppm. HPLC purity: 98.3% (220 nm), 92.1% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 244.1 [M+H]⁺. [0390] 1-(Methylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol

[0391] The title compound was prepared by the scheme and procedures shown below:

[0392] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (100 mg, 411 umol) and Et3N (119 mg, 1.18 mmol, 164 uL, 2.87 eq) in THF (4 mL) was added methanesulfonyl chloride (47 mg, 411 umol, 31.8 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2 N). Then the mixture was extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)- ACN]; B%: 10%-35%,10min) to give 1-(methylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (17 mg, 12.7% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.08 (s, 1H), 9.34 (br s, 1H), 8.56 (s, 1H), 7.58 (t, J = 3.2 Hz, 1H), 6.64 (t, J = 1.6 Hz, 1H), 3.67 (d, J = 11.6 Hz, 2H), 3.14 (t, J = 11.2 Hz, 2H), 3.00 (s, 3H), 2.42-2.32 (m, 2H), 1.58 ( d, J = 13.6 Hz, 2H). HPLC purity: 98.71% (220 nm) and 97.08% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 322.1 [M+H]⁺. [0393] 1-(Ethylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol

[0394] The title compound was prepared by the scheme and procedures shown below:

[0395] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (100 mg, 411 umol) and Et₃N (119 mg, 1.18 mmol, 164 uL, 2.87 eq) in THF (4 mL) was added ethanesulfonyl chloride (53 mg, 411 umol, 39 uL) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2 N). Then the mixture was extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 5%-30%, 10min) to give 1-(ethylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (22 mg, 15.4% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 9.34 (br s, 1H), 8.55 (s, 1H), 7.58 (t, J = 2.8 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 3.71 (d, J = 9.2 Hz, 2H), 3.26-3.20 (m, 2H), 3.18-3.15 (m, 2H), 2.35-2.31 (m, 2H), 1.55 (d, J = 12.8 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H) ppm. HPLC: 96.47% (220 nm) and 96.83% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 336.1 [M+H]⁺. [0396] 1-(Propylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol

[0397] The title compound was prepared by the scheme and procedures shown below:

[0398] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (300 mg, 751.11 umol) and TEA (114 mg, 1.13 mmol, 156.82 uL, 1.5 eq) in THF (5 mL) was added propane-1-sulfonyl chloride (107 mg, 751.11 umol, 84.54 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The residue was poured into ice- water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N). It was then extracted with (5 mL x 3), and the combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18100*25mm*3um; mobile phase: [water(0.1%TFA)- ACN]; B%: 25%-47%,10min) to give the desired product, 1'-(phenylsulfonyl)spiro[[1,2]oxa- borole[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (32 mg, 12.2% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 11.99 (s, 1H), 9.31 (s, 1H), 8.54 (s, 1H), 7.56 (t, J = 3.0 Hz, 1H), 6.56 (t, J = 3.0 Hz, 1H), 3.70 (d, J = 8.8 Hz, 2H), 3.24-3.12 (m, 4H), 2.35-2.32 (m, 2H), 1.78-1.75 (m, 2H), 1.55 (d, J = 12.8 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H) ppm. HPLC purity: 98.80% (220 nm) and 90.73% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI+): m/z = 350.2 [M+H]⁺. [0399] 1-(Butylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol

[0400] The title compound was prepared by the scheme and procedures shown below:

[0401] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (100 mg, 250 umol) and Et₃N (73 mg, 718 umol, 0.1 mL, 2.9 eq) in THF (4 mL) was added butane-1-sulfonyl chloride (39 mg, 250 umol, 1.0 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into ice-water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted to pH 4-5 with HCl (2N), and then extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%-40%,10min) to give the desired product, 1- (butylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (31 mg, 33.4% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.08 (s, 1H), 9.38 (br s, 1H), 8.56 (s, 1H), 7.60 (d, J = 3.6 Hz, 1H), 6.60 (t, J = 2.4 Hz, 1H), 3.72-3.24 (m, 2H), 3.25-3.13 (m, 4H), 2.40-2.28 (m, 2H), 1.75-1.66 (m, 2H), 1.56 (d, J = 12.8 Hz, 2H), 1.48-1.42 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H) ppm. HPLC: 98.05% (220 nm) and 90.82% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 364.1 [M+H]⁺. [0402] 1-(Isobutylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol

[0403] The title compound was prepared by the scheme and procedures shown below:

[0404] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (100 mg, 250 umol) and Et₃N (73 mg, 718 umol, 0.1 mL, 2.9 eq) in THF (4 mL) was added 2-methylpropane-1-sulfonyl chloride (39 mg, 250 umol, 1.0 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into ice-water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted to pH 4-5 with HCl (2N), and then extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%-40%,10min) to give the desired product, 1- (isobutylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (25 mg, 26.2% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.07 (s, 1H), 9.37 (br s, 1H), 8.56 (s, 1H), 7.59 (t, J = 3.2 Hz, 1H), 6.60 (t, J = 1.6 Hz, 1H), 3.72-3.68 (m, 2H), 3.19 (t, J = 11.2 Hz, 2H), 3.03 (d, J = 6.4 Hz, 3H), 2.41-2.28 (m, 2H), 2.21-2.14 (m, 1H), 1.56 (d, J = 13.2 Hz, 2H), 1.09 (d, J = 6.4 Hz, 6H) ppm. HPLC purity: 95.37% (220 nm). MS (ESI⁺): m/z = 364.1 [M+H]⁺. [0405] 1-(Cyclohexylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol

[0406] The title compound was prepared by the scheme and procedures shown below:

[0407] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (300 mg, 1.23 mmol), DMAP (15 mg, 123 umol, 0.1 eq) and Et₃N (312 mg, 3.09 mmol, 429 uL, 2.5 eq) in THF (6 mL) was added cyclohexanesulfonyl chloride (270 mg, 1.48 mmol, 32.1 uL, 1.2 eq) dropwise at 25°C. The mixture was stirred at 25°C for 2 h. The mixture was poured into ice-water (w/w = 1/1) (8 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-35%, 10min) to 1-(cyclohexylsulfonyl)spiro[piperidine-4,1'- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (56 mg, 135 umol, 10.9% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.07 (s, 1H), 9.34 (br s, 1H), 8.55 (s, 1H), 7.59 (t, J = 3.2 Hz, 1H), 6.52 (s, 1H), 3.75 (d, J = 9.2 Hz, 2H), 3.34-3.22 (m, 3H), 2.34-2.26 (m, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H), 1.65 (d, J = 12.8 Hz, 1H), 1.52 (d, J = 13.2 Hz, 2H), 1.48-1.34 (m, 3H), 1.32-1.15 (m, 2H). HPLC purity: 98.4% (220 nm) and 100% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 390.1 [M+H]⁺. [0408] 1-(Phenylsulfonyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 3'(6'H)-ol

[0409] The title compound was prepared by the scheme and procedures shown below:

[0410] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (300 mg, 751.11 umol) and Et3N (114 mg, 1.13 mmol, 156.82 uL, 1.5 eq) in THF (5 mL) was added benzenesulfonyl chloride (132 mg, 751.11 umol, 96.13 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h and poured into ice-water (w/w = 1/1, 5 mL). The aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Welch Xtimate C18100*25mm*3um; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-47%, 10min) to give the desired product, 1-(phenylsulfonyl)spiro[piperidine-4,1'- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (158 mg, 54.74% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.18 (s, 1H), 9.30 (broad s, 1H), 8.52 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.80 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 8.0 Hz, 2H), 7.60 (t, J = 3.2 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 3.80 (d, J = 9.2 Hz, 2H), 2.70-2.64 (m, 2H), 2.38-2.33 (m, 2H), 1.54 (d, J = 13.2 Hz, 2H) ppm. HPLC purity: 99.72% (220 nm) and 100% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 384.1 [M+H]⁺. [0411] 1-Tosylspiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol

[0412] The title compound was prepared by the scheme and procedures shown below:

[0413] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (200 mg, 500.74 umol, 1 eq) in THF (5 mL) were added Et₃N (109 mg, 1.08 mmol, 0.15 mL, 2.15 eq) and 4-methylbenzenesulfonyl chloride (95 mg, 500.74 umol, 1 eq) at 25°C. The mixture was stirred at 25°C for 1 h. The residue was poured into ice-water (w/w = 1/1) (5 mL) and the aqueous phase was acidified to pH 4-5 with HCl (2 N). The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-45%, 10min) to give 1-tosylspiro[piperidine-4,1'-[1,2] oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (77 mg, 193.83 umol, 38.71% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.06 (s, 1H), 9.27 (broad s, 1H), 8.50 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 3.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 1.6 Hz, 1H), 3.79- 3.76 (m, 2H), 2.67 (t, J = 10.4 Hz, 2H), 2.47 (s, 3H), 2.35 (t, J = 9.2 Hz, 2H), 1.50 (d, J = 13.6 Hz, 2H) ppm. HPLC purity: 98.13% (220 nm) and 92.66 (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm).MS (ESI⁺): m/z = 398.1 [M+H]⁺. [0414] 3-(3'-Hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-1-yl)-3-oxopropanenitrile

[0415] The title compound was prepared by the scheme and procedures shown below:

[0416] To a solution of 2-cyanoacetic acid (1 g, 11.76 mmol) in CH₂Cl2 (10 mL) were added DMF (180 mg, 2.47 mmol, 189.95 uL, 0.21 eq) and oxalyl chloride (1.64 g, 12.93 mmol, 1.13 mL, 1.1 eq) dropwise at 25°C under N2. The mixture was stirred at 25°C for 1 h and concentrated under reduced pressure to give a residue to give 2-cyanoacetyl chloride (1.3 g, crude) as a brown oil. To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol (200 mg, 500.74 umol, 1 eq) and TEA (101mg, 1.00 mmol, 139.39 uL, 2 eq) in THF (5 mL) was added 2-cyanoacetyl chloride (51 mg, 500.74 umol, 84.34 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The residue was poured into ice-water (w/w = 1/1, 5 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18100*30mm*3um;mobile phase: [water(0.1%TFA)- ACN]; B%: 1%-25%,10min) to give the desired product, 3-(3'-hydroxy-3',6'- dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-3-oxopropanenitrile (21 mg, 8.25% yield) as a yellow solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.00 (s, 1H), 9.30 (broad s, 1H), 8.50 (s, 1H), 7.54 (t, J = 2.8 Hz, 1H), 6.66 (s, 1H), 4.45 (d, J = 14.0 Hz, 1H), 4.09 (q, J = 18.4 Hz, 2H), 3.73-3.69 (m, 1H), 3.43-3.36 (m, 1H), 2.96-2.93 (m, 1H), 2.39-2.33 (m, 1H), 2.13-2.11 (m, 1H), 1.42 (d, J = 13.6 Hz, 2H) ppm.¹H NMR (DMSO-d₆ + D2O, 400 MHz): δ 8.54 (s, 1H), 7.59 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.44 (dd, J = 8.4 & 3.6 Hz, 1H), 4.05 (q, J = 18.8 Hz, 2H), 3.71 (d, J = 10.4 Hz, 1H), 3.45 (t, J = 14.2 Hz, 1H), 3.01 (t, J = 12.2 Hz, 1H), 2.44-2.33 (td, 1H), 2.20-2.10 (td, 1H), 1.47 (d, J = 12.0 Hz, 2H) ppm. HPLC purity: 93.5% (220 nm). MS (ESI⁺): m/z = 311.1 [M+H]⁺. [0417] Cyclohexyl(3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-1-yl)methanone

[0418] The title compound was prepared by the scheme and procedures shown below:

[0419] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and Et₃N (218 mg, 2.16 mmol, 0.3 mL, 2.5 eq) in THF (5 mL) was added cyclohexanecarbonyl chloride (120 mg, 822 umol, 110 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1, 5 mL). The aqueous phase was adjusted pH to 4-5 with HCl (2 N) and then extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um; mobile phase: [water(0.1%TFA)-ACN]; B%: 10%- 40%, 10min) to give cyclohexyl(3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-1-yl)methanone (90 mg, 248 umol, 30.2% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.13 (s, 1H), 9.37 (br s, 1H), 8.56 (s, 1H), 7.59 (t, J = 2.8 Hz, 1H), 6.53 (s, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.07 (d, J = 13.2 Hz, 1H), 3.47-3.40 (m, 3H), 2.91 (t, J = 11.6 Hz, 1H), 2.65-2.55 (m, 1H), 2.15-2.08 (m, 1H), 2.07-2.02 (m, 1H), 1.76-1.63 (m, 4H), 1.52-1.47 (m, 2H), 1.46-1.16 (m, 4H) ppm. HPLC purity: 97.49% (220 nm) and 100% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 354.2 [M+H]⁺. [0420] (3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-1-yl)(phenyl)methanone

[0421] The title compound was prepared by the scheme and procedures shown below:

[0422] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and Et₃N (218 mg, 2.16 mmol, 0.3 mL, 2.5 eq) in THF (5 mL) was added benzoyl chloride (116 mg, 822.81 umol, 96.0 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1) (5 mL). The aqueous phase was adjusted pH to 4-5 with HCl (2 N) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um; mobile phase: [water(0.1%TFA)-ACN]; B%: 8%-38%,10min) to give (3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1- yl)(phenyl)methanone (107 mg, 304 umol, 36.9% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.16 (s, 1H), 9.36 (br s, 1H), 8.57 (s, 1H), 7.62 (s, 1H), 7.55-7.52 (m, 2H), 7.48-7.46 (m, 3H), 6.83 (d, J = 2.0 Hz, 1H), 4.67-4.64 (m, 1H), 3.97-3.57 (m, 1H), 3.55-3.16 (m, 1H), 3.15- 3.05 (m, 1H), 2.35-2.29 (m, 2H), 1.57-1.46 (m, 2H). HPLC purity: 98.68% (220 nm) and 99.55% (254 nm). MS (ESI⁺): m/z = 348.1 [M+H]⁺. [0423] 3'-hydroxy-N-methyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0424] The title compound was prepared by the scheme and procedures shown below:

[0425] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and Et₃N (218 mg, 2.16 mmol, 0.3 mL, 2.6 eq) in THF (5 mL) was added N- methylcarbamoyl chloride (77 mg, 822 umol, 96 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1) (8 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um;mobile phase: [water(0.1%TFA)-ACN]; B%: 1%- 28%,10min) to give 3'-hydroxy-N-methyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide (103 mg, 328 umol, 39.8% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.30 (s, 1H), 8.58 (s, 1H), 7.63 (s, 1H), 6.59 (d, J = 2.0 Hz, 1H), 4.05 (d, J = 11.8 Hz, 2H), 3.09 (t, J = 12.8 Hz, 2H), 2.63 (s, 3H), 2.19 (t, J = 11 Hz, 2H), 1.43 (d, J = 12.8 Hz, 2H). HPLC purity: 95.58% (220 nm) and 93.16% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 301.1 [M+H]⁺. [0426] N-Ethyl-3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0427] The title compound was prepared by the scheme and procedures shown below:

[0428] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (200 mg, 500.74 umol) and Et3N (101 mg, 1.00 mmol, 139.39 uL, 2 eq) in THF (5 mL) was added isocyanatoethane (36 mg, 500.74 umol, 39.63 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h and poured into ice-water (w/w = 1/1, 5 mL). The aqueous phase was acidified to pH 4-5 with HCl (2N), and then extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Nano- micro Kromasil C18100*30mm 8um; mobile phase: [water(0.1%TFA)-ACN]; B%: 1%-30%, 10 min) to give N-ethyl-3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (73 mg, 229.10 umol, 45.75% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.20 (s, 1H), 8.57 (s, 1H), 7.61 (t, J = 3.0 Hz, 1H), 6.54 (br s, 1H), 6.53 (d, J = 3.0 Hz, 1H), 4.06 (dd, J = 9.6, 3.2 Hz, 2H), 3.14 - 3.05 (m, 4H), 2.23 - 2.15 (m, 2H), 1.42 (d, J = 13.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H) ppm. HPLC purity: 98.59% (220 nm) and 96.56% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 315.1 [M+H]⁺. [0429] 3'-hydroxy-N-(2,2,2-trifluoroethyl)-3',6'-dihydrospiro[piperidine-4,1'- [1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0430] The title compound was prepared by the scheme and procedures shown below:

[0431] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and 2,2,2-trifluoroethanamine (244 mg, 2.47 mmol, 194 uL, 3 eq) in THF (8 mL) was added Et₃N (250 mg, 2.47 mmol, 343 uL, 3 eq) and bis(trichloromethyl) carbonate (390 mg, 1.32 mmol, 1.6 eq) in portions at 0°C under N2. The mixture was stirred at 25°C for 5 h. The mixture was poured into ice-water (w/w = 1/1, 10 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um; mobile phase: [water(0.1%TFA)-ACN]; B%: 1%-30%, 10min) to give 3'- hydroxy-N-(2,2,2-trifluoroethyl)-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (23 mg, 62.0 umol, 7.54% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.21 (s, 1H), 9.40 (br s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 7.31 (s, 1H), 6.50 (s, 1H), 4.11-4.08 (m, 2H), 3.76-3.75 (m, 2H), 3.17 (t, J = 11.2 Hz, 2H), 2.23-2.17 (m, 2H), 1.45 (d, J = 12.4 Hz, 2H) ppm. HPLC purity: 99.33% (220 nm) and 98.43% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 369.1 [M+H]⁺. [0432] 3'-Hydroxy-N-propyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0433] The title compound was prepared by the scheme and procedures shown below:

[0434] To a mixture of 6'-(triisopropylsilyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol (200 mg, 500.74 umol) and Et3N (101 mg, 1.00 mmol, 139.39 uL, 2 eq) in THF (5 mL) was added 1-isocyanatopropane (43 mg, 500.74 umol, 47.35 uL, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h and poured into ice-water (w/w = 1/1, 5 mL). The aqueous phase was acidified to pH 4-5 with HCl (2N), and then extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18100*25mm*3um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 25%-45%, 10min) to give 3'-hydroxy-N-propyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide (45 mg, 135.68 umol, 27.10% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 11.95 (s, 1H), 9.24 (s, 1H), 8.53 (s, 1H), 7.54 (d, J = 2.8 Hz, 1H), 6.61 (t, J = 5.6 Hz, 1H), 6.41 (s, 1H), 4.07-4.03 (m, 2H), 3.13 - 3.02 (m, 4H), 2.21 - 2.14 (m, 2H), 1.50 – 1.44 (m, 2H), 1.40 (d, J = 13.2 Hz, 2H), 0.87 (t, J = 7.6 Hz, 3H) ppm. MS (ESI⁺): m/z = 329.2 [M+H]⁺. HPLC purity: 98.95% (220 nm) and 95.34 (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). [0435] N-butyl-3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0436] The title compound was prepared by the scheme and procedures shown below:

[0437] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and Et₃N (2.06 mmol, 286 uL, 2.5 eq) in THF (5 mL) was added 1- isocyanatobutane (907 umol, 102 uL, 1.10 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1, 10 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um; mobile phase: [water(0.1%TFA)-ACN]; B%: 15%-40%, 10min) to give N-butyl-3-hydroxy-3,6-dihydrospiro[[1,2]oxaborolo[4,3-d] pyrrolo[2,3-b]pyridine-1,4'- piperidine]-1'-carboxamide (50 mg, 145 umol, 17.7% yield) as a white solid.¹H NMR (DMSO-d_6, 400 MHz): δ 12.12 (s, 1H), 9.27 (br s, 1H), 8.55 (s, 1H), 7.59 (t, J = 2.8 Hz, 1H), 6.60 (br s, 1H), 6.46 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 12.0 Hz, 2H), 3.12-3.05 (m, 4H), 2.22-2.15 (m, 2H), 1.47- 1.42 (m, 4H), 1.35-1.30 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). HPLC purity: 99.66% (220 nm) and 100% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 343.1 [M+H]⁺. [0438] 3'-Hydroxy-N-isobutyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridine]-1-carboxamide

[0439] The title compound was prepared by the scheme and procedures shown below:

[0440] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (200 mg, 822 umol) and Et₃N (208 mg, 2.06 mmol, 286 uL, 2.5 eq) in THF (7 mL) was added 1- isocyanato-2-methyl-propane (82 mg, 822 umol, 1 eq) dropwise at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into ice-water (w/w = 1/1, 10 mL) and the aqueous phase was adjusted pH to 4-5 with HCl (2N), and then extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18100*30mm*3um; mobile phase: [water(0.1%TFA)-ACN]; B%: 5%-30%, 10min) to give 3'-Hydroxy-N-isobutyl-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridine]-1-carboxamide (131 mg, 380 umol, 46.2% yield) as a white solid.¹H NMR (DMSO- d_6, 400 MHz): δ 12.17 (s, 1H), 9.38 (br s, 1H), 8.56 (s, 1H), 7.61 (d, J = 2.8 Hz, 1H), 6.65 (br s, 1H), 6.47 (t, J = 2.4 Hz, 1H), 4.07 (dd, J = 12.8 & 3.6 Hz, 2H), 3.11 (t, J = 12.8 Hz, 2H), 2.92- 2.90 (m, 2H), 2.23-2.15 (m, 2H), 1.79-1.74 (m, 1H), 1.42 (d, J = 12.8 Hz, 2H), 0.87 (d, J = 6.8 Hz, 6H) ppm. HPLC purity: 99.3% (220 nm) and 96.74% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 343.1 [M+H]⁺. [0441] 1-(2-(Propylsulfonyl)ethyl)spiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3'(6'H)-ol HCl salt

[0442] The title compound was prepared by the scheme and procedures shown below:

[0443] To a mixture of propane-1-sulfonyl chloride (1 g, 7.01 mmol, 787 uL) in THF (11 mL) was added vinylmagnesium bromide (1 M, 7.71 mL, 1.1 eq) dropwise at 0°C under N2. The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl (20 mL) at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 1-vinylsulfonylpropane (0.5 g, 3.73 mmol, 53.1% yield) as a yellow oil.¹H NMR (DMSO-d₆, 400 MHz): δ 6.96 (dd, J = 10.0 Hz & 6.4 Hz, 1H), 6.25 (d, J = 3.2 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 3.11-3.06 (m, 2H), 1.66-1.59 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H) ppm. To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (300 mg, 1.23 mmol) and 1-vinylsulfonylpropane (166 mg, 1.23 mmol, 1 eq) in DMF (3 mL) were added K2CO3 (341 mg, 2.47 mmol, 2 eq) and NaI (92.5 mg, 617 umol, 0.5 eq) in one portion at 20°C under N2. The mixture was stirred at 50°C for 3 h, and H2O (0.2 mL) was added and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um; mobile phase: [water(0.1%TFA)-ACN]; B%: 1%-30%, 10min) to give 1-(2-(propylsulfonyl)ethyl)spiro[piperidine- 4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3'(6'H)-ol HCl salt (57 mg, 136.61 umol, 11.1% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz) δ 12.69 (s, 1H), 12.21 (s, 1H), 8.74 (s, 1H), 7.76 (s, 1H), 7.21 (s, 1H), 3.71-3.64 (m, 6H), 3.38-3.34 (m, 2H), 3.26-3.21 (m, 2H), 2.98-2.96 (m, 2H), 1.80-1.72 (m, 4H), 1.03 (t, J = 7.6 Hz, 3H). HPLC purity: 99.2% (220 nm), 98.85% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 378.2 [M+H]⁺. [0444] 2-(3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-1-yl)-N-methylethane-1-sulfonamide HCl salt and 2-(3'-hydroxy-3',6'- dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-N-methyl-N- (2-(N-methylsulfamoyl)ethyl)ethane-1-sulfonamide HCl salt

[0445] The title compound was prepared by the scheme and procedures shown below:

[0446] To a mixture of spiro[[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridine-1,4'-piperidin]-3(6H)-ol (300 mg, 1.23 mmol) and 2-chloro-N-methyl-ethanesulfonamide (194 mg, 1.23 mmol, 1 eq) in DMF (3 mL) were added K₂CO₃ (341 mg, 2.47 mmol, 2 eq) and NaI (93 mg, 617 umol, 0.5 eq) in one portion at 20°C under N₂. The mixture was stirred at 50°C for 1 h, and H₂O (0.2 mL) was added and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water(0.1%TFA)-ACN]; B%: 1%-20%, 10min) to give 2-(3'- hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-1-yl)-N- methylethane-1-sulfonamide HCl salt (95 mg, 236 umol, 19.1% yield) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.13 (s, 1H), 10.46 (br s, 1H), 9.45 (br s, 1H), 8.60 (s, 1H), 7.63 (t, J = 2.4 Hz, 1H), 7.38 (q, J = 4.8 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 3.72-3.59 (m, 6H), 3.43-3.39 (m, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.64-2.60 (m, 2H), 1.74 (t, J = 14.4 Hz, 2H) ppm. HPLC purity: 99.63% (220 nm) and 98.68% (254 nm, note that pyrrolopyridine scaffold generally has very weak UV absorption at 254 nm). MS (ESI⁺): m/z = 365.1 [M+H]⁺. [0447] 2-(3'-hydroxy-3',6'-dihydrospiro[piperidine-4,1'-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]- 1-yl)-N-methyl-N-(2-(N-methylsulfamoyl)ethyl)ethane-1-sulfonamide HCl salt (15 mg, 26.4 umol, 2.14% yield) was also obtained as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 12.09 (s, 1H), 10.19 (br s, 1H), 9.45 (br s, 1H), 8.59 (s, 1H), 7.63 (t, J = 3.2Hz, 1H), 7.10-7.07 (m, 1H), 6.64 (s, 1H), 3.78-3.74 (m, 4H), 3.59-3.54 (m, 4H), 3.40-3.37 (m, 4H), 2.92 (s, 3H), 2.67-2.65 (m, 1H), 2.62 (d, J = 4.8 Hz, 3H), 2.60-2.58 (m, 1H), 1.75 (d, J = 13.2 Hz, 2H). HPLC purity: 91.94% (220 nm), N/A% (254 nm). MS (ESI⁺): m/z = 486.1 [M+H]⁺. [0448] Additional General Procedure: [0449] The experimental procedures described for the preparation of 1- (propylsulfonyl)dispiro[pyrrolidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3- b]pyridin]-3''(6''H)-ol can be adapted to synthesize these analogues by replacing tert-butyl 2- oxo-6-azaspiro[3.4]octane-6-carboxylate with other corresponding ketone spiro Boc-amines, such as tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate, tert-butyl 7-oxo-2- azaspiro[4.4]nonane-2-carboxylate or tert-butyl 2-oxo-7-azaspiro[4.5]decane-7-carboxylate. See, for example, Figure 7. Other reaction conditions and purification methods may be applied to the syntheses of these analogues. [0450] With reference to Figures 8a and 8b, one synthetic route for the preparation of compounds depicted therein started with the oxidation of bromo-pyrrolopyridine (Figure 8a, Compound 23) using m-CPBA giving the N-oxide (Figure 8a, Compound 24), which was then chlorinated to yield (Figure 8a, Compound 25) Chloro-compound (Figure 8a, Compound 25) was converted to the corresponding iodo-compound 26 (Figure 8a, Compound 26), followed by a protection reaction of the pyrrole nitrogen (Figure 8a, Compound 27). It was reacted with a Grignard reagent (i-PrMgCl) and then ketone (Figure 8a, Compound 28) to obtain the alcohol (Figure 8a, Compound 29). Boronylation of (Figure 8a, Compound 29) and the subsequent hydrolysis gave both compound (Figure 8a, Compound 1) and compound (Figure 8a, Compound 30) when purified under a basic preparative-HPLC condition, while Compound 1 TFA was obtained under an acidic TFA condition. Debenzylation of both 1 and 30 by catalytic hydrogenation yielded key intermediates (Figure 8a, Compound 2) and (Figure 8a, Compound 31), respectively. These two compounds were used to react with sulfonyl chloride (RSO2Cl), carboxylic acid chloride (RCOCl), isocyanatoalkane (RNCO) or alkyl halide (RX) to generate the final compounds 3-22, with reference to Figure 8a. BIOLOGICAL EXAMPLES [0451] The compounds of the present disclosure were tested in multiple assays. The results are compiled in Table 1. Biochemical Kinase Assay Protocol(JAK) [0452] Reagent: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij^TM 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO, where required cofactors were added individually to each kinase reaction. [0453] Reaction Procedure: 1. Prepared indicated substrate in freshly prepared Base Reaction Buffer 2. Delivered any required cofactors to the substrate solution above 3. Delivered indicated kinase into the substrate solution and gently mix 4. Delivered compounds in DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), incubate for 20 minutes at room temperature 5. Delivered 33P-ATP into the reaction mixture to initiate the reaction. 6. Incubated kinase reaction for 2 hours at room temperature 7. Reactions were spotted onto P81 ion exchange paper 8. Detected kinase activity by filter-binding method. Cytokine inhibition Assay Protocol [0454] T-Cell Inhibition Assay Protocol: Testing of compounds in T-cell Inflammation Activation and T-cell Inflammation Inhibition assays, at five (5) concentrations, in duplicate, using peripheral blood mononuclear cells (PBMC’s) from three (3) human donors, with an exposure time of 24 hours. The secretion of IL-4, IL-13, and TNFα may be measured. [0455] Procedure: [0456] The test compounds will be solubilized in DMSO, then again to make appropriate stocks for use in the assay, and diluted in culture medium to 20X assay concentrations. PBMC’s will be plated and allowed to settle for 1 hour at 37°C, 5% CO2. For the activation assay, the test compounds and controls will be added to the settled PBMC’s and incubated for 24 hours at 37°C, 5% CO2. PHA (5 μg/mL) will be used as a positive control and vehicle will be used as a negative control. For the inhibition assay, the test compounds and controls will be added to the settled PBMC’s and incubated for 1 hour at 37°C, 5% CO₂. The PBMC’s will then be treated with PHA (5 μg/mL) and incubated for 24 or 48 hours at 37°C, 5% CO₂. Vehicle will be used as a positive control and dexamethasone (100 nM) will be used as a reference inhibitor control. After the main incubations, cell culture supernatants from both assays will be harvested and assayed for the cytokines listed above, using standard Luminex protocols. Levels of cytokine induction will be interpolated from standard curves using 5-parameter non-linear regression analyses, where y = (A+((B-A)/(1+(((B-E)/(E-A))*((x/C)^D))))). The interpolated data will then be normalized to vehicle controls. [0457] Cytokine Function assay protocol for IL-4/pSTAT6 and GM-CSF/pSTAT5: [0458] GM-CSF/pSTAT5: [0459] Whole blood from a healthy donor was lysed to remove red blood cells. Cells were plated onto a 96w plate. Compound was added and incubated for 1 hour (at 37 degrees C). After 1 hour, cells were stimulated with GM-CSF for 15 minutes. Cells were fixed and stained with anti pSTAT5 antibody. After staining, cells were read on Beckman-Coulter CytoFLEX. [0460] IL-4/pSTAT6: [0461] PBMC from a healthy donor was plated onto a 96w plate. Compound was added and incubated for 1 hour (at 370C). After 1 hour, cells were stimulated with IL-4 for 15 minutes. Cells were fixed and stained with anti-pSTAT6 antibody. After staining, cells were read on Beckman- Coulter CytoFLEX. [0462] All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used. [0463] Test compounds for the experiments described herein were employed in free or salt form. [0464] The specific responses observed may vary according to and depending on the particular active compound selected or whether there are present carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present disclosure. [0465] Although specific embodiments of the present disclosure are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present disclosure and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

CLAIMS That which is claimed is: 1. A compound of formula (I): wherein:

X is (CR^a2)g, wherein g is 1, 2, or 3, Z is (CR^a2)j, wherein j is 1, 2, or 3, each R^a is independently selected from the group consisting of: hydrogen, halogen, and C₁-C₆ hydrocarbyl, R¹ is selected from the group consisting of: H, (CH₂)nC(O)O(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)O(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted aryl), (CH₂)nSO₂(substituted or unsubstituted heteroaryl), (CH₂)nSO₂(substituted or unsubstituted heterocyclyl), (CH₂)nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted aryl), (CH₂)nSO₂NH(substituted or unsubstituted heteroaryl), (CH₂)nSO₂NH(substituted or unsubstituted heterocyclyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)_nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)_nC(O)(substituted or unsubstituted aryl), (CH₂)_nC(O)(substituted or unsubstituted heteroaryl), (CH₂)_nC(O)(substituted or unsubstituted heterocyclyl), C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl), substituted or unsubstituted aryl, substituted or unsubstituted C₃-C₆ cyclohydrocarbyl, and substituted or unsubstituted C₁-C₆ hydrocarbyl, and each n independently is 0, 1, 2, or 3; or a stereoisomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is a compound of formula (Ia):

3. A compound of formula (II),

wherein: R¹ is selected from the group consisting of: H, (CH₂)nC(O)O(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)O(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂(substituted or unsubstituted aryl), (CH₂)nSO₂(substituted or unsubstituted heteroaryl), (CH₂)nSO₂(substituted or unsubstituted heterocyclyl), (CH₂)nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nSO₂NH(substituted or unsubstituted aryl), (CH₂)nSO₂NH(substituted or unsubstituted heteroaryl), (CH₂)nSO₂NH(substituted or unsubstituted heterocyclyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)-substituted or unsubstituted aryl, (CH₂)_nC(O)(substituted or unsubstituted heteroaryl), (CH₂)_nC(O)(substituted or unsubstituted heterocyclyl), C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl), substituted or unsubstituted aryl, substituted or unsubstituted C₃-C₆ cyclohydrocarbyl, and substituted or unsubstituted C₁-C₆ hydrocarbyl, each n independently is 0, 1, 2, or 3; X is (CR^a ₂)_g, wherein g is 1, 2, or 3, Z is a bond or (CR^a ₂)_j, wherein j is 1, 2, or 3 each R^a, where present, is independently selected from the group consisting of: hydrogen, halogen, and C₁-C₆ hydrocarbyl, and a) E is a bond or (CH₂)_k, where k is 1, 2, or 3, wherein: R² is selected from the group consisting of hydrogen, C₁-C₆ hydrocarbyl, and C₁- C₆ halohydrocarbyl; and A is hydrogen, C₁-C₆ hydrocarbyl, or C₁-C₆ halohydrocarbyl; or b) E is a bond or (CH₂)_k, where k is 1, 2, or 3, wherein: R² is absent; and A is (CH₂)_m where m is 1, 2, or 3, and A is taken together with the depicted nitrogen atom to form a 3 to 8 membered ring, or a stereoisomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein the compound is selected from a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) and (IIf):

5. The compound of claim 4, wherein the compound is a compound of formula (IIa).

6. The compound of any one of claims 1 to 5, wherein R¹ is selected from the group consisting of: (CH₂)nC(O)O(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)O(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)_nC(O)(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)-substituted or unsubstituted aryl, (CH₂)nC(O)(substituted or unsubstituted heteroaryl), and (CH₂)_nC(O)(substituted or unsubstituted heterocyclyl).

7. The compound of any one of claims 1 to 6, wherein R¹ is other than hydrogen and is substituted with one or more of halogen, haloalkyl, R', OR', OH, SH, SR', NO₂, CN, C(O)R', C(O)OR', OC(O)R', CON(R')₂, OC(O)N(R')₂, NH₂, NHR', N(R')₂, NHCOR', NHCOH, NHCONH₂, NHCONHR', NHCON(R')₂, NRCOR', NRCOH, NHCO₂H, NHCO₂R', NHC(S)NH₂, NHC(S)NHR', NHC(S)N(R')₂, CO₂R', CO₂H, CHO, CONH₂, CONHR', CON(R')₂, S(O)₂H, S(O)₂R', SO₂NH₂, S(O)H, S(O)R', SO₂NHR', SO₂NR’(CH₂)_1-3SO₂NHR’, SO₂N(R')₂, NHS(O)₂H, NR'S(O)₂H, NHS(O)₂R', NR'S(O)₂R', Si(R')₃, =O, =S, =NNHR', =NNH₂, =NN(R')₂, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO₂R', =NNHCO₂H, =NNHSO₂R', =NNHSO₂H, =N-CN, =NH, and =NR', wherein each R’ is the same or different and is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

8. The compound of claim 7, wherein R¹ is other than H and is substituted with at least one halogen, CN, C₁-C₆ hydrocarbyl, or C₃-C₆ cyclohydrocarbyl.

9. The compound of claim 8, wherein halogen is fluorine.

10. The compound of claim 7, wherein R¹ is substituted with at least one fluorine or CN.

11. The compound of any one of claims 1 to 10, wherein R¹ is selected from H, (CH₂)_nSO₂(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)_nSO₂(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)n SO₂(substituted or unsubstituted aryl), (CH₂)nSO₂NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)NH(substituted or unsubstituted C₁-C₆ hydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted C₃-C₆ cyclohydrocarbyl), (CH₂)nC(O)(substituted or unsubstituted aryl), and C₁-C₆ hydrocarbyl(substituted or unsubstituted aryl).

12. The compound of any one of claims 1 to 11, wherein each occurence of aryl is phenyl.

13. The compound of any one of claims 1 to 5, wherein R¹ is selected from the group consisting of:

.

14. The compound of any one of claims 1 to 13, wherein n is 0.

15. A compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

or a stereoisomer thereof.

16. A compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

or a stereoisomer thereof.

17. A compound or a veterinary or pharmaceutically acceptable salt thereof selected from the group consisting of:

or a stereoisomer thereof.

18. A method for treating a subject having a disease or disorder susceptible to modulation of JAK comprising administering a therapeutically effective amount of a compound of claims 1 – 17.

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

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

21. The method according to any one of claims 18 - 20, wherein the compound is administered in an amount to perturb an immune regulatory pathway in a cell.

22. The method of claim 21, wherein the perturbation results in an effect on the JAK-STAT pathway.

23. A method of inhibiting JAK in a mammalian cell comprising contacting the mammalian cell with a compound any one of claims 1 – 17.

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

25. A composition comprising a compound of any one of claims 1 – 17 and a pharmaceutically or veterinary acceptable carrier.

26. A combination comprising a compound of any one of claims 1 – 17, and one or more other pharmaceutical or veterinary active substances.

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

28. The method of claim 27, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

29. The method of any one of claims 18 to 28, wherein the subject is a mammal.

30. The method of claim 29, wherein the mammal is selected from humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, livestock mammals, domestic mammals, or companion mammals.

31. A compound of any one of claims 1 – 17 for use in medicine.

32. A compound of any one of claims 1 – 17 for the manufacture of a medicament for the treatment of one or more diseases or disorder of inflammation, auto-immune dysfunction, and cancer.

33. The compound of claim 32, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.

34. Use of a compound of any one of claims 1 – 17 for the treatment of one or more diseases or disorders of inflammation, auto-immune dysfunction, and cancer.

35. The use of claim 34, wherein the disease or disorder is atopic dermatitis, psoriasis, or rheumatoid arthritis.