OA20225A

OA20225A - Baron containing PDE4 inhibitors.

Info

Publication number: OA20225A
Application number: OA1202100144
Authority: OA
Inventors: Peter Jones; Joseph Walter Strohbach; David Clive Blakemore; David Christopher Limburg; Martins Sunday ODERINDE; Rubben Federico TORELLA; Thean Yeow Yeoh; Tsutomu Akama; Robert Toms Jacobs; Matthew Alexander PERRY; Jacob John Plattner; Yasheen Zhou
Original assignee: Pfizer Inc.
Priority date: 2018-10-05
Filing date: 2019-10-01
Publication date: 2022-03-18

Abstract

The present invention relates to boron containing compounds of Formula (I)

Description

BORON CONTAINING PDE4 INHIBITORS

FIELD OF THE INVENTION

The présent invention relates to pharmaceutically active boron containing compounds that inhibit phosphodiesterase 4 (PDE4), pharmaceutical compositions containing these compounds, and the use of these compounds for treating or preventing diseases, conditions, or disorders ameliorated by inhibition of PDE4.

BACKGROUND

Inflammation is a major component of numerous diseases and individuals with such diseases often exhibit high levels of inflammatory regulators that include, but are not limited to, the following cytokines IL-1a, IL-Ιβ, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12, IL-13, IL-17, IL18, IL-23, IL-31, IL-33, TNF-α, IFN-a, IFN-β, and IFN-γ. A non-limiting list of disease States that are directly associated with inflammatory cytokines include: atopie dermatitis wherein inflammatory cytokines induce inflammation; psoriasis wherein inflammatory cytokines induce dermatitis; arthritis wherein inflammatory cytokines can lead to lésions in the synovial membrane and destruction of joint cartilage and bone; fibrosis wherein inflammatory cytokines can attack traumatized tissue; lupus wherein inflammatory cytokines can exacerbate the immune complex déposition and damage; allergy wherein inflammatory cytokines can induce inflammation, production of IgE, and congestion; fibromyalgia wherein inflammatory cytokines are elevated in patients; and surgical complications wherein inflammatory cytokines can avert healing.

Other diseases associated with chronic inflammation include: cancer; heart attack wherein chronic inflammation contributes to coronary atherosclerosis; Alzheimer's disease wherein chronic inflammation negatively effects brain cells; congestive heart failure wherein chronic inflammation causes heart muscle wasting; stroke wherein chronic inflammation promûtes thromboembolie events; and aortic valve stenosis wherein chronic inflammation damages heart valves. Arteriosclerosis, osteoporosis, Parkinson's disease, bacterial infection, viral infection, inflammatory bowel disease including Crohn's disease and ulcerative colitis, as well as multiple sclerosis (a typical autoimmune inflammatory-related disease) are also related to inflammation. Current methods available for the treatment of such inflammatory diseases can be unsatisfactory due to a lack of sufficient efficacy and/or drug related side effects associated therein. Therefore a need exists for new therapeutic methods that modulate inflammatory process involved in the diseases, conditions, and disorders, disclosed herein.

In particular, Atopie Dermatitis (AD) is an inflammatory skin disease that, typically, manifests during early childhood but can appear in adolescence or adulthood and follows either a chronic or a relapsing/remitting disease progression. AD patients display pruritic skin and show susceptibility to cutaneous secondary bacterial, viral and fungal infections. Patients with

AD can also demonstrate a compromised barrier function that leads to activation of kératinocytes and other immune cells. A number of inflammatory cytokines are involved in the symptoms characteristic of AD including, but not limited to, IL-1 IL-2, IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-18, IL-22, IL-23, IL-31, IL-33, IL-36, and TNF-α. Inflammatory cytokines facilitate the production of various chemoattractants or chemokines which support the recruitment of leukocytes to the disease site. Chemokines that contribute to inflammation in AD patients include, but not limited to, CCL1, CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL17, CCL18, CCL20, CCL22, CCL26 and CCL27.

There are limited therapeutic options for the treatment of AD. The topical use of antiinflammatory steroids has been utilized in AD treatment particularly in the case of acute disease flares. The steroids suppress the activation and prolifération of inflammatory cells as well as kératinocytes and fibroblasts. However, steroids can cause adverse local side effects that include, but are not restricted to, skin atrophy, telangiectasia (abnormal dilation of capillary vessels), epidermal barrier disturbance, striae, rosacea, acné, hypertrichosis, hypopigmentation, delayed wound healing and alterations in skin elasticity. Emollients including petrolatum and over-the-counter moisturizers hâve been used to reduce the use of topical steroids. Topical application of mevalonic acid and nicotinamide has been used to improve the epidermal barrier permeability through the production of cholestérol and ceramide. Topical calcineurin inhibitors (TCI) such as tacrolimus and pimecrolimus hâve been used in the treatment of AD. Cyclosporine A (CyA) has been used as an immunosuppressant to inhibit calcineurin phosphatase thereby leading to réduction in levels of IL-2 and inhibition of T cell prolifération. Systemic treatment include humanized monoclonal antibodies such as Omalizumab, Efalizumab and Etanercept, Dupilumab that target sérum IgE, LFA-1, TNF-α, and IL-4r respectively [Rahman, Inf. & AH. 2011,10, 486], Additional eczema, skin and disease conditions include hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/druginduced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, and hidradenitis suppurativa [Eyerich and Eyerich, J. Eur. Ac. Derm. Ven., 32, 692 (2018)].

Psoriasis is an immune-mediated chronic skin disease that exists in several different forms including plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, and inverse psoriasis. Plaque psoriasis (psoriasis vulgaris) is the most common form of psoriasis and typically appears as patches of b raised red skin covered by a flaky white buildup. Pustular psoriasis appears as raised bumps that are filled with non-infectious pus (pustules). The skin under and surrounding pustules is red and tender. Pustular psoriasis can be localized, commonly to the hands and feet, or generalized with widespread patches occurring on any part ofthe body. Nail psoriasis produces a variety of changes in the appearance of finger and toe nails. These changes include discoloring under the nail plate, pitting ofthe nails, lines going across the nails, thickening ofthe skin under the nail, and the loosening (onycholysis) and crumbling ofthe nail. Flexural psoriasis (inverse psoriasis) appears as smooth inflamed patches of skin. It occurs in skin folds, particularly around the genitals (between the thigh and groin), the armpits, under an overweight stomach (pannus), and under the breasts (inframammary fold). It is aggravated by friction and sweat, and is vulnérable to fungal infections. Guttate psoriasis is characterized by numerous small oval spots. These spots of psoriasis appear over large areas ofthe body, such as the trunk, limbs, and scalp. Psoriatic arthritis involves joint and connective tissue inflammation. Psoriatic arthritis can affect any joint but is most common in the joints of the fingers and toes. Psoriatic arthritis can resuit in swelling of the fingers and toes known as dactylitis. Psoriatic arthritis can also affect the hips, knees and spine (spondylitis). Erythrodermie psoriasis involves the widespread inflammation and exfoliation ofthe skin over most ofthe body surface. It may be accompanied by severe itching, swelling and pain. It is often the resuit of an exacerbation of unstable plaque psoriasis, particularly following the abrupt withdrawal of systemic treatment. Current thérapies available for treatment of psoriasis include topical treatment, phototherapy, and systemic applications. The treatments are either cosmetically undesirable, inconvénient for long-term use, or hâve limited effectiveness.

Inflammatory Bowel Disease (IBD) describes a group of intestinal disorders that involve inflammation of the digestive tract including ulcerative colitis and Crohn's disease. Ulcerative

Colitis (UC) causes periodic and chronic inflammation and ulcers in the lining of the large intestine (colon). Crohn's disease (CD) is characterized by inflammation ofthe lining ofthe gastrointestinal tract and can penetrate into related tissues. Patients with IBD can exhibit diarrhea, abdominal pain, fatigue, and weight loss, and these conditions can be severe and debilitating. As the symptoms vary depending on the level and duration of inflammation, an agent that modulâtes said inflammation would be useful in treating IBD.

Phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDEs regulate the level of cyclic nucléotides within cells and maintain cyclic nucléotide homeostasis by hydrolyzing such cyclic mononucleotides resulting in termination of their messenger rôle. PDE enzymes can be grouped into families according to their specificity toward hydrolysis of cAMP and/or cGMP, their sensitivity to régulation by calcium and calmodulin, and their sélective inhibition by various compounds.

The PDE4 enzyme sub-family consists of four genes which produce 4 isoforms ofthe

PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [Wang étal., Biochem. Biophys. Res. Comm., 234, 320 (1997)]. In addition, various splice variants of each PDE4 isoform hâve been identified. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5'-monophosphate (AMP). Régulation of cAMP activity is important in many biological processes including inflammation.

The compounds ofthe présent invention inhibit phosphodiesterases, including PDE4, and modulate inflammatory cytokine levels and are, therefore, useful in treating inflammatory disorders such as atopie dermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, and inflammation resulting from surgical complications.

SUMMARY OF THE INVENTION

The présent invention provides compounds of Formula (I) that inhibit PDE4 and are useful for treating or preventing disorders ameliorated by inhibition of PDE4 in humans,

X-Y-Z

Formula (I) or a pharmaceutically acceptable sait thereof, wherein

X is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, ortriazine, wherein each is optionally substituted with 1,2, 3, 4, or 5 substituents that are independently deuterium, (C2-C₆)alkenyl, (C₂-C6)alkenyloxy, (C2-C₆)alkenylthio, (Ci-Cejalkoxy, (Ci-C₆)alkoxy-c/i-i3, (C-i-CejalkoxyfCi-CeJalkoxy, (Ci-C6)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-Ce)alkyl, (Ci-C₆)alkyl-c/i-i3, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, (C₂-C6)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, (C₃-Ca)cycloalkyl, (C3-Cs)cycloalkyl(Ci-C₆)alkoxy, (C3-C₈)cycloalkyl(Ci-C6)alkyl, C3-C₈)cycloalkyl(Ci-C6)alkylthio, (C₃-C₈)cycloalkyloxy, (C3-C₈)cycloalkylthio, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, halo(Ci-C₆)aIkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C6)alkyl, (5-6 membered)heteroaryl(Ci-C₆)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C6)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C6)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl· mercapto, nitro, thioiCrCsJalkyl, -NR_AR_B, NR_ARB(Ci-C₆)alkoxy, NR_AR_B(Ci-C₆)alkyl, or (NR_AR_B)carbonyl; R_Aand R_b are independently hydrogen, (Ci-Ce)alkyl, or (Ci-Ce)alkylcarbonyl; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, oxadiazole, thiadiazole, or triazole, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently deuterium, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i3, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-c/i-7, (Ci-Ce)alkyl, (Ci-Ce)alkyl-c/i-i3, (Ci-Cejalkylcarbonyl, (Ci-Cejalkylthio, carboxy, carboxy(Ci-C6)alkoxy, carboxy(Ci-C6)alkyl, cyano, halogen, halo(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C_s)alkyl, mercapto, nitro, -NR_cRd, NR_cRD(Ci-C₆)alkoxy, NR_cRD(Ci-C₆)alkyl, or (NRcRo)carbonyl; Rc and Rd are independently hydrogen, (Ci-C₆)alkyl, or (Ci-C₆)alkylcarbonyl; Z is

wherein B is boron; Rio at each occurrence is independently H, deuterium, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-Ce)alkyl, (Ci-C₆)alkyl-di-₁₃, (Ci-C₆)alkylthio(Ci-C6)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; Ru at each occurrence is independently deuterium, (Ci-C₃)alkyl, or (Ci-Cftalkyl-dw; R12 is independently H, (Ci-C_s)alkyl, or hydroxy(Ci-C₆)alkyl; m is 0, 1, 2, or 3; n is 0, 1,2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1,2, 3, 4, 5, or 6; and r is 0, 1,2, 3, 4, 5, 6 or 7.

In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (I) and at least one pharmaceutically acceptable excipient, 10 diluent, or carrier.

In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof.

in another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases in a mammal, particularly a human, comprising topically administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof.

In another aspect, the présent invention provides the use of compounds of Formula (I) in 20 the manufacture of a médicament for treating inflammatory diseases in a mammal, particularly a human.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is an X-ray structure (ORTEP drawing) of crystalline (R)-4-(5-(3-ethoxy-425 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3).

Figure 2 is an X-ray structure (ORTEP drawing) of crystalline (R) 4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4).

Figure 3 is an X-ray structure (ORTEP drawing) of crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5).

Figure 4 is an X-ray structure (ORTEP drawing) of crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19).

Figure 5 is a powder X-ray diffraction analysis of crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3).

Figure 6 is a powder X-ray diffraction analysis of crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4).

Figure 7 is a powder X-ray diffraction analysis of crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5).

Figure 8 is a powder X-ray diffraction analysis of crystalline (-) 4-(5-(2-(difluoromethyl)-3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 10).

Figure 9 is a powder X-ray diffraction analysis of crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19).

Figure 10 is a powder X-ray diffraction analysis of crystalline (4-methoxy-3propoxyphenyl)boronic acid.

Figure 11 is a powder X-ray diffraction analysis of crystalline 3-bromo-5-(4-methoxy-3propoxyphenyl)pyridine.

Figure 12 is a powder X-ray diffraction analysis of crystalline 3-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

DETAILED DESCRIPTION OF THE INVENTION In another embodiment, the présent invention provides compounds of Formula (I)

X-Y-Z

Formula (I) or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently deuterium, (C2-C₆)alkenyl, (C2-C₆)alkenyloxy, (C2-C₆)alkenylthio, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i3, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, (C₂C₆)alkynyl, (C2-C₆)alkynyloxy, (C2-C₆)alkynylthio, aryl, aryl(Ci-C6)alkoxy, aryl(Ci-C6)alkyl, aryl(Ci-C_s)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₆)alkoxy, (C₃-C₈)cycloalkyl(Ci-C6)alkyl, C₃-C₈)cycloalkyl(Ci-C6)alkylthio, (C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(Ci-C6)alkoxy, halo(Ci-C6)alkyl, halo(Ci-Ce)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C₆)alkyl, (5-6 membered)heteroaryl(Ci-C6)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C6)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, thio(Ci-C6)alkyl, -NRaRb, NRARsfCi-Cejalkoxy, NRARB(Ci-C₆)alkyl, or (NRARejcarbonyl; Ra and Rb are independently hydrogen, (Ci-C₆)alkyl, or (Ci-Cejalkylcarbonyl; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1,2, or 3 substituents that are independently deuterium, (Ci-Cs)alkoxy, (Ci-C₆)alkoxy-di-i3, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-Cs)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-c/i-₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-c/i-i₃, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C6)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, halo(Ci-C₈)alkoxy, halo(Ci-C6)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, -NRcRd, NRcRD(Ci-Cs)alkoxy, NRcRofCi-Cejalkyl, or (NRcRo)carbonyl; Rc and Rd are independently hydrogen, (Ci-Cejalkyl, or (Ci-Ce)alkylcarbonyl; Z is as defined in the Summary section herein; Rio at each occurrence is H, deuterium, (Ci-C₆)alkyl, (Ci-C₆)alkyl-c/i-i₃, or hydroxy(Ci-C₆)alkyl; Ru at each occurrence is deuterium, methyl, or methyl-d₃; Ri₂ is independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C_s)alkyl; m is 0, 1,2, or 3; n is 0 or 1 ; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and r is 0, 1,2, 3, 4, 5, 6 or 7

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Ce)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C6)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (CrC₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C6)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is p

^(Rioip ^(Rlo)m , wherein B is boron;

Rw at each occurrence is H, methyl or hydroxymethyl; m is 1; and p is 1.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Cs)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (3-7membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (O-Csjalkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C_s)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

OH wherein B is boron.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Ce)alkyl, (Ci-Cejalkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-Cs)alkoxy, halo(Ci-Cs)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-Cs)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is OH / ^B \ ^X° wherein B is boron.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-Cejalkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-Ce)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-Cs)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (Ci-Csjalkyl, (Ci-Ce)alkyl, carboxy(Ci-C6)alkyl, halogen, halo(Ci-C_s)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

OH / ^•B fTy° X wherein B is boron.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-Cejalkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-C₈)alkoxy, halo(C-i-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Ce)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-Ce)alkoxy, or hydroxy(Ci-Ce)alkyl; Z is

Rio at each occurrence is H, methyl or hydroxymethyl; p is 1; and r is 1.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (Ci-Csjalkyl, (Ci-Cs)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

wherein B is boron; Rw at each occurrence is H, methyl or hydroxymethyl; R12 is at each occurrence independently H, (Ci-C₆)alkyl, or hydroxy(Ci-Ce)alkyl.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-Ce)alkoxy, (Ci-Ce)alkyl, (Ci-Cejalkylthio, cyano, (Ca-Csjcycloalkyloxy, halogen, halo(Ci-C6)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, 20 pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C_s)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C_s)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-Ce)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

ORi₂ wherein B is boron; Ri₂ is at each occurrence independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Cejalkyl, (Ci-C₈)alkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-C6)alkoxy, halo(Ci-C6)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Cs)alkoxy, (Ci-C6)alkoxy(Ci-Cs)alkyl, (Ci-CejalkoxycarbonyKCi-Cejalkyl, (Ci-Cs)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C6)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C_s)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

OR12 ' B-OR₁₂ vL/OH wherein B is boron; Ri₂ is at each occurance independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C6)alkyl.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Cejalkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-Cs)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Ce)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is θ^12 wherein B is boron; and R12 is at each occurrence independently H, (Ci-Ce)alkyl, or hydroxy(Ci-C6)alkyl.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C3-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C6)alkyl, hydroxy(Ci-C₈)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

boron; R_w at each occurrence is H, methyl or hydroxy methyl; Rn at each occurrence is independently (Ci-Csjalkyl; and n is 0, 1,2, 3, or 4.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-Cs)cycloalkyloxy, halogen, halo(Ci-C₈)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Cejalkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is oO<

, wherein B is boron; Rn is methyl; and n is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (I), or a 15 pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-Ce)alkoxy, (Ci-Cs)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-Cs)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₈)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C_s)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C6)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(C-i-Ce)alkyl; Z is /(^R1l)n οχ I >

'' , wherein Β is boron; Rn is methyl; and n is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (I), or a 25 pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-Cs)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C6)alkoxy(Ci-Cs)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-Csjalkyl, (Ci-Ce)alkyl, carboxy(Ci-Ce)alkyl, halogen, halo(Ci-C6)alkyl, hydroxy(Ci-Ce)alkoxy, or hydroxy(Ci-C6)alkyl; Z is

, wherein B is boron; Rn is methyl; and n is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-Ce)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-Cs)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-Ce)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-Ce)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

wherein B is boron; Rio at each occurrence is H, methyl or hydroxymethyl;

Rn at each occurrence is independently (Ci-C₃)alkyl; and q is 0, 1, 2, 3, 4, 5, or 6.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1, 2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-Cejalkylthio, cyano, (C₃-C8)cycloalkyloxy, halogen, halo(Ci-C6)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, 25 pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy(Ci-C6)alkoxy, or hydroxy(Ci-C6)alkyl; Z is

(Rn)q

Ο

OH wherein B is boron; Ru at each occurrence is methyl; and q is 0, 1,2, or 3.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-C₆)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazoie, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₈)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C6)alkyl; Z is (Rll)q

J r ''^v wherein B is boron; Rn at each occurrence is methyl; and q is 0, 1,2, or 3.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is phenyl, pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, or 3 substituents that are independently (Ci-Cs)alkoxy, (Ci-C₆)alkyl, (Ci-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, (4-7 membered)heterocycleoxy, or hydroxy(Ci-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazoie, pyrazole, or thiadiazole, wherein each is optionally substituted with 1 substituent that is (Ci-Ce)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C_s)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₈)alkyl, hydroxy(Ci-Ce)alkoxy, or hydroxy(Ci-C_s)alkyl; Z is (Rn )q 0^1

O

OH wherein B is boron; Ru at each occurrence is methyl; and q is 0, 1,2, or 3.

In another embodiment, the présent invention provides compounds of Formula (I), or a pharmaceutically acceptable sait thereof, wherein X is

Ai and A₂ are independently O or S; R^ R₂, and R₅ are independently H, deuterium, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently H, (Ci-Ce)alkyl, (Ci-C₆)alkyl-di-i₃, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; Y is

0-N , N-0

S-N . N-S > N-N >

Re, R7, Rs, and R₉ are independently H, deuterium, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i3, (Ci-C₆)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-Ce)alkyl, (Ci-Ce)alkoxycarbonyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C3)alkyl-c/i.₇, (Ci-Ce)alkyl, (Ci-C₆)alkyl-c/i-i₃, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, -NR_cRd, NR_cRD(Ci-C_s)alkoxy, NRcRo(Ci-C₆)alkyl, or (NRcRo)carbonyl; Rc and Rd are independently hydrogen, (Ci-Ce)alkyl, or (Ci-Cejalkylcarbonyl; Z is as defined in the Summary section herein; Rw at each occurrence is independently H, deuterium, (Ci-Cs)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylthio(Ci-C6)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; Rn at each occurrence is independently (Ci-C₃)alkyl or (C^Csjalkyl-di-y; R12 is independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; m is 0, 1,2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1,2, 3, 4, 5, 6 or 7.

Ri, R₂, and R₅ are independently H, cyano, halogen, or halo(Ci-Ce)alkyl; R3 and R₄ are independently (Ci-Ce)alkyl, (Cs-Csjcycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C6)alkyl; Y is ^R6 ^R6

Re, R7, Rs, and Rg are independently H, (Ci-C₆)alkoxy, (Ci-C6)alkoxy(Ci-C₆)alkyl, (Ci-C_s)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy^-Ce^lkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C6)alkoxy, or hydroxy(Ci-Ce)alkyl; Z is as defined in the Summary section herein; R10 at each occurrence is independently H, (Ci-C₆)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkyl, (Ci-C₆)alkylthio(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; Rn at each occurrence is independently (Ci-C3)alkyl; R12 is independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; m is 0, 1,2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1,2, 3, 4, 5, 6 or 7.

Ri, R₂, and R_s are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; Y is

Re, R₇, Rs, and R₉ are independently H, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halofCi-CeJalkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; Z is

OH

, wherein B is boron;

R10 at each occurrence is independently H, (Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; m is 0, 1,2, or 3; and p is 0, 1,2, 3, 4, or 5.

Ri, R2, and R₅ are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-Ce)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C6)alkyl, or hydroxy(Ci-C₈)alkyl; Y is

Re, Rz, Rs, and R₉ are independently H, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C6)alkyl, hydroxy(Ci-C₈)alkoxy, or hydroxy(Ci-C₈)alkyl; and Z is

OH /

wherein B is boron.

Ri, R₂, and R₅ are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; Y is

Re, R?, Ra, and R₉ are independently H, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(C-i-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; and Z is

OH /

wherein B is boron.

Re, R7, Ra, and R₉ are independently H, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxyCCrCsjalkyl; and Z is

OH

wherein B is boron.

In another embodiment, the présent invention provides compounds of Formula (IA)

Formula (IA) or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are independently

O or S; Ri, R₂, and R₅ are independently H, deuterium, (C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio, (Ci-C_s)alkoxy, (Ci-C₆)alkoxy-di-i₃, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-Cs)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ch-Cejalkyl, (Ci-C₆)alkyl-di-i₃, (Ci-Cejalkylcarbonyl, (Ci-Cejalkylthio, (C₂-C6)alkynyl, (C₂-C6)alkynyloxy, (C₂-C6)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-Cs)alkoxy, carboxy(Ci-C6)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CiC₆)alkoxy, (C₃-C8)cycloalkyl(Ci-C₆)alkyl, C₃-C₈)cycloalkyl(Ci-C6)alkylthio, (C₃-C₈)cycloalkyloxy, (C₃-C8)cycloalkylthio, halogen, halo(Ci-Ce)alkoxy, halo(Ci-C6)alkyl, halo(Ci-C₈)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C6)alkyl, (5-6 membered)heteroaryl(Ci-C6)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-Ce)alkyl, mercapto, nitro, thio(Ci-C₆)alkyl, -NR_aRb, NR_ARB(Ci-C₆)alkoxy, NR_ARB(Ci-C₆)alkyl, or (NR_AR_B)carbonyl; R_Aand Rb are independently hydrogen, (Ci-C₆)alkyl, or (Ci-C₆)alkylcarbonyl; R₃ and R₄ are independently H, deuterium, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and R₉ are independently, H, deuterium, (Ci-Cs)alkoxy, (Ci-C6)alkoxy-c/i-i₃, (Ci-Ce)alkoxy(Ci-C6)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-Ce)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, -NR_cRd, NR_cRD(Ci-C₆)alkoxy, NRcRD(Ci-C₆)alkyl, or (NRcRo)carbonyl; R_c and Rd are independently hydrogen, (Ci-Cs)alkyl, or (Ci-C₆)alkylcarbonyl; R_w at each occurrence is independently deuterium, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-Ce)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylthio(Ci-C6)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the présent invention provides compounds of Formula (IA), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and R₉ are independently, H, (Ci-Ce)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C6)alkyl, halogen, halo(Ci-C₈)alkyl, hydroxy(Ci-C₈)alkoxy, or hydroxy(Ci-C₆)alkyl; R₁₀ is (Ci-C₃)alkyl, (Ci-Cs)alkyl or hydroxy(Ci-C₆)alkyl; and p is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (IA), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R?, and R₉ are independently H or (C-i-C₃)alkyl; Rio is methyl; and p is 0, 1, or 2.

In another embodiment, the présent invention provides compounds of Formula (IA), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C_s)alkyl, or hydroxy(Ci-C₈)alkyl; R₆, R?, and R_g are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IA), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R₈, R7, and R₉ are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IA), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R₆, R7, and R₉ are H; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IB)

Formula (IB) or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are independently O or S; Ri, R₂, and R₅ are independently H, deuterium, (C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i₃, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C6)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di.₁₃, (Ci-Cs)alkylcarbonyl, (Ci-C₈)alkylthio, (C₂-C₈)alkynyl, (C₂-C₈)alkynyloxy, (C₂-C₈)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CiC₈)alkoxy, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, C₃-C₈)cycloalkyl(Ci-C6)alkylthio, (C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, halo(Ci-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C₆)alkyl, (5-6 membered)heteroaryl(Ci-C₆)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C_s)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, thio(Ci-C₆)alkyl, -NR_aRb, NR_AR_B(Ci-C₆)alkoxy, NR_AR_B(Ci-C₆)alkyl, or (NR_AR_B)carbonyl; R_Aand R_b are independently hydrogen, (Ci-C₆)alkyl, or (Ci-C₆)alkylcarbonyl; R₃ and R₄ are independently H, deuterium, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di.₇, (Ci-C₆)alkyl, (Ci-C_s)alkyl-di-i₃, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and R₉ are independently, H, deuterium, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i₃, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C6)alkoxycarbonyl(Ci-C_s)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, (Ci-C₆)alkylcarbonyl, (Ci-C₈)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-Ce)alkyl, cyano, halogen, halo(Ci-C6)alkoxy, halo(Ci-C₈)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, -NRcRd, NRcRo(Ci-C₈)alkoxy, NRcRD(Ci-C₈)alkyl, or (NRcRo)carbonyl; Rc and R_D are independently hydrogen, (Ci-Cs)alkyl, or (Ci-C₆)alkylcarbonyl; Rw at each occurrence is independently deuterium, (Ci-C₈)alkoxy(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-c/-i-₇, (Ci-Ce)alkyl, (Ci-C₈)alkyl-di-i₃, (Ci-C_s)alkylthio(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; and p is 0, 1,2, 3, 4, or 5.

In another embodiment, the présent invention provides compounds of Formula (IB), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-Ce)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R_s, R₇, and R₉ are independently, H, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-Cs)alkyl, carboxy(Ci-C₈)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl; R™ is (Ci-C₃)alkyl, (Ci-C₆)alkyl or hydroxy(Ci-C₆)alkyl; and p is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (IB), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; R_b R₂, and R₅are H; R₃ and R₄ are independently (Ci-Ce)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and R₉ are independently H or (Ci-C₃)alkyl; Rio is methyl; and p is 0, 1, or 2.

In another embodiment, the présent invention provides compounds of Formula (IB), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and R₉ are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IB), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; R_b R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R₆, R₇, and R₉ are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IB), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; R^ R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R_s, R₇, and R₉ are H; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IC)

Formula (IC) or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are independently O or S; Ri, R₂, and R₅ are independently H, deuterium, (C₂-C_s)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio, (Ci-Cs)alkoxy, (Ci-C₆)alkoxy-c/i-₁₃, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(CrC₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-Cejalkyl, (Ci-C₆)alkyl-di-i₃, (Ci-Cejalkylcarbonyl, (Ci-C₆)alkylthio, (C₂-C₆)alkynyl, (C₂-C6)alkynyloxy, (C₂-C6)alkynylthio, aryl, aryl(Ci-C6)alkoxy, aryl(Ci-C₆)alkyl, aryl(C-i-C6)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(C-i-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci10 C₆)alkoxy, (C₃-C₈)cycloalkyl(Ci-C₆)alkyl, C₃-C₈)cycloalkyl(Ci-C₆)alkylthio, (C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, halo(Ci-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C₆)alkyl, (5-6 membered)heteroaryl(Ci-C₆)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C6)alkyl, (4-7 membered)heterocycle(Ci-C6)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C_s)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, thio(Ci-C₆)alkyl, -NRaRb, NRARB(Ci-C₈)alkoxy, NRARB(Ci-C₈)alkyl, or (NRARB)carbonyi; Ra and R_B are independently hydrogen, (Ci-C₆)alkyl, or (Ci-C₆)alkylcarbonyl; R₃ and R₄ are independently H, deuterium, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-c/i-i₃, (C₃-C₈)cycloalkyl, halo(Ci-Ce)alkyl, or hydroxy(Ci-C₈)alkyl; R₆, R₇, and Rg are independently, H, deuterium, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-d1-13, (Ci-C₆)alkoxy(Ci-C6)alkoxy, (Ci-Cs)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-Cs)alkyl, (Ci-Ce)alkyl-c/i.i₃, (Ci-Cejalkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, haloiCrCejalkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-C₆)alkyl, mercapto, nitro, -NR_cRd, NRcR_D(Ci-C₆)alkoxy, NR_cRD(Ci-C₆)alkyl, or (NR_cR_D)carbonyl; R_c and Rd are independently hydrogen, (Ci-Ce)alkyl, or (Ci-C₆)alkylcarbonyl; Rw at each occurrence is independently deuterium, (Ci-C₆)alkoxy(Ci-C_s)alkyl, (Ci-C₃)alkyl, (C₁-C₃)alkyl-c/₁.₇, (Ci-Ce)alkyl, (Ci-C₆)alkyl-di-i3, (Ci-C₆)alkylthio(Ci-C6)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the présent invention provides compounds of Formula (IC), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅ are independently H, cyano, halogen, or halo(Ci-C₆)alkyl; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₈)alkyl, or hydroxy(Ci-C₈)alkyl; R₆, R₇, and R₉ are independently, H, (Ci-Ce)alkoxy, (Ci-C6)aIkoxy(Ci-C₆)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₆)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₈)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-Ce)alkyl; Rw is (Ci-C₃)alkyl, (Ci-Ce)alkyl or hydroxy(Ci-C₈)alkyl; and p is 0 or 1.

In another embodiment, the présent invention provides compounds of Formula (IC), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₈)alkyl, or hydroxy(Ci-Ce)alkyl; R₈, R₇, and Rg are independently H or (Ci-C₃)alkyl; Rw is methyl; and p is 0, 1, or 2.

In another embodiment, the présent invention provides compounds of Formula (IC), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl; R₆, R₇, and Rg are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IC), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R₆, R₇, and Rg are independently H or (Ci-C₃)alkyl; and p is 0.

In another embodiment, the présent invention provides compounds of Formula (IC), or a pharmaceutically acceptable sait thereof, wherein B is boron; Ai and A₂ are O; Ri, R₂, and R₅are H; R₃ and R₄ are independently (Ci-C₃)alkyl; R₈, R₇, and R₉ are H; and p is 0.

In another embodiment, the présent invention provides the following compounds:

(R) 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3,4dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(2-hydroxyethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(2-hydroxyethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(3-hydroxypropoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(3-hydroxypropoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-chloro-5-ethoxy-420225 p methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-chloro-5-ethoxy-45 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (S) 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)1,2-oxaborolan-2-ol; (R) 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2ol; (R) 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol; (S) 4-(6'-methoxy-5'10 propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6methylpyridin-3-yI)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3yI)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(415 methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(4-methoxy-3propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin2-yl)-1,2-oxaborolan-2-ol; 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol;

(R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin2-yl)-3-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl1,2-oxaborolan-2-ol; 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol2(5H)-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (S) 425 (6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (R) 4-(hydroxymethyl)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(hydroxymethyl)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(2-fluoroethoxy)-430 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(2-fluoroethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)1,2-oxaborolan-2-ol; (R) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'biphenyl]-2-carbonitrile; (S) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'35 biphenyl]-2-carbonitrile; (R) 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy[1,1'-biphenyl]-2-carbonitrile; (S) 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3propoxy-[1,1 '-biphenyl]-2-carbonitrile; (R) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3yl)-1,2-oxaboroIan-2-ol; (S) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,220225

B oxaborolan-2-ol; (R) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol; (S) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol; (R) 4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (2R)-2-(5-(4-methoxy-35 propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol; (2S)-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol; (R) 4-(5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol: (S) 4-(5-methoxy-6propoxy-^.S'-bipyridinl-S'-yO-l ,2-oxaborolan-2-ol; (R) 4-(3'-(2-fluoroethoxy)-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-(2-fluoroethoxy)-4'-methoxy-[1,1 '-biphenyl]-3-yl)10 1,2-oxaborolan-2-ol; (R) 4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (S) 4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (R) 4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-315 (thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan20 2-ol; (S) 4-(5-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'isopropoxy-4'-methoxy-[1,1 '-biphenyl]-3-yI)-1,2-oxaborolan-2-ol; (S) 4-(3'-isopropoxy-4'methoxy-[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-ethoxy-4'-methoxy-[1,1 ’-biphenyl]-3yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-ethoxy-4'-methoxy-[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 425 (5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-fluoro-4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)-4-(6-((S)-1-hydroxyethyl)-2-(4methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R)-4-(6-((R)-1-hydroxyethyl)-2(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S)-4-(6-((S)-1-hydroxyethyl)30 2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S)-4-(6-((R)-1hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (R) 4-(5-(4methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 6-(6-(2-hydroxy-1,2-oxaborolan-4yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile; (S) 6-(6-(2-hydroxy-1,2-oxaborolan-435 yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile; (R) 4-(4'-methoxy-3’-propoxy-[1,1'-biphenyl]-3yI)-1,2-oxaborolan-2-ol; (S) 4-(4'-methoxy-3'-propoxy-[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(5ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(3-(4-(cyclopentyloxy)20225

P 5-methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(4-(cyclopentyloxy)-5methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxy-2(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxy-2(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3,4-diethoxyphenyl)pyridin-35 yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(4-methoxy-3propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-310 propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(4'-methoxy-3'(pentyloxy)-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(4'-methoxy-3'-(pentyloxy)-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,215 oxaborolan-2-ol; (S) 4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(2'-fluoro-4'-methoxy-3'-propoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(2'-fluoro-4'-methoxy-3'-propoxy-[1,r-biphenyl]-3-yl)1,2-oxaborolan-2-ol; (R) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1 '-biphenyl]-320 carbonitrile; (S) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1'-biphenyl]-3-carbonitrile; (R) 3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile; (S) 3ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile; 4-(3-(6-ethoxy5-methoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-(6-ethoxy-5-methoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,225 oxaborolan-2-ol; (R) 4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-230 ol; 4-(3'-(cyclopentyloxy)-4'-methoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3'(cyclopentyloxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-(cyclopentyloxy)4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol (R) 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(3-(cyclopentyloxy)-435 methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) ethyl 2-(6-(2-hydroxy-1,2oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate; (S) ethyl 2-(6-(2hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate; (R) 2-(6-(220225

P hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetic acid; (S) 2-(6(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetic acid; (R) 4(5-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-fluoro-6-(4methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-35 propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(4-(difluoromethyl)-5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(difluoromethyl)-5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-410 methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-(methylthio)phenyl)pyridin-3-yl)1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-propoxyphenyl)pyridin3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-215 ol; (R) 4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(2'-fluoro-4',5'dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(2'-fluoro-4',5'-dimethoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2yl)-3-methoxybenzonitrile; (S) 2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-320 methoxybenzonitrile; (R) 4-(3-(5,6-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3(5,6-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R) 6-(5-(2-hydroxy-1,2-oxaborolan-4yl)pyridin-3-yl)-2,3-dimethoxybenzonitrile; (S) 6-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)2,3-dimethoxybenzonitrile; (R) 4-(2-(2-fluoro-4-methoxy-5-propoxyphenyl)-6(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(2-fluoro-4-methoxy-525 propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; 4-(3-(5-methoxy-6propoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-(5-methoxy-6-propoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2oxaborolan-2-ol; (R) 4-(3',4',5-trimethoxy-[1,r-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3',4',5trimethoxy-[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)-430 methylpyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin2-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (S) 4(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(3-(5,6-dimethoxypyridin-3yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5,6-dimethoxypyridin-3-yl)phenyl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-fluoro-3,435 dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-2,6-difluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-2,6-difluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-(cyclopropylmethoxy)-4'-methoxy[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-(cyclopropylmethoxy)-4'-methoxy-[1,r biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-ethoxy-2'-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)1,2-oxaborolan-2-ol; (S) 4-(3'-ethoxy-2'-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2ol; (R) 4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2,4dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-ethoxy-4'-(methylthio)-[1,1 'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-ethoxy-4'-(methylthio)-[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol; (R) 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3-(4,5dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(4,5-dimethoxypyridin-2-yl)phenyl)1,2-oxaborolan-2-ol; (R) 4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)1,2-oxaborolan-2-ol; (S) 4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)1,2-oxaborolan-2-ol; (R) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4-dimethoxy-[1,1 '-biphenyl]-2carbonitrile; (S) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4-dimethoxy-[1,1 '-biphenyl]-2-carbonitrile; (R) 4-(5-methoxy-4-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-methoxy-4propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-cyclopropoxy-4-methoxyphenyl)1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-cyclopropoxy-4-methoxyphenyl)-1,2,4thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(4'-ethoxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol; (S) 4-(4'-ethoxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'isobutoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-isobutoxy-4'-methoxy[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-cyclobutoxy-4’-methoxy-[1,1 '-biphenyl]-3-yl)1,2-oxaborolan-2-ol: (S) 4-(3'-cyclobutoxy-4'-methoxy-[1,1 '-biphenyl]-3-yI)-1,2-oxaborolan-2-ol; (R) 4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-3methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol; (R) 3-ethoxy-3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1'biphenyl]-2-carbonitriIe; (S) 3-ethoxy-3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1'biphenyl]-2-carbonitrile; (R) 4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-hydrOxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4(6-(3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(4-(hydroxymethyl)-6-(4methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(hydroxymethyl)-6-(4methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-2-fluoro-4 methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(1-(4-methoxy-3-propoxyphenyl)-1Hpyrazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(1-(4-methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2oxaborolan-2-ol; (R) 4-(5-(3-methoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-methoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-4(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-4,6dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-4,6dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-methoxy-4'-(methylthio)-[1,1'-biphenyl]-3-yl)1,2-oxaborolan-2-ol; (S) 4-(3'-methoxy-4'-(methylthio)-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3',4'-dimethoxy-5-methyl-[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3',4'-dimethoxy5-methyl-[1,1 biphenyl]-3-yI)-1,2-oxaborolan-2-ol; (R) 4-(2'-fluoro-3',4'-dimethoxy-[1,1 ’-biphenyl]3-yl)-1,2-oxaborolan-2-ol; (S) 4-(2'-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2ol; (R) 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-2-fluoro-3methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-2-fluoro-3methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6'-methoxy-2-methyl-5'-propoxy-[3,3'bipyridin]-5-yl)-1,2-oxaborolan-2-ol; (S) 4-(6'-methoxy-2-methyl-5'-propoxy-[3,3'-bipyridin]-5-yl)1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (R) 4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2ol; (S) 4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-methoxy2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 2-(cyclopentyloxy)-6-(6(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile; (S) 2-(cyclopentyloxy)-6-(6(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile; 4-(2-(3,4dimethoxyphenyl)pyridin-4-yl)-1,2-oxaborol-2(5H)-ol; 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3yl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (S) 4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-methoxy-2'-methyl-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (S) 4-(5methoxy-2'-methyl-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (R) 4-(3',4'-dimethoxy[1,1 '-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3',4'-dimethoxy-[1,1 '-biphenyl]-3-yI)-1,2oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; and (S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides the use of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the présent invention provides the use of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

P In another embodiment, the présent invention provides the use of a compound of

Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of a compound of

Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(3-ethoxy-410 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.5 ± 0.2, 18.3 ± 0.2, and 24.9 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(3-ethoxy-415 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.5 ± 0.2, 12.3 ± 0.2, 13.5 ± 0.2, 15.8 ± 0.2, 16.0 ± 0.2,18.3 ± 0.2, and 24.9 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.5 ± 0.2, 12.3 ± 0.2, 13.5 ± 0.2, 15.8 ± 0.2, 16.0 ± 0.2,18.3 ± 0.2, 21.5 ± 0.2, 22.9 ± 0.2, 24.4 ± 0.2, 24.9 ± 0.2, 25.4 ± 0.2, 26.5 ± 0.2, 27.8 ± 0.2, and 30.2 ± 0.2 degrees two thêta.

In another embodiment, the present invention provides crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 7.

In another embodiment, the present invention provides crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 7.

In another embodiment, the present invention provides crystalline (R)-4-(5-(3-ethoxy-430 methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern as depicted in Figure 5.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-

(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel. .

In another embodiment, the présent invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaboroIan-2-ol in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 22.9 ± 0.2, and 25.1 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 18.8 ± 0.2, 22.9 ± 0.2, 25.1 ± 0.2, and 26.4 ± 0.2 degrees two thêta.

P In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 21.3 ± 0.2,

22.9 ± 0.2, 25.1 ± 0.2, and 26.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 15.1 + 0.2, 15.6 ± 0.2, 15.9 ± 0.2, 17.7 ± 0.2,18.8 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.5 ± 0.2, 21.3 ± 0.2, and 22.9 ± 0.2, degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 15.1 ± 0.2, 15.6 ± 0.2, 15.9 ± 0.2, 17.7 ± 0.2,18.8 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.5 ± 0.2, 21.3 ± 0.2, 22.9 ± 0.2, 25.1 ± 0.2, 25.9 ± 0.2, 26.4 ± 0.2, 27.5 ± 0.2, and 28.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 8.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 8.

In another embodiment, the présent invention provides crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern as depicted in Figure 6.

In another embodiment, the présent invention provides a pharmaceutical composition 25 comprising crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(4-methoxy-330 propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper 35 dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaboroIan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 18.7 ± 0.2, 22.8 ± 0.2, and 25.0 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ±0.2, 18.7 ± 0.2, 22.8 ± 0.2, and 25.0 ± 0.2, degrees two thêta.

In another embodiment, the présent invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 15.1 ± 0.2, 15.6 ± 0.2, 18.7 ± 0.2, 22.8 ± 0.2, and 25.0 ± 0.2, degrees two thêta.

In another embodiment, the présent invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 15.1 ± 0.2, 15.6 ± 0.2,

18.7 ± 0.2, 19.7 ± 0.2, 21.2 ± 0.2, 22.8 ± 0.2, 25.0 ± 0.2, and 26.4 ± 0.2 degrees two thêta.

In another embodiment, the present invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 15.1 ± 0.2, 15.6 ± 0.2, 18.7 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.5 ± 0.2, 21.2 ± 0.2, 22.8 ± 0.2, 25.0 ± 0.2, 26.4 ± 0.2, 27.4 ± 0.2, and 28.3 ± 0.2, degrees two thêta.

In another embodiment, the present invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 9.

In another embodiment, the present invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 9.

In another embodiment, the present invention provides crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern as depicted in Figure 7.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides the use of crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the présent invention provides the use of crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

In another embodiment, the présent invention provides the use of crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 12.8 ± 0.2, 20.4 ± 0.2, and 25.7 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 12.8 ± 0.2, 17.9 ± 0.2, 20.4 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, and 25.7 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 8.9 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2,12.8 ± 0.2, 17.8 ± 0.2, 20.4 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, and 25.7 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 8.9 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2,12.8 ± 0.2, 13.9 ± 0.2, 14.2 ± 0.2, 17.6 ± 0.2, 17.8 ± 0.2, 19.2 ± 0.2, 19.4 ± 0.2, 19.6 ± 0.2, and 20.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 8.9 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2,12.8 ±

0.2, 13.9 ± 0.2, 14.2 ± 0.2, 17.6 ± 0.2, 17.8 ± 0.2, 19.2 ± 0.2, 19.4 ± 0.2, 19.6 ± 0.2, 20.4 ± 0.2,

21.4 ± 0.2, 22.0 ± 0.2, 22.3 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, and 25.7 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 10.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 10.

In another embodiment, the présent invention provides crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern as depicted in Figure 8.

In another embodiment, the présent invention provides a pharmaceutical composition comprising crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5-(2-(difluoromethyl)-3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the présent invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol.

In another embodiment, the présent invention provides the use of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the présent invention provides the use of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

In another embodiment, the présent invention provides the use of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of crystalline (-) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 21.1 ± 0.2, 22.7 ± 0.2, and 23.8 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.9 ± 0.2, 11.3 ± 0.2, 19.3 ± 0.2, 21.1 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, and 30.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.9 ± 0.2, 11.3 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2, 19.3 ± 0.2, 21.1 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, and 30.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising diffraction peaks 10.9 ± 0.2, 11.3 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2, 19.0 ± 0.2, 19.3 ± 0.2, 21.1 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, 25.4 ± 0.2, 26.5 ± 0.2, and 30.4 ± 0.2 degrees two thêta.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 11.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 11.

In another embodiment, the présent invention provides crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern as depicted in Figure 9.

In another embodiment, the présent invention provides a pharmaceutical composition comprising crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2oxaborolan-2-ol and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5-(3-ethoxy-4methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the présent invention provides a method for treating or preventing atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagiharada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an omtment, a lotion, a cream, or a gel.

In another embodiment, the present invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method for treating or preventing an arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human comprising topically administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the form of a transdermal patch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the present invention provides a method for treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan2-ol.

In another embodiment, the present invention provides the use of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating an inflammatory disease in a human.

In another embodiment, the present invention provides the use of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating atopie dermatitis, hand dermatitis, contact dermatitis, allergie contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acné, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, érythrodermie psoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human.

In another embodiment, the présent invention provides the use of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a médicament for treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease in a human.

In another embodiment, the présent invention provides pharmaceutical combinations for topical administration comprising a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in combination with another pharmaceutical agent for the treatment ofthe diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention for topical administration include, but are not limited to: a second compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC); a PDE4 isoenzyme inhibitor including, but not limited to, crisaborole, ampremilast, roflumilast, rolipram and piclamilast; a corticosteroid including, but not limited to, fluocinonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone and mapracorat; a calcineurin inhibitor including, but not limited to, tacrolimus, pimecrolimus and cyclosporine; a JAK inhibitor including, but not limited to, tofacitinib, ATI-502, SNA-152, SHR0302, JTE052, BMS-986165, filgotinib, baricitinib, upadacitinib, ruxolitinib, peficitinib, PF04965842, PF-06651600, PF-06700841, and PF06826647; an aryl hydrocarbon receptor agonist including, but not limited to, tapinarof; an IRAK4 inhibitor including, but not limited to, PF-06650833; a non-steroidal anti-inflammatory including, but not limited to, WBI-1001 and MRX-6; vitamin D analog such as calcipotriene; retinoic acid dérivatives including, but not limited to, alitretinoin; a liver X receptor (LXR) sélective agonist including, but not limited to, VTP-38543; a H4 receptor antagonists including, but not limited to, ZPL-389; a NKI receptor antagonists including, but not limited to, Aprepitant and Tradipitant; a CRTH2 receptor antagonists including, but not limited to, Fevipiprant and OC-459; a Chymase inhibitors including, but not limited to, SUN 13834; a GATA-3 inhibitors including, but not limited to, SB011 and GR-MD-02; and a ROR inverse agonists including, but not limited to, VTP-43742, ARN6039, TAK-828 and JTE-451; immunomodulators such as PF-06763809, and inhibitors of SYK, BTK, and ITK, including but not limited to, R-348, cerdulatinib, ibrutinib, entospletinib, tirabrutinib, and JTE-051.

In another embodiment, the présent invention provides pharmaceutical combinations for oral administration comprising a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in combination with another pharmaceutical agent for the treatment ofthe diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention for oral administration include, but are not limited to: oral retinoic acid dérivatives including, but not limited to, alitretinoin; oral liver X receptor (LXR) sélective agonists including, but not limited to, vTP-38543; oral H4 receptor antagonists including, but not limited to, ZPL-389; oral NKI receptor antagonists including, but not limited to, Aprepitant and Tradipitant; oral CRTH2 receptor antagonists including, but not limited to, Fevipiprant and OC459; oral Chymase inhibitors including, but not limited to, SUN 13834; oral GATA-3 inhibitors including, but not limited to, SB-011; oral ROR inverse agonists including, but not limited to, VTP-43742, ARN6039, TAK-828 and JTE-451; oral JAK inhibitors including, but not limited to, baricitinib, cerdulatinib, decernotinib, delgocitinib, fedratinib, filgotinib, gandotinib, ilginatinib, itacitinib, lestaurtinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, upadacitinib, ASN-002, AT9283, ATI-501, ATI-502, AZD1480, AZD4205, BMS-911543, BMS986165, INCB-52793, INCB-54707, PF-04965842, PF-06263276, PF-06651600, PF-06700841, PF-06826647, SHR-0302, SNA-125, orTD-1473; immunomodulators and inhibitors of SYK, BTK, and ITK, including but not limited to, fostamatinib, ibrutinib, mastinib, mivavotinib, entospletinib, sperbrutinib, tirabrutinib, fenebrutinib, TOP-1288, R-348, cerdulatinib, SKI-O-703, TAS-05567, CG-806, R-343, CG-103065, PRT-2607, GSK-143, VRT-750018, UR-67767, PRN1008, BMS-935177, PRN-473, ABBV-105, AS-550, M-7583, WXFL-10230486, LOU-064, AEG42766, HCI-1401, KBP-7536, ARQ-531, GNE-4997, and GNE-9822; and oral IRAK4 inhibitors including, but not limited to, PF-06650833 and BAY-1830839.

In another embodiment, the présent invention provides pharmaceutical combinations for injectable administration comprising a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptable sait thereof, in combination with another pharmaceutical agent for the treatment ofthe diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention for injectable administration include, but are not limited to: TNFa inhibitors including, but not limited to, infliximab, adalimumab, golimumab, certolizumab pegol; injectable anti-IL4, IL-12, IL-17, IL-22, IL-23, IL-31, IL-33, IgE treatments such as dupilumab, lebrikizumab, nemolizumab, tralokinumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, OmaZumilab, and CIM-331.

Combination therapy includes administration ofthe two or more therapeutic agents concurrently or sequentially. The agents may be administered in any order. Altematively, the multiple therapeutic agents can be combined into a single composition that can be administered to the patient. For instance, a single pharmaceutical composition could comprise the compound or pharmaceutically acceptable sait, ester or prodrug thereof according to the Formulae (I), (IA), (IB), and (IC), another therapeutic agent or a pharmaceutically acceptable sait, ester or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds ofthe présent invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable sait, ester, amide, or prodrug form. Altematively, the compound can be administered as a pharmaceutical composition containing the compound of interest m combination with one or more pharmaceutically acceptable carriers. The phrase therapeutically effective amount ofthe compound ofthe présent invention means a sufficient amount ofthe compound to treat the diseases, conditions, or disorders indicated herein at a reasonable benefit/risk ratio applicable to any medical treatment. The spécifie therapeutically effective dose level for any particular patient will dépend upon a variety of factors including the disorder being treated and the severity ofthe disorder; activity ofthe spécifie compound employed; the spécifie composition employed; the âge, body weight, general health, sex and diet ofthe patient; the time of administration, route of administration, and rate of excrétion ofthe spécifie compound employed; the duration of the treatment; drugs used in combination or coincidental with the spécifie compound employed; and like factors well known in the medical arts.

Pharmaceutical Compositions or Formulations

In another embodiment, the présent invention provides pharmaceutical compositions, or formulations, comprising a therapeutically effective amount of a compound ofthe présent invention and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions, or formulations, ofthis invention may be administered to humans and other mammals topically, orally, parenterally, intracisternally, intravaginally, intraperitoneally, bucally, as an oral spray, as a nasal spray, rectally as a suppository, or in the form of a liposome.

A typical pharmaceutical composition or formulation is prepared by mixing a compound ofthe présent invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will dépend upon the means and purpose for which the compound ofthe présent invention is being applied. Suitable aqueous solvents include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an élégant présentation ofthe drug (i.e., a compound ofthe présent invention or pharmaceutical composition thereof) or aid in the manufacturing ofthe pharmaceutical product (i.e., for use in the preparing a médicament).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the présent invention or stabilized form ofthe compound (e.g., complex with a cyclodextrin dérivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more ofthe excipients described above. The dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray-dried dispersion, such as those described by Takeuchi, H., et al. in “Enhancement ofthe dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent déposition method and disintegrants’ J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786 B1 (US2002/009494), incorporated herein by reference. The compound of the présent invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage ofthe drug and to give the patient an élégant and easily handleable product.

The pharmaceutical composition, or formulation, for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, métal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents ofthe package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The term pharmaceutically acceptable carrier refers to carrier medium that provides the appropriate delivery of an effective amount of a active agent as defined herein, does not interfère with the effectiveness ofthe biological activity ofthe active agent, and that is sufficiently non-toxic to the host or patient. Représentative carriers include water, oils, both vegetable and minerai, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, pénétration enhancers, and the like. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference. Further examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnésium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonie saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnésium stéarate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent in the composition, according to the judgment ofthe formulator.

The term “pharmaceutically acceptable topical carrier refers to pharmaceutically acceptable carriers, as described herein above, suitable for topical application. An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically-acceptable topical carrier. This term is specifîcally intended to encompass carrier matenals approved for use m topical cosmetics as well.

The term topical administration refers to the application of a pharmaceutical agent to the external surface ofthe skin, nail, hair, claw or hoof, such that the agent crosses the external surface ofthe skin, nail, hair, claw or hoof and enters the underlying tissues. Topical administration includes application of the composition to intact skin, nail, hair, claw or hoof, or to a broken, raw or open wound of skin, nail, hair, claw or hoof. Topical administration of a pharmaceutical agent can resuit in a limited distribution ofthe agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can resuit in systemic distribution ofthe agent.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Compounds that are volatile in may require admixture with spécial formulating agents or with spécial packaging materials to assure proper dosage delivery. In addition, compounds ofthe présent invention that hâve poor human skin permeability may require one or more permeability enhancers whereas compounds rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers.

The ointments, pastes, creams, lotions, gels, powders, and solutions, for topical administration may contain, in addition to an active compound ofthe présent invention, pharmaceutically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose dérivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, émollients, coloring agents, preservatives, buffering agents, perméation enhancers, or mixtures thereof. Topical excipients should not interfère with the effectiveness ofthe biological activity ofthe active agent and not be deleterious to the épithélial cells or their function.

The terms permeability enhancer, or “perméation enhancer,” relates to an increase in the permeability ofthe skin, nail, hair, claw or hoof to a drug, so as to increase the rate at which the drug permeates through the skin, nail, hair, claw or hoof. The enhanced perméation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion ofthe drug through animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Pénétration, J of Controlled Release, 1 (1984) pp. 161-162. The term perméation enhancer or pénétration enhancer intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability ofthe skin, nail, hair or hoof to a drug.

The term transdermal delivery refers to the diffusion of an agent across the barrier of the skm, nail, haïr, claw or hoof resulting from topical administration or other application of a composition. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutés and absorption of drugs therefore occurs more readily through skin, nail, hair, claw or hoof that is abraded or otherwise stripped ofthe stratum corneum to expose the epidermis. Transdermal delivery includes injection or other delivery through any portion ofthe skin, nail, hair, claw or hoof or mucous membrane and absorption or perméation through the remaining portion. Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin, nail, hair, claw or hoof. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with émollients or pénétration enhancers. As used herein, transdermal delivery is intended to include delivery by perméation through or past the integument, i.e. skin, nail, hair, claw or hoof.

Powders and sprays can contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

The term parenterally, as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. Pharmaceutical compositions of this invention for parentéral injection comprise pharmaceutically acceptable stérile aqueous or nonaqueous solutions, dispersions, suspensions or émulsions and stérile powders for reconstitution into stérile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, éthanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodégradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature ofthe particular polymer employed, the rate of drug release can be controlled. Examples of other biodégradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved or dispersed in stérile water or other stérile injectable medium just prior to use.

Injectable préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3butanediol. Among the acceptable vehicles and solvents that may be employed are water,

Ringer's solution, U.S.P. and isotonie sodium chloride solution.

In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the préparation of injectables.

Pharmaceutical compositions, or formulations, for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient température but liquid at body température and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds ofthe présent invention may also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances and are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The présent compositions in liposome form may contain, in addition to the compounds ofthe présent invention, stabilizers, preservatives, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separateiy or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academie Press, New York, N. Y., (1976), p 33 et seq.

Pharmaceutical compositions, or formulations, ofthe présent invention may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prévention ofthe action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, sorbic acid, and the like. It may also be désirable to include isotonie agents, for example, sugars, sodium chloride and the like. Proionged absorption ofthe injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

The pharmaceutical compositions, or formulations, ofthe invention may be suspensions. Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

The pharmaceutical compositions also include solvatés and hydrates ofthe compounds of the présent invention. The term “solvaté” refers to a molecular complex of a compound represented by Formulae (I), (IA), (IB), and (IC), including pharmaceutically acceptable salts thereof, with one or more solvent molécules. Such solvent molécules are those commonly used in the pharmaceutical art, which are known to be innocuous to the récipient, e.g., water, éthanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol, and the like, The term “hydrate” refers to the complex where the solvent molécule is water. The solvatés and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvatés in the préparation of more désirable solvatés. Intermediate solvents include, but are not limited to, methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, 1,4-butyne-diol, and the like.

Actual dosage levels of active ingrédients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will dépend upon the activity ofthe particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical history ofthe patient being treated. However, it is within the skiil of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose ofthe compounds of this invention administered to a human or lower animal may range from about 0.000001 to about 10 mg/kg/day. For purposes of oral administration, more préférable doses can be in the range of from about 0.001 to about 1 mg/kg/day. For topical administration, more préférable doses can be in the range of 0.00001 mg/kg/day to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

Définitions

As used throughout this spécification and the appended claims, the following terms hâve the following meanings:

The term (C2-C6)alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond. Représentative examples of (C₂-C₆)alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term (C₂-C₆)alkenyloxy as used herein, means a (C₂-C₆)alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

The term (C₂-C_s)alkenylthio as used herein, means a (C₂-Cs)alkenyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.

The term (Ci-C₆)alkoxy as used herein, means a (Ci-Ce)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of (Ci-Ce)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertbutoxy, pentyloxy, and hexyloxy.

The term (Ci-C₆)alkoxy-c/i-i₃ as used herein, means a (Ci-C₆)alkyl-di-i₃, group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of (Ci-C₆)alkoxy-di-i₃ include, but are not limited to, methoxy-d₃, ethoxy-d₅, propoxy-d₇, 2-propoxy-d₇, butoxy-d₉, tert-butoxy-d₉, pentyloxy-dn, and hexyloxy-di₃.

The term (Ci-C6)alkoxy(Ci-C₆)alkoxy as used herein, means a (CrCejalkoxy group, as defined herein, appended to the parent molecular moiety through another (Ci-C₆)alkoxy group, as defined herein. Représentative examples of (Ci-C_s)alkoxy(Ci-C_s)alkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.

The term (Ci-C₆)alkoxy(Ci-C₆)alkyl as used herein, means a (Ci-C_s)alkoxy group, as defined herein, appended to the parent molecular moiety through a (Ci-Ce)alkyl group, as defined herein. Représentative examples of (Ci-C₆)alkoxy(Ci-C₆)alkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term (CvCejalkoxycarbonyl as used herein, means a (Ci-Ce)alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Représentative examples of (Ci-Ce)alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term (Ci-Csjalkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Représentative examples of (CrC3)alkyl include methyl, ethyl, n-propyl, and iso-propyl.

The term “(Ci-C₃)alkyl-di-7” as used herein, means a straight or branced chain hydrocarbon containing from 1 to 3 carbon atoms wherein one to seven of the hydrogens hâve been exchanged for deuterium (²H or D). Représentative examples of (Ci-Csjalkyl-dw include methyl-d₃, ethyl-d₅, ethyl-2,2,2-d₃, propyl-d₇, and 2-propyl-c/₇.

The term (Ci-C₆)alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Représentative examples of (Ci-C₆)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyi, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “(Ci-C₆)alkyl-di.i3” as used herein, means a straight or branced chain hydrocarbon containing from 1 to 6 carbon atoms wherein one to thirteen ofthe hydrogens hâve been exchanged for deuterium (²H or D). Représentative examples of (Ci-Ce)alkyl-di-i3 include, but are not limited to, methyl-ds, ethyl-ds, ethyl-2,2,2-ds, propyl-d7, 2-propyl-d7, butyl-dg, tert-butyl-dg, pentyl-dn, and hexyl-di₃.

The term (Ci-C₆)alkylcarbonyl as used herein, means a (Ci-C₆)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Représentative examples of (Ci-C₆)alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term (Ci-Cejalkylthio as used herein, means a (Ci-Ce)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of (Ci-Cejalkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

The term (Ci-C₆)alkylthio(Ci-C_s)alkyl as used herein, means a (Ci-C₆)alkylthio group, as defined herein, appended to the parent molecular moiety through a (Ci-Ce)alkyl group, as defined herein. Représentative examples of (Ci-C₆)alkylthio(Ci-C6)alkyl include, but are not limited to, methylthiomethyl and 2-(ethylthio)ethyl.

The term (C₂-C6)alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one carboncarbon triple bond. Représentative examples of (C₂-C₆)alkynyl include, but are not limited to, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term (C₂-C₆)alkynyloxy as used herein, means a (C₂-C6)alkynyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

The term (C₂-C6)alkynylthio as used herein, means a (C₂-C6)alkynyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.

The term aryl, as used herein, means a phenyl or naphthyl group.

The term aryl(Ci-C6)alkoxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (Ci-Cejalkoxy group, as defined herein.

The term aryl(Ci-C₆)alkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (C-i-CeJalkyl group, as defined herein. Représentative examples of aryl(Ci-C₆)alkyl include, but are not limited to, benzyl, 2phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term aryl(Ci-C6)alkylthio as used herein, means an aryl(C-i-C6)alkyl group, as defined herein, appended to the parent molecular moiety through sulfur atom, as defined herein. Représentative examples of aryl(Ci-C₆)alkylthio include, but are not limited to, benzylthio, phenylethylthio, 3-phenylpropylthio, and 2-naphth-2-ylethylthio.

The term aryloxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of aryloxy include, but are not limited to, phenoxy and naphthalenyloxy.

The term arylthio as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of arylthio include, but are not limited to, phenylthio and naphthalenylthio.

The term carbonyl as used herein, means a -C(O)- group.

The term carboxy as used herein, means a -C(O)OH group.

The term carboxy(Ci-C₆)alkoxy as used herein, means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (Ci-C₆)alkoxy group, as defined herein.

The term carboxy(Ci-C6)alkyl as used herein, means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (Ci-Ce)alkyl group, as defined herein.

The term cyano as used herein, means a -CN group.

The term (Cs-Csjcycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons, examples of (C3-Cs)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term (Cs-CsjcycloalkylCCi-Cejalkoxy as used herein, means a (C₃-C₈)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a (Ci-Ce)alkoxy group, as defined herein.

The term (C3-C₈)cycloalkyl(Ci-C6)alkyl as used herein, means a (C3-C₆)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a (Ci-Cejalkyl group, as defined herein. Représentative examples of (C3-C₈)cycloalkyl(Ci-C6)alkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term (C3-C₈)cycloalkyl(Ci-C6)alkylthio as used herein, means a (C3-C₈)cycloalkyl(Ci-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.

The term (C₃-C₈)cycloalkyloxy as used herein, means (C₃-C₈)cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein. Représentative examples of (C₃-C₈)cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The term (C₃-C₈)cycloalkylthio as used herein, means (C₃-C₈)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom, as defined herein. Représentative examples of (C3-C₈)cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, and cyclooctylthio.

The term formyl as used herein, means a -C(O)H group. .

The term halo or halogen as used herein, means -Cl, -Br, -I or -F.

The term halo(Ci-C₆)alkoxy as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-Ce)alkoxy group, as defined herein. Représentative examples of halo(Ci-C6)alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term halo(Ci-C₆)alkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-C₆)alkyl group, as defined herein. Représentative examples of halo(Ci-C₆)alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term halo(Ci-C₆)alkylthio” as used herein, means a halo(Ci-C₆)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of halo(Ci-C₆)alkylthio include, but are not limited to, trifluoromethylthio.

The term (5-6 membered)heteroaryl, as used herein, means a 5 or 6 membered monocyclic heteroaryl. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and/or optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contamed within the heteroaryl. Représentative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.

The term (5-6 membered)heteroaryl(Ci-C₆)alkoxy as used herein, means a (5-6 membered)heteroaryl, as defined herein, appended to the parent molecular moiety through an (Ci-Cs)alkoxy group, as defined herein. Représentative examples of heteroaryl(Ci-C₆)alkoxy include, but are not limited to, fur-3-ylmethoxy, 1H-imidazol-2-ylmethoxy, 1H-imidazol-4ylmethoxy, 1-(pyridin-4-yl)ethoxy, pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, pyridin-4ylmethoxy, (6-(trifluoromethyl)pyridin-3-yl)methoxy, (6-(cyano)pyridin-3-yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy, (5-(cyano)pyridin-2-yl)methoxy, (2-(chloro)pyridin-4-yl)methoxy, pyrimidin-5-ylmethoxy, 2-(pyrimidin-2-yl)propoxy, thien-2-ylmethoxy, and thien-3-ylmethoxy.

The term (5-6 membered)heteroaryl(Ci-C6)alkyl as used herein, means a (5-6 membered)heteroaryl, as defined herein, appended to the parent molecular moiety through an (CrCejalkyl group, as defined herein. Représentative examples of heteroaryl(Ci-C₆)alkyl include, but are not limited to, fur-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl, (6-(trifluoromethyl)pyridin-3-yl)methyl, (6-(cyano)pyridin-3-yl)methyl, (2-(cyano)pyridin-4yl)methyl, (5-(cyano)pyridin-2-yl)methyl, (2-(chloro)pyridin-4-yl)methyl, pyrimidin-5-ylmethyl, 2(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term (5-6 membered)heteroaryl(C-i-C₆)alkylthio as used herein, means a (5-6 membered)heteroaryl(Ci-C₆)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of heteroaryl(Ci-C₆)alkylthio include, but are not limited to, fur-3-ylmethylthio, 1 H-imidazol-2-ylmethylthio, 1 H-imidazol-4-ylmethylthio, pyridin-3-ylmethylthio, 6-chloropyridin-3-ylmethylthio, pyridin-4-ylmethylthio, (6-(trifluoromethyl)pyridin-3-yl)methylthio, (6-(cyano)pyridin-3-yl)methylthio, (2-(cyano)pyridin-4yl)methylthio, (5-(cyano)pyridin-2-yl)methylthio, (2-(chloro)pyridin-4-yl)methylthio, pyrimidin-5ylmethylthio, 2-(pyrimidin-2-yl)propylthio, thien-2-ylmethylthio, and thien-3-ylmethylthio.

The term (5-6 membered)heteroaryloxy as used herein, means a (5-6 membered)heteroaryl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of heteroaryloxy include, but are not limited to, fur-3yloxy, 1H-imidazol-2-yloxy, 1 H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin4-yloxy, (6-(trifluoromethyl)pyridin-3-yl) oxy, (6-(cyano)pyridin-3-yl) oxy, (2-(cyano)pyridin-4yl)oxy, (5-(cyano)pyridin-2-yl)oxy, (2-(chloro)pyridin-4-yl)oxy, pyrimidin-5-yloxy, pyrimidin-2yloxy, thien-2-yloxy, and thien-3-yloxy.

The term (5-6 membered)heteroarylthio as used herein, means a (5-6 membered)heteroaryl, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of heteroarylthio include, but are not limited to, pyridin-3ylthio and quinohn-3-ylthio.

The term (4-7 membered)heterocycle or heterocyclic as used herein, means a 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring contains zéro or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zéro, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Représentative examples of heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

The term (4-7 membered)heterocycle(Ci-C₆)alkoxy as used herein, means a (4-7 membered)heterocycle, as defined herein, appended to the parent molecular moiety through an (Ci-Ce)alkoxy group, as defined herein.

The term (4-7 membered)heterocycle(Ci-C6)alkyl as used herein, means a (4-7 membered)heterocycle, as defined herein, appended to the parent molecular moiety through an (Ci-C₆)alkyl group, as defined herein.

The term (4-7 membered)heterocycle(Ci-C6)alkylthio as used herein, means a (4-7 membered)heterocycle(Ci-C₆)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.

The term (4-7 membered)heterocycleoxy as used herein, means a (4-7 membered)heterocycle, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of heteroaryloxy include, but are not limited to, pyridin3-yloxy and pyrimidin-2-yloxy.

The term (4-7 membered)heterocyclethio as used herein, means a (4-7 membered)heterocycle, as defined herein, appended to the parent molecular moiety through a sulfur atom. Représentative examples of heteroarylthio include, but are not limited to, pyridin-3ylthio and pyrimidin-2-ylthio.

The term hydroxy as used herein, means an -OH group.

The term hydroxy(Ci-C_s)alkoxy as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (Ci-C₆)alkoxy group, as defined herein. Représentative examples of hydroxy(Ci-C₆)alkoxy include, but are not limited to, hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy, and 2-ethyl-4hydroxyheptoxy.

The term hydroxy(Ci-C6)alkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (Ci-Ce)alkyl group, as defined herein. Représentative examples of hydroxy(Ci-Ce)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4hydroxyheptyl.

The term mercapto as used herein, means a -SH group.

The term nitro as used herein, means a -ΝΟ₂ group.

The term thio(Ci-C₆)alkyl as used herein, means a sulfur atom appended to the parent molecular moiety through a (Ci-C₆)alkyl group, as defined herein. Représentative examples of thio(Ci-C₆)alkyl include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl, and 4-thiobutyl.

The term “-NRaRb” as used herein, means two groups, Ra and Rb appended to the parent molecular moiety through a nitrogen atom. Ra and Rb are each independently hydrogen, (Ci-C₆)alkyl, or (Ci-C₆)alkylcarbonyl. Représentative examples of-NRaRb include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term “NR_ARB(Ci-C₆)alkoxy” as used herein, mean a NRaRb group attached to the parent molecular moiety through a (Ci-Ce)alkoxy group.

The term “NRARB(Ci-C6)alkyl” as used herein, mean a NRaRb group attached to the parent molecular moiety through a (Ci-C₆)alkyl group.

The term (NR_ARB)carbonyl as used herein, means a NRaRb group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Représentative examples of (NRARejcarbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.

The term “-NR_cRd” as used herein, means two groups, Rc and Rd appended to the parent molecular moiety through a nitrogen atom. R_c and R_D are each independently hydrogen, (Ci-Ce)alkyl, or (Ci-C₆)alkylcarbonyl. Représentative examples of-NR_cRo include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term “NRcRD(Ci-C₆)alkoxy” as used herein, mean a NRcRd group attached to the parent molecular moiety through a (Ci-Ce)alkoxy group.

The term “NRcRD(Ci-C₆)alkyl” as used herein, mean a NRcRd group attached to the parent molecular moiety through a (Ci-Ce)alkyl group.

The term (NRcRojcarbonyl as used herein, means a NRcRd group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

The compounds ofthe présent invention may form boron-oxygen dative bonds following exposure to water, alcohols (ROH, R is alkyl), and diols (ROH, R is hydroxyalkyl) as depicted in

Scheme A.

Scheme A

When a boron atom is covalently bonded to an oxygen atom and datively bonded to a second oxygen atom, the dative bond and covalent bond can interconvert or form a résonance hybrid as exemplified by structures (1), (2), (3), and (4) in Scheme A. Compounds ofthe présent invention following exposure to water, alcohols, and diols may exist as neutral compounds, exemplified by compounds (1)-(4), or as negatively charged compounds depicted by compounds (5) and (6), wherein Ri, R₂, R₃, R4, Rs, Rs, R7, Rg, R10 and p are as defined in the Summary section herein. In addition to oxygen, boron may form dative bonds with sulfur and

F nitrogen. It is to be understood that the présent invention encompasses the compounds of Formula (I), Formula (IA), Formula (IB), and Formula (IC) that form dative bonds with oxygen, sulfur, and nitrogen including, but not limited to compounds (7)-(12). Suitable counter ions include, but are not limited to, lithium, sodium, potassium, ammonium, tétraméthylammonium, 5 tetraethylammonium, méthylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, calcium, magnésium, and aluminum.

The compounds ofthe présent invention may form oxygen-linked dimers following exposure to water. Représentative dimers ofthe présent invention are shown in Scheme B wherein Ri, R₂, Rs, R4, Rs, Rs, R7, Rg, R10, and p are as defined in the Summary section herein.

Scheme B

It is to be understood that the présent invention encompasses the oxygen-linked dimers of Formula (I), Formula (IA), Formula (IB) and Formula (IC) including, but not limited to, bis((R)3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronic acid and bis((S)-315 hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronic acid.

The compounds ofthe présent invention may also form acyclic and cyclic trimers with exposure to water. Représentative acyclic and cyclic trimers ofthe présent invention are shown in Scheme C wherein Ri, R₂, R3, R4, Rs, Rs, R7, Rg, Rio and p are as defined in the Summary section herein.

It is to be understood that the present invention encompasses acyclic and cyclic trimers of Formula (I), Formula (IA), Formula (IB) and Formula (IC) including, but not limited to, the acyclic trimers (13) and (14) shown in Scheme C and the cyclic trimers (2R,2'R,2R)-3,3',3(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propan-1-ol) and (2S,2'S,2S)-3,3',3-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(2-(5-(410 methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1 -ol).

The present invention encompasses anhydrides of Formula (I), Formula (IA), Formula (IB) and Formula (IC) formed under dehydrating conditions. Représentative anhydrides ofthe présent invention are shown in Scheme D wherein Ri, R₂, R3, R4, Rs, Re, R7, Rg, R10, and p are as defined in the Summary section herein.

Scheme D (Rio)p (Rw)p (^1θ)ρ

It is to be understood that the présent invention encompasses the anhydrides of Formula (I), Formula (IA), Formula (IB) and Formula (IC) including, but not limited to, 5,5'-((4S,4'S)oxybis(1,2-oxaborolane-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine) and 5,5'-((4R,4'R)oxybis(1,2-oxaborolane-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine).

The compounds ofthe présent invention may form poly- or multi-valent species assembled from a single species or from more than one species ofthe présent invention. The polymeric constructs can be “homopolymeric consisting ofthe same or related constructs, or “hetereropolymeric” consisting of multiple different constructs.

The présent invention encompasses compounds that can be formulated with excipients such that one or more excipients interact with the compounds ofthe présent invention to afford single, poly-, or multi-valent species, including, for example, species such as esters, dimers, trimers, tetramers and higher homologs. For example, compounds of Formula (I), Formula (IA), Formula (IB) and Formula (IC) may form boron-esters with propylene glycol or hexylene glycol under appropriate conditions. Représentative esters ofthe présent invention are shown in Scheme E wherein R_b R₂, R₃, R₄, R5, Re, R7, Rg, R10, and p are as defined in the Summary section herein.

Scheme E

It is to be understood that the présent invention encompasses boron-esters of Formula (I), Formula (IA), Formula (IB) and Formula (IC) including, but not limited to, 1-hydroxypropan-2yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)1 -hydroxypropan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-310 yl)propyl)boronate, (R)-1-hydroxypropan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronate, 2-hydroxypropyl hydrogen ((R)-3-hydroxy-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-2-hydroxypropyl hydrogen ((R)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-2-hydroxypropyl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 415 hydroxy-2-methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-2-methylpentan-2-yl hydrogen ((R)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-2methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronate, 4-hydroxy-4-methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-320 propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-4-methylpentan-2-yl hydrogen ((R)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-4methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronate, 1-hydroxypropan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3 propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-1-hydroxypropan-2-yl hydrogen ((S)-3-hydroxy2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-1-hydroxypropan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 2hydroxypropyl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronate, (S)-2-hydroxypropyl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-2-hydroxypropyl hydrogen ((S)-3-hydroxy-2-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-2-methylpentan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4hydroxy-2-methylpentan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-2-methylpentan-2-yl hydrogen ((S)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-4methylpentan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronate, (S)-4-hydroxy-4-methylpentan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, and (R)-4-hydroxy-4-methylpentan-2-yl hydrogen ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate.

The présent invention also encompasses cyclic esters formed by interaction of compounds of Formula (I), Formula (IA), Formula (IB), and Formula (IC) with certain diols that include, but are not limited to, propylene glycol and hexylene glycol. Représentative cyclic esters are shown in Scheme F wherein Ri, R₂, Rs, R4, Rs, Re, R7, R9, R10, and pare as defined in the Summary section herein.

Scheme F

It is to be understood that the présent invention encompasses cyclic boron-esters of Formula (I), Formula (IA), Formula (IB) and Formula (IC) including, but not limited to, (2R)-2-(5(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol, (R)2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4-methyl-1,3,2-dioxaborolan-2-yl)propan1 -ol, (R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2-dioxaborolan-2yl)propan-1-ol, (2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2dioxaborinan-2-yl)propan-1-ol, (R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4,4,6 trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol, (R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)-3-((R)-4,4,6-tnmethyl-1,3,2-dioxabonnan-2-yl)propan-1-ol, (2S)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-3-(4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-oI, (S)-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol, (S)2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2-dioxaborolan-2-yl)propan1-ol, (2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan2-yl)propan-1-ol, (S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4,4,6-trimethyl-1,3,2dioxaborinan-2-yl)propan-1-ol, and (S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol.

The salts, esters, anhydrides, dimers, and trimers exemplified in Schemes A-F are prodrugs that can hydrolyze back to the parent compounds under aqueous conditions which include in vivo conditions reforming the oxaborole ring.

The compounds ofthe présent invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. By pharmaceutically acceptable sait is meant those salts which are, within the scope of Sound medical judgement, suitable for use in contact with the tissues of humans and animais without undue toxicity, irritation, allergie response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, herein incorporated by reference. The salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe présent invention or separately by reacting a free base (basic nitrogen) with a suitable organic or inorganic acid. Représentative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycérophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Compounds ofthe present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R or “S depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976,45: 13-30. In particular, the stereochemistry at the point of attachment of Y and Z, as shown in Formulae (I), (IA), and (IB) may independently be either (R) or (S), unless specifically noted otherwise. The enantiomers ofthe present invention indicated by (R), (S), or * are substantially free ofthe other enantiomer. “Substantially free” means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, and more preferably greater than about 99%. Within the context of enantiomeric excess, the term “about” means ±1.0%. The symbol * désignâtes a chiral carbon atom as either (R) or (S) stereochemistry depending on the configuration of substituents around the chiral carbon atom. The present invention contemplâtes various stereoisomers and mixtures thereof that are specifically included within the scope of this invention. Stereoisomers include enantiomers and mixtures of enantiomers. Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by préparation of racemic mixtures followed by resolution wellknown to those of ordinary skill in the art. These methods of resolution include, but are not limited to, (1) attachment of a chiral auxiliary to a mixture of enantiomers, séparation ofthe resulting mixture of diastereomers by recrystallization orchromatography and libération ofthe optically pure product from the auxiliary or (2) direct séparation ofthe mixture of optical enantiomers on chiral chromatographie columns.

Compounds ofthe present invention not designated (R), (S), or * may exist as racemates (i.e. 50% (R) and 50% (S)) or as a mixture of two enantiomers wherein one enantiomer is in excess. For example, enantiomeric mixtures may include the (R) enantiomer in 51 % and the (S) enantiomer in 49% or vice versa or any combination of (R) and (S) other than the racemic mixture of 50% (R) and 50% (S). The present invention includes racemates and enantiomeric mixtures ofthe compounds ofthe present invention.

Compounds ofthe present invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit séparation of different conformers. The compounds ofthe present invention further include each conformational isomer of compounds of Formulae (I), (IA), (IB), and (IC) and mixtures thereof.

Tautomers may exist in the compounds ofthe present invention and are specifically included within the scope ofthe present invention. The term tautomer, as used herein, means a proton shift from one atom of a molécule to another atom ofthe same molécule wherein two or more structurally distinct compounds are in equilibrium with each other. Compounds ofthe present invention may exist as tautomers. The present invention contemplâtes tautomers due to proton shifts from one atom to another atom ofthe same molécule generating two or more distinct compounds that are m equilibnum with each other.

The compounds ofthe présent invention may be isolated and used perse or in the form of their pharmaceutically acceptable salts. In accordance with the présent invention, compounds with multiple basic nitrogen atoms can form salts with varying number of équivalents (eq.) of acid. It will be understood by practitioners that ail such salts are within the scope ofthe présent invention.

Compounds ofthe présent invention may exist in more than one crystal form. Polymorphs of compounds of Formulae (I), (IA), (IB), and (IC) and salts thereof (including solvatés and hydrates) form part of this invention and may be prepared by crystallization of a compound ofthe présent invention under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different températures; various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound ofthe présent invention followed by graduai or fast cooling. The presence of polymorphs may be determined by solid probe nuclear magnetic résonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

This invention also includes isotopically-labeled compounds, which are identical to those described by Formulae (I), (IA), (IB), and (IC), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, iodine, and fluorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ³⁶CI, ¹²⁵l, ¹²⁹l, ¹⁸F, and ¹⁹F respectively. Certain isotopically-labeled compounds ofthe présent invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C), isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H), can 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. Isotopically labeled compounds ofthe présent invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In particular, the présent invention includes deuterated compounds of Formula (I), (IA), (IB), and (IC). Any ofthe hydrogens contâined on the compounds ofthe présent invention may be exchanged for deuterium. Représentative examples of deuterated compounds ofthe présent invention include, but are not limited to, the compounds listed below wherein D is deuterium.

AH patents, patent applications, and literature references cited in the spécification are herein incorporated by reference in their entirety.

Compounds ofthe présent invention were named by Chemdraw Professional version

15.0 or 16.0 or were given names which appeared to be consistent with Chemdraw nomenclature.

The présent invention encompasses compounds of Formulae (I), (IA), (IB), and (IC) when prepared by synthetic processes or by metabolic processes. Préparation of the compounds ofthe invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.

The présent invention also contemplâtes pharmaceutically active métabolites formed by in vivo biotransformation of compounds of Formulae (I), (IA), (IB), and (IC). The term pharmaceutically active métabolite, as used herein, refers to a compound formed by the in vivo biotransformation of compounds of Formulae (I), (IA), (IB), and (IC). A thorough discussion of biotransformation is provided in (Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, seventh édition, MacMillan Publishing Company, New York, NY, (1985)).

Compounds ofthe présent invention may be synthesized by synthetic routes that include processes analogous to those well-known in the Chemical arts, particularly in light ofthe description contained herein. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including suppléments (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds ofthe présent invention as well as intermediates for preparing compounds ofthe présent invention. For a more detailed description ofthe individual réaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although spécifie starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of dérivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistrv well known to those skilled m the art.

In the préparation of compounds ofthe présent invention protection of remote functionalities such as carboxylic acids, amines, and/or hydroxy groups of intermediates may be necessary. The need for such protection will vary depending on the nature ofthe remote functionality and the conditions ofthe préparation methods. Suitable amino-protecting groups (NH-PG) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and 9fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-PG) include for example, allyl, acetyl, silyl, benzyl, paramethoxybenzyl, trityl, and the like. Carboxylic acid protecting groups include alkyl esters such as methy, ethyl, propyl, and tert-butyl. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality présent on the molécule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme over another in order to obtain a desired compound ofthe invention.

It will also be recognized that another major considération in the planning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functional groups présent in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide (SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups. The BOC protecting group may be removed by treatment with an acid such as trifluoroacetic acid or concentrated hydrochîoric acid and the SES protecting group may be removed with a fluoride sait, such as césium fluoride or tetrabutylammonium fluoride. The CBZ and Bn protection groups may be removed by catalytic hydrogénation. Additional suitable protecting groups for hydroxy substituents include, but are not limited to, t-butyldimethylsilyl (TBDMS), tetra-hydropyranyl (THP), or isopropyl (i-Pr) protecting groups. The TBDMS and THP protecting groups may be removed by treatment with an acid such as acetic acid or hydrochîoric acid while the i-Pr protecting group may be removed by aluminum trichloride.

Isolation and purification ofthe compounds and intermediates described herein can be effected, if desired, by any suitable séparation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick layer chromatography, préparative low, medium, or high-pressure liquid chromatography, or a combination of these procedures. Spécifie illustrations of suitable séparation and isolation procedures can be had by reference to the Examples herein below. However, other équivalent séparation or isolation procedures could also be used.

The compounds of the invention may be prepared by any method known in the art for the préparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the spécifie methods described in the Examples, or by similar processes to either.

The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or désirable to vary the précisé conditions employed for the préparation of compounds of Formulae (I), (IA), (IB), and (IC). It will be further appreciated that it may be necessary or désirable to carry out the transformations in a different order from that described in the schemes, orto modify one or more ofthe transformations, to provide the desired compound ofthe invention.

The dérivatives of Formulae (I), (IA), (IB), and (IC) can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The présent invention also encompasses one or more of these processes for preparing the dérivatives of Formulae (I), (IA), (IB), and (IC), in addition to any novel intermediates used therein. The person skilled in the art will appreciate that the following reactions may be heated thermally or under microwave irradiation.

The routes below, including those mentioned in the Examples and Préparations, illustrate methods of synthesising compounds of Formulae (I), (IA), (IB), and (IC). The skilled person will appreciate that the compounds ofthe invention, and intermediates thereto, could be made by methods other than those specifîcally described herein, for example by adaptation of the methods described herein, for example by methods known in the art. Suitable guides to synthesis, functional group interconversions, use of protecting groups, etc., are for example: “Comprehensive Organic Transformations” by RC Larock, VCH Publishers Inc. (1989); Advanced Organic Chemistry” by J. March, Wiley Interscience (1985); “Designing Organic Synthesis” by S Warren, Wiley Interscience (1978); “Organic Synthesis - The Disconnection Approach” by S Warren, Wiley Interscience (1982); “Guidebookto Organic Synthesis” by RK Mackie and DM Smith, Longman (1982); “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and “Protecting Groups” by PJ Kocienski, Georg Thieme Verlag (1994); and any updated versions of said standard works.

In addition, the skilled person will appreciate that it may be necessary or désirable at any stage in the synthesis of compounds ofthe invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or désirable to protect alcohol, amino or carboxylic acid groups. The protecting groups used in the préparation ofthe compounds ofthe invention may be used in a conventional manner. See, for example, those described m Greene s Protective Groups in Organic Synthesis' by Theodora W Greene and Peter GM Wuts, fifth édition, (John Wiley and Sons, 2014), incorporated herein by reference, which also describes methods for the removal of such groups.

In the general synthetic methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of Formula (I) above. Where ratios of solvents are given, the ratios are by volume unless otherwise specified.

The compounds ofthe invention may be prepared by any method known in the art for the préparation of compounds of analogous structure. In particular, the compounds ofthe invention can be prepared by the procedures described by reference to the Schemes that follow, or by the spécifie methods described in the Examples, or by similar processes to either. The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or désirable to vary the précisé conditions employed for the préparation of compounds of Formula (I).

According to the first process, compounds of Formula (1D) (where Ri, R₂, R3, R4, Rs, Re, R7, Rg, R10, and pare as defined in the Summary section herein and v = 0, 1,2, 3, 4, 5) may be prepared from compounds of Formula (II) and (III) as illustrated by Scheme 1.

Scheme 1 /Rl5 (^R1o)p λχ (^R10)p^V

R9

In Scheme 1, compounds ofthe Formula (II), wherein R14 is a suitable protecting group (preferably TBS), are converted to a compound of Formula (III) wherein R15 is boronic acid (preferably) or 4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Bpin) by treatment with a suitable hydroborating source such as catecolborane or bis(pinacolato)diboron, in the presence of a suitable catalyst (bis(1,5-cyclooctadiene)di-p-methoxydiiridium(l) or (1.5cycloocatdiene)(methoxy)iridium(l) dimer) and ligand (ethylenebis(diphenylphosphine), in a suitable solvent such as DCE or THF at an appropriate température (15 °C to 70 °C). A skilled person also knows alternative methods for hydroboration of alkenes are achievable using alternative reagents, solvents and températures. A compound of Formula (III) is converted into a compound of Formula (1D) under aqueous acidic conditions, treating with a suitable acid (acetic or hydrochloric) at a suitable température. It is well understood by a skilled person that a compound ofthe Formula (III) is prepared and isolated as described above or prepared in situ without isolation in a sequential reaction strategy leading to a compound of Formula (1D). In the case of compounds of Formula (III) and (1 D) lead to the presence of a chiral center, it is well understood by a skilled person that the individual enantiomers can be obtained using a suitable séparation method such as HPLC or SFC chromatography to afford both the (+) and (-) enantiomers of compounds of Formula (III) and (1 D). It is well understood by a skilled person that an individual enantiomer of a compound of Formula (III) and (1 D) is prepared and isolated as described above or isolated using an alternative séparation technique such as HPLC or SFC using a suitable chiral stationary phase eluting with a suitable mobile phase as determined to be necessary to isolate the required enantiomers.

According to a second process, compounds of Formula (1E) or (1F) may be prepared from Formula (II) as illustrated in Scheme 2.

Scheme 2

In Scheme 2, compounds of Formula (1E) or (1F) may be prepared in a similar manner as in Scheme 1 using suitable chiral ligands such as (S,S)-[2-(4'-i-propyloxazolin-2yl)ferrocynyl]diphenylphosphine or (R,R)-[2-(4'-i-propyloxazolin-2yl)ferrocynyl]diphenylphosphine leading to chiral compounds of Formula (IV). A person of skill in the art knows that chiral hydroboration strategies can use alternative chiral ligands, catalysts, boron sources, solvents and température combinations. It is well understood by a skilled person that a compound ofthe Formula (IV) can be prepared and isolated as described above or prepared in situ without isolation in a sequential reaction strategy leading to a compound of Formula (1 E) or (1 F). A skilled person also knows that compounds of Formula (1 E) or (1 F) can be further enriched through crystallization techniques or chiral chromatography (HPLC or SFC) using a suitable chiral stationary phase eluting with a suitable mobile phase as determined to be necessary to isolate the required enantiomers.

According to a third process, compounds of Formula (1G) may be prepared from Formula (II) as illustrated in Scheme 3.

Scheme 3

In Scheme 3, compounds of Formula (II) are converted to compounds of Formula (V) when treated with a halogenating agent such as pyridinium tribromide, in a suitable solvent, such as DCM, at an appropriate température such as 0 °C. A skilled person also knows that alternative methods for specifically introducing a suitable halogen group such as Br are achievable using alternative reagents, solvents and températures. Compounds of Formula (VI) can be synthesized by this method or by the reaction of compounds of Formula (V) using DBU with a suitable solvent, such as DCM, at a suitable température, such as 25 °C. Compounds of Formula (VI) can be converted to compounds of Formula (VII) (where R15 = Bpin) using Miyaura borylation conditions. Typical boronate ester formation conditions comprise of Pd(dppf)Cl2-DCM and potassium acetate with bispinacolatoboron in 1,4-dioxane at a suitable température, such as 55 °C. A compound of Formula (VII) can be converted into a compound of Formula (1G) under aqueous acidic conditions, treating with a suitable acid (acetic or hydrochîoric) at a suitable température.

Compounds of Formula (II) may be prepared from compounds of Formulae (VIII), (IX), (X) and (XI) as illustrated by Scheme 4.

Scheme 4

vin ix x n

In Scheme 4, compounds of Formula (X), wherein R₁₇ is chlore, bromo or iodo may be prepared from compounds of Formula (VIII) and (IX) using a suitable organometallic crosscoupling reaction such as Suzuki cross-coupling reaction preceded if necessary by a boronic acid or ester formation. Typical Suzuki cross-coupling conditions comprise of a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in aqueous dioxane or methanol, at elevated températures either thermally or under microwave irradiation.

Preferred conditions comprise Pd(OAc)₂, Pd(dppf)CI₂ or Pd(PPh₃)4 with either sodium, césium or potassium carbonate in aqueous dioxane or methanol at from room température to 120 °C. A skilled person knows that organometallic cross-coupling reaction strategies can be used involving alternative metals, catalysts, ligands, bases, solvents and température combinations. Typical boronic ester formation conditions comprise of Pd(dppf)CI₂ and potassium acetate with bispinacolatodiboron with compounds of Formula (VIII), where Rw = chloro, bromo or iodo, in dioxane at reflux. Compounds of Formula (VIII) may also be obtained commercially or be synthesized by those skilled in the art according to the literature or by analogy with the methods described herein.

Compounds of Formula (II) may be prepared from compounds of Formula (X) and (XI), (where Ris = boronic acid or Bpin) through an organometallic cross-coupling reaction, similar to the ones previously described. A skilled person knows that alternative organometallic crosscoupling reaction strategies can also be used involving alternative metals, catalysts, ligands, bases, solvents and température combinations. Preferred Suzuki conditions comprise of Pd(dppf)CI₂ with potassium carbonate and potassium acetate in aqueous dioxane from room température to 120 °C.

Alternatively, compounds of Formula (II) may be prepared from compounds of Formulae (VIII), (IX), (XI) and (XII), in a reverse sequence of that in Scheme 4, illustrated by Scheme 5.

Scheme 5 r₂

Compounds of Formula (XII) may be prepared from compounds of Formula (XI) (where Ris = boronic acid or pinacol) and (IX) (where R17 is chloro, bromo or iodo) using an organometallic cross-coupling reaction as described in Scheme 4. Preferred conditions comprise of Pd(dppf)CI₂ with potassium carbonate in aqueous dioxane from room température to 120 °C. Compounds of Formula (XI) may be synthesized by those skilled in the art according to the literature or by analogy with the methods described herein. Compounds of Formula (XII) may be converted to compounds of Formula (II) using a similar method as previously described in Scheme 4, a Suzuki cross-coupling reaction preceded if necessary by a boronic acid or ester formation. A skilled person knows that alternative organometallic cross-coupling reaction strategies can also be used involving alternative metals, catalysts, ligands, bases, solvents and température combinations.

According to a sixth process, compounds of Formula (1H) may be prepared from Formula (XIII) and (XIV) as illustrated in Scheme 6.

Compounds of Formula (1H), where A is carbon or nitrogen, may be prepared in an analogous manner as compounds of Formula (1D), (1E) or (1F) as described in Schemes 1-5. It 5 is well understood by a skilled person that the individual enantiomers can be obtained using a suitable séparation method such as HPLC or SFC chromatography to afford both the (+) and (-) enantiomers of compounds of Formula (XIV) and (1H). It is also well understood by a skilled person that an individual enantiomer of a compound of Formula (XIV) and (1 H) is prepared and isolated as described above or isolated using an alternative séparation technique such as HPLC 10 or SFC using a suitable chiral stationary phase eluting with a suitable mobile phase as determined to be necessary to isolate the required enantiomers. Additionally, compounds of Formula (1H) in which the central ring is replaced by a substituted 5-membered heterocycle (exemplified by Y, in Formula (1)) can also be synthesized in an analogous manner by one skilled in the art.

The compounds and processes ofthe présent invention will be better understood in connection with the following Examples which are intended as an illustration of and not a limitation upon the scope ofthe invention as defined in the appended claims.

Abbreviations which hâve been used in the descriptions ofthe schemes and the examples that follow are: Ac is acetyl; AcOH is acetic acid; Ac₂O is acetic anhydride; Adam’s 20 catalyst is platinum (IV) oxide; Br₂ is bromine; n-BuLi is n-butyl lithium; °C is degrees celcius; CDCh isdeutero-chloroform; CD3OD is deuteromethanol; CO₂ is carbon dioxide; Cs₂CO3 is césium carbonate; δ is Chemical shift; DAST is N,N-Diethylamino-S,S-difluorosulfinium tetrafluoroborate; DBU is 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE is 1,2-dichloroethane; DCM is dichloromethane or methylene chloride; DEA is diethylamine; DMAP is 425 dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; DMSO-ch is deuterodimethylsulfoxide; Et₂O is diethyl ether; EtOAc is ethyl acetate; EtOH is éthanol; EtsN is triethylamine; Fe is iron; g is gram; HCl is hydrochloric acid; HCO₂H is formic acid; HMTA is hexamethylenetetramine; HPLC is high pressure liquid chromatography; H₂ is hydrogen; H₂O is water; h is hours; Hr is hour; Hz is hertz; IPA is isopropyl alcohol; IPAm: is isopropylamine;

[lr(COD)CI]₂ is bis(1,5cyclooctadiene)diiridium(l) dichloride; [lr(COD)OMe]₂ is (1.5cycloocatdiene)(methoxy)iridium(l) dimer; K₂CO₃ is potassium carbonate; K₃PO₄ is potassium phosphate tribasic; KBr is potassium bromide; KMnO₄ is potassium permanganate; KOAc is poatssium acetate; L is liter; LCMS is liquid chromatography mass spectrometry; LDA is lithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide; LiOH is lithium hydroxide monohydrate; LTMP is lithium tetramethylpiperidine; M is molar; m-CPBA is metachloroperoxybenzoic acid; MeCN is acetonitriie; MeOH is methanol; MeNH₂ is methyl amine; mg is milligram; MgSO₄ is magnésium sulphate; MHz is mega Hertz; min is minutes; mL is milliliter; mm is millimeter; mmol is millimole; mol is mole; MS m/z is mass spectrum peak;

MTBE is tert-butyl methyl ether; MsCI is mesyl chloride; NaBH₄ is sodium borohydride; Na₂COs is sodium carbonate; NaOH is sodium hydroxide; NaOMe is sodium methoxide; Na₂SO₄ is sodium sulphate; NBS is N-bromo succinimide; NH₃ is ammonia; NH₄CI is ammonium chloride; NH₂OH-HCI is hydroxylamine hydrochloride; NH₄OH is ammonium hydroxide; nM is nanomolar; PCI₅ is phosphorus pentachloride; Pd/C is palladium on carbon; Pd(dppf)CI₂ is [1,1 ’-

F monohydrate; LTMP is lithium tetramethylpiperidine; M is molar; m-CPBA is metachloroperoxybenzoic acid; MeCN is acetonitrile; MeOH is methanol; MeNH₂ is methyl amine;

mg is milligram; MgSO₄ is magnésium sulphate; MHz is mega Hertz; min is minutes; mL is milliliter, mm is millimeter; mmol is millimole; mol is mole; MS m/z is mass spectrum peak;

MTBE is tert-butyl methyl ether; MsCI is mesyl chloride; NaBH₄ is sodium borohydride; Na₂CO₃is sodium carbonate; NaOH is sodium hydroxide; NaOMe is sodium methoxide; Na₂SO₄ is sodium sulphate; NBS is N-bromo succinimide; NH₃ is ammonia; NH₄CI is ammonium chloride; NH₂OH HCI is hydroxylamine hydrochloride; NH₄OH is ammonium hydroxide; nM is nanomolar; PCI₅ is phosphorus pentachloride; Pd/C is palladium on carbon; Pd(dppf)CI₂ is [1,1’- bis(diphenylphosphino) ferrocene]dichloropalladium(ll); Pd(dppf)CI₂ DCM is[1,1 bis(diphenylphosphino) ferrocene]dichloropalladium(ll), complex with dichloromethane; Pd(dppf)-tBu is [1 ,T-bis(di-t-butylphosphino) ferrocene]dichloropalladium(ll); Pd(OAc)₂ is palladium acetate; PPh₃ is triphenylphosphine; pet. ether is petroleum ether; pH is power of hydrogen; Pin₂B₂ is bis(pinacolato)diboron; PinBO-iPr is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane; psi is pounds per square inch; ppm is parts per million; POCI₃ is phosphorus oxychloride; PrOH is 1-propanol; PtO₂ is platinum (IV) oxide; rt is room température, RT is rétention time; SEM-CI is 2-(trimethylsilyl)ethoxymethyl chloride; SFC is supercritical fluid chromatography; TBS is ί-butyldimethylsilyl; TBS-CI is ί-butyldimethylsilyI chloride; tBu₃P is tri-tbutylphosphine; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TiCI₄ is titanium tetrachloride; TfO is trifluoromethanesulfonyl; Tf₂O is trifluoromethanesulfonic anhydride; pTsOH is p-toluenesulfonic acid; Turbo Grignard is isopropylmagnesium chloride lithium chloride complex solution; Xantphos is 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos-Pd-G2 is Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(ll).

¹H and ¹⁹F Nuclear magnetic résonance (NMR) spectra were in ail cases consistent with the proposed structures. Characteristic Chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for¹ H-NMR) and upfield from trichloro-fluoro-methane (for ¹⁹F NMR) using conventional abbreviations for désignation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets;

m, multiplet; br, broad. The following abbreviations hâve been used for common solvents: CDCI₃, deuterochloroform; DMSO-d₆, deuterodimethylsulphoxide; and CD₃OD, deuteromethanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible.

Mass spectra, MS (m/z), were recorded using either electrospray ionization (ESI) or atmospheric pressure Chemical ionization (APCI).

Where relevant and unless otherwise stated the m/z data provided are for isotopes ¹⁹F, ³⁵CI, ⁷⁹Br and ¹²⁷l.

I Wherein préparative TLC or column chromatography (silica) has been used, one skilled in the art may choose any combination of appropriate solvents to purify the desired compound.

Specific rotations based on the équation [a] = (100 a)/(l c) are reported as unitless numbers where the concentration c is in g/100 mL and the path length I is in decimeters. The units ofthe specific rotation, (degmL)/g-dm) are implicit and are not included with the reported value.

The following are analytical and préparative chromatography methods used for the analysis and purification of compounds ofthe invention.

Préparative SFC Methods

Prep SFC Method A: Column: Chiralpak IC-H, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH, 60/40 (v/v); Flow rate: 65 mL/min

Prep SFC Method B: Column: Lux Amylose-1 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/MeOH + 0.2% (7N ammonia in MeOH) 80/20 (v/v); Flow rate: 150 mL/min

Prep SFC Method C: Column: Chiralpak IC-H, 250 mm x 50 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/IPA 85/15 (v/v); Flow rate: 250 mL/min

Prep SFC Method D: Column: Chiralcel OJ, 250 mm X 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/IPA, 65/35 (v/v); Flow rate: 50 mL/min)

Prep SFC Method E: Column: Daicel Chiralpak AD, 250 mm X 30 mm, 5μ; Mobile Phase Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flow rate: 50 mL/min

Prep SFC Method F: Column: Daicel Chiralpak IC, 250 mm x 30 mm, 5μ; Mobile Phase Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flow rate: 200 mL/min)

Prep SFC Method G: Column: Daicel Chiralpak AD, 250 mm x 50 mm, 10 μ; Mobile Phase 30 Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 55/45 (v/v); Flow rate: 200 mL/min

Prep SFC Method H: Column: Chiralpak IC-H, 250 mm X 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 75/25 (v/v); Flow rate: 200 mL/min

Prep SFC Method I: Column: Chiralpak IC, 250 mm x 30 mm, 10μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flow rate: 60.0 mL/min

Prep SFC Method J: Column: Chiralpak IC 250 mm x 30mm, 10u; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 80/20 (v/v); Flow rate: 60 mL/min

Prep SFC Method K: Column: Chiralpak AD, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/MeOH (0.1% NH₄OH), 75/25 (v/v); Flow rate: 50.0 mL/min

Prep SFC Method L: Column: Chiralpak AD, 250 mm x 30 mm, 10μ; Mobile Phase - Isocratic conditions: CO₂/MeOH (0.1% NH₄OH), 75/25 (v/v); Flow rate: 200.0 mL/min

Prep SFC Method M: Column: Chiralpak IC, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 55/45 (v/v); Flow rate: 50.0 mL/min

Prep SFC Method N: Column: Chiralpak IC, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 75/25 (v/v); Flow rate: 60.0 mL/min

Prep SFC Method O: Column: Daicel Chiralpak AD, 250 mm x 50 mm, 10μ; Mobile Phase Isocratic conditions: CO₂/MeOH, 60/40 (v/v); Flow rate: 200 mL/min

Prep SFC Method P: Column: Chiralcel OJ-H, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 85/15 (v/v); Flow rate: 50 mL/min

Prep SFC Method Q: Column: Daicel Chiralpak AD, 250 mm x 30 mm, 5μ; Mobile Phase Isocratic conditions: CO₂/IPA (0.1% NH₄OH), 75/25 (v/v); Flow rate: 60 mL/min

Prep SFC Method R: Column: Chiral Technologies AD-H, 250 mm x 21 mm, 5μ; Mobile Phase Isocratic conditions: CO₂/MeOH (0.2% NH₄OH), 80/20 (v/v); Flow rate: 75 mL/min

Prep SFC Method S: Column: Princeton PPU, 250 mm x 30 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/MeOH, 80/20 (v/v); Flow rate: 80 mL/min

Analytical SFC Methods

Analytical SFC Method A: Column: Chiralpak IC, 250 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% isopropylamine); Gradient: A:B=65:35; Flow rate: 2.5 mL/min

Analytical SFC Method B: Column: Lux Amylose-1, 250 mm x4.6 mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% MeNH₂); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (1.0 min, 95%A, 5%B), (9.0 min, 40%A, 60%B), (10 min, 95%A, 5%B); Flow rate: 3.0 mL/min

Analytical SFC Method C: Column: Chiralpak IC-3, 150 mm x4.6 mm, 3u; Mobile Phase A: CO₂,

Mobile Phase B: IPA (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method D: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method E: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method F: Column: Chiralpak AD-3, 50 mm x 3.0 mm, 3μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.0 mL/min

Analytical SFC Method G: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3 μ ; Mobile phase A: CO₂, Mobile Phase B: MeOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method H: Column: Chiralcel OJ-3, 100 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (7.5 min, 60%A, 40%B), (8.5 min, 95%A, 5%B), Flow rate: 2.8 mL/min

Analytical SFC Method I: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH; Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method J: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method K: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution (time, %A, %B): (5 min, 60%A, 40%B, [Flow rate: 1.5 mL/min

Analytical SFC Method L: Column: ChiralCel OJ-H, 150 mm x 4.6 mm, 5μ; Mobile Phase A: CO2, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method M: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂,

Mobile Phase B: MeOH (0.2% 7N NH3 in MeOH); Gradient Elution (time, %A, %B): (0 min, 95%A,

5%B), (1.0 min, 95%A, 5%B), (9.0 min, 40%A, 60%B), (9.5 min, 40%A, 60%B), (10 min, 95%A,

5%B), Flow rate: 3.0 mL/min

Analytical SFC Method N: Column: Chiralcel OJ-H 250 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B; IPA (0.05% IPAm), Gradient Elution: B in A from 10% to 40% in 10 minutes, Flow rate: 2.5 mL/min

Analytical SFC Method O: Column: ChiralPak AY-3 150 mm * 4.6 mm, 3 μ;

Mobile Phase: A: CO₂, Mobile Phase B: Methanol (0.05% DEA); Gradient Elution: (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (8.5 min, 60%A, 40%B) (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method P: Column: Chiralcel OJ-3 100 mm χ 4.6 mm, 3 μ;

Mobile Phase: A: CO₂, Mobile Phase B: Methanol (0.05% DEA); Gradient Elution: (time, %A, %B): (0 min, 95%A, 5%B), (5.5 min, 60%A, 40%B), (7.5 min, 60%A, 40%B) (10 min, 95%A, 5%B), Flow rate: 2.8 mL/min

Analytical SFC Method Q: Column: ChiralCel OD-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (5.5 min, 95%A, 5%B), (7 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method R: Column: Chiralpak AD-3, 100 mm x 4.6 mm, 3μ; Mobile Phase Isocratic conditions: CO₂/EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.08 mL/min

Analytical SFC Method S: Column: Chiral Technologies OJ-H, 100 mm x 4.6 mm, 5μ; Mobile Phase - Isocratic conditions: CO₂/EtOH (0.2% ΝΗ₄ΟΗ), 95/5 (v/v); Flow rate: 3.0 mL/min

Analytical SFC Method T: Column: Chiralpak IC, 100 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (0.5 min, 95%A, 5%B) (4.5 min, 60%A, 40%B), (7.0 min, 60%A, 40%B), (9.5 min, 95%A, 5%B), Flow rate: 1.5 mL/min ) Analytical SFC Method U: Column: Lux Amylose-2, 100 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂,

Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution (time, %A, %B): (0 min, 70%A, 30%B), (5.0 min, 70%A, 30%B); Flow rate: 1.5 mL/min

Analytical SFC Method V: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% Ammonium hydroxide); Gradient Elution (time, %A, %B): (0 min, 85%A, 15%B) (10 min, 85%A, 15%B). Flow rate: 1.5 mL/min

Analytical SFC Method W: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂, 10 Mobile Phase B: EtOH; Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (1.0 min, 95%A, 5%B), (9.0 min, 40%A, 60%B), (9.5 min, 40%A, 60%B), (10 min, 95%A, 5%B), Flow rate: 3.0 mL/min

Analytical SFC Method X: Column: ChiralPak AY, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, 15 Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5.0 min, 40%A, 60%B), (7.5 min, 40%A, 60%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method Y: Column: Chiral Tech OJ-H, 100 mm x 4.6 mm, 5μ; Mobile Phase A:

CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution (time, %A, %B): (0 min, 95%A, 20 5%B), (10 min, 95%A, 5%B), Flow rate: 1.5 mL/min

Analytical SFC Method Z: Column: Chiralcel OJ-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5 min, 60%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min 25

Analytical SFC Method AA: Column: ChiralPak AD-3 100 mm χ 4.6 mm, 3 μ; Mobile Phase: A: CO₂, Mobile Phase B: MeOH (0.05% DEA); Gradient Elution: (time, %A, %B): (0 min, 60%A, 40%B), Flow rate: 2.8 mL/min

Analytical SFC Method BA: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: IPA (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (5 min, 60%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method CA: Column: Lux Cellulose 100 mm χ 4.6 mm, 5 μ; Mobile Phase: A: 35 CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution: (time, %A, %B): (0 min, 70%A, 30%B), (5 min, 70%A, 30%B), Flow rate: 1.5 mL/min ) Analytical SFC Method DA: Column: Lux Cellulose-2, 150 mm x4.6 mm, 5μ; Mobile Phase A:

CO₂, Mobile Phase B: MeOH (0.05% DEA); Gradient Elution (time, %A, %B): (0 min, 95%A,

5%B), (5.0 min, 60%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 mL/min

Analytical SFC Method EA: Column: Chiralcel OJ-3, 150 mm x 4.6 mm, 3μ; Mobile Phase Isocratic conditions: CO2/EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.5 mL/min

Analytical SFC Method FA: Column: ChiralPak AD-3, 250 mm x 4.6 mm, 5μ; Mobile Phase A: 10 CO₂, Mobile Phase B: EtOH (0.05% IPAm); Gradient Elution (time, %A, %B): (0 min, 65%A, 35%B), Flow rate: 2.5 mL/mi

Analytical SFC Method GA: Column: Chiral Tech IC, 250 mm x 4.6 mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B: IPA (0.2% NH₃ in MeOH); Gradient Elution (time, %A, %B): (0 min, 15 95%A, 5%B), (1 min, 95%A, 5%B), (9 min, 40%A, 60%B), (9.5 min, 40%A, 60%B), (10 min,

95%A, 5%B), Flow rate: 2.5 mL/min

Préparative HPLC Methods

Prep HPLC Method A: Column: Xtimate C18, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05%

NH₄OH v/v), Mobile Phase B MeCN; B%: 18%-58%, 12 min; Flow rate: 25 mL/min

Prep HPLC Method B: Column: Phenomenex XB-C18, 250 mm x 21.2 mm, 5μ; Mobile Phase A: water (0.1% HCO2H), Mobile Phase B: MeCN (0.1% HCO₂H); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (1.5 min, 95%A, 5%B), (10.0 min, 0%A, 100%B), (11 min, 0%A, 100%B), (12.5 min, 95%A, 5%B); Flow rate: 27 mL/min

Prep HPLC Method C: Column: Waters Atlantis C18, 50 mm x 4.6 mm, 5μ; Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN (0.05% TFA); Gradient Elution (time, %A, %B): (0 min, 95%A, 5%B), (4 min, 5%A, 95%B), (5 min, 5%A, 95%B); Flow rate: 2 mL/min

Prep HPLC Method D: Column: Xtimate C18,150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05% ammonium hydroxide), Mobile Phase B: MeCN; B%: 25% to 65% in 12 min, Flow rate: 25 ml/min

Prep HPLC Method E: Column: Waters Xbridge, 150 mm x 25 mm, 5μ; Mobile Phase A: water (10mM NH₄HCO₃), Mobile Phase B: MeCN; B%: 20%-50%, 12 min

Prep HPLC Method F: Column: Phenomenex luna C18, 250 mm x 80 mm, 10μ; Mobile Phase A: water (0.1%TFA), Mobile Phase B: MeCN; B%: 1 %-25%, 20 min

Prep HPLC Method G: Column: Phenomenex Synergi Max-RP, 250 mm x 80 mm, 10μ; Mobile Phase A: water (0.1%TFA), Mobile Phase B: MeCN; B%: 10%-40%, 20 min

Prep HPLC Method H: Column: Boston Green ODS, 150 mm x 30 mm, 5μ; Mobile Phase A: water (0.225% HCO2H), Mobile Phase B: MeCN; B%: 5%-53%, 11 min, Flow rate: 25 mL/min

Prep HPLC Method I: Column: Agela Durashell C18, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.225% HCO₂H), Mobile Phase B: MeCN; B%: 9%-39%, 12 min, flow rate: 25 mL/min

Prep HPLC Method J: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase A: water (0.05% ammonium hydroxide), Mobile Phase B: MeCN; B%: 5%-25%, 15 min, flow rate: 100 mL/min

Prep HPLC Method K: Column: Agela Durashell C18, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.225% HCO2H), Mobile Phase B: MeCN; B%: 0%-32%, 11 min, Flow rate 25 mL/min

F Prep HPLC Method L: Column: Xtimate C18,150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05%

NH₄OH v/v), Mobile Phase B: MeCN; B%: 15%-55%, 12 min, Flow rate: 25 mL/min

Prep HPLC Method M: Column: Agela Durashell 150 mm x 25 mm, 5μ; Mobile Phase A: water 5 (0.05% NH4OH v/v), Mobile Phase B: MeCN; B%: 30%-60%, 2.5 min, Flow rate: 25 mL/min

Prep HPLC Method N: Column: Phenomenex luna C18, 250 mm x 80 mm, 10μ; Mobile Phase A: water (0.1%TFA), Mobile Phase B: MeCN; B%: 25%-55%, 20 min, Flow rate: 25 mL/min

Prep HPLC Method O: Column: Agela Durashell, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05% NH4OH v/v), Mobile Phase B: MeCN; B%: 25%-55%, 10 min, Flow rate: 25 mL/min

Prep HPLC Method P: Column: Agela Durashell, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05% NH4OH v/v), Mobile Phase B: MeCN; B%: 30%-60%, 10 min, flow rate: 25 mL/min

Prep HPLC Method Q: Column: Agela Durashell, 150 mm x 25 mm, 5μ; Mobile Phase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B%: 23%-53%, 10 min, flow rate: 25 mL/min

Prep HPLC Method R: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase

A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 20 90%A, 10%B), (15 min, 60%A, 40%B), (18 min, 0%A, 100%B), Flow rate: 110 mL/min)

Prep HPLC Method S: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 80%A, 20%B), (15 min, 60%A, 40%B), (18 min, 0%A, 100%B), Flow rate: 110 mL/min 25

Prep HPLC Method T: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase

A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B%: 20%-40%, 15 min, flow rate 110 ml/min

Prep HPLC Method U: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 75%A, 25%B), (15 min, 55%A, 45%B), (18 min, 0%A, 100%B), Flow rate: 110 mL/min

Prep HPLC Method V: Column: Phenomenex Synergi Max-RP, 150 mm x 50 mm, 10μ; Mobile 35 Phase A: Water (0.225% HCO₂H), Mobile Phase B: MeCN; B%: 0%-30%, 25 min, flow rate 120 mL/min

Prep HPLC Method W: Column: Xtimate C18, 150 mm x 25 mm, 5μ; Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B%: 17%-57%, 12 min, Flow rate: 25 mL/min

Prep HPLC Method X: Column: Agela Durashell C18, 150 mm x 30 mm, 5μ; Mobile Phase A: Water, Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 82%A, 18%B), (10 min, 42%A, 58%B), (18 min, 0%A, 100%B), Flow rate: 25 mL/min

Prep HPLC Method Y: Column: Boston Green ODS, 150 mm x 30 mm, 5μ; Mobile Phase A: water (0.05% NH4OH v/v), Mobile Phase B: MeCN; B%: 45%-65%, 9 min, Flow rate 25 mL/min

Prep HPLC Method Z: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase A: Water (0.05% NH4OH v/v), Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 80%A, 20%B), (15 min, 60%A, 40%B), (18 min, 0%A, 100%B), Flow rate: 110 mL/min

Prep HPLC Method AA: Column: Gemini C18, 15 mm x 21.2 mm, 5 μ; Mobile Phase A: water (0.1% HCO2H) Mobile Phase B: MeCN (0.1% HCO₂H); B% 25% - 35%; 25 mL/min

Prep HPLC Method BA: Column: Agela Durashell C18, 150 mm x 30 mm, 5μ; Mobile Phase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B%: 20%-55%, 15 min, Flow rate: 25 mL/min

Prep HPLC Method CA: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10μ; Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; Gradient Elution (time, %A, %B): (0 min, 75%A, 25%B), (15 min, 55%A, 45%B), (18 min, 0%A, 100%B); Flow rate: 110 mL/min

Examples

Préparation 1: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (Préparation 2, 1.6 g, 3.13 mmol) in EtOAc (50 mL) was added Pd/C (0.5 g, 10% loading). The mixture was stirred under H₂ (5 psig) at 20 °C for about 3 h. The mixture was filtered and concentrated to afford 3-(1((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3,4dimethoxyphenyl)pyridine (1.2 g), which was used directly without further purification. ¹H NMR (CDCI₃,400 MHz): δ 8.69 (d, J=7.6 Hz, 1H), 8.48 (s, 1 H), 7.78 (s, 1H), 7.32 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.04-7.01 (m, 1H), 4.15-4.20 (m, 1H), 4.00 (d, J = 8.4

Hz, 6H), 3.75-3.79 (m, 1H), 2.10 (s, 12H), 1.31 (d, J = 11.2 Hz, 9H), 1.15 (d, J = 12.8 Hz, 1H),

0.88 (d, J = 8.8 Hz, 1H), 0.01-0.02 (m, 6H). LCMS m/z = 514 [MH]⁺.

Préparation 2: 3-(3-((tert-butyldimethylsilyl)oxy)-1 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

A solution of 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4dimethoxyphenyl)pyridine (Préparation 37, 0.83 g, 1.79 mmol), Pd(dppf)Cl2-DCM (73 mg, 89 umol), KOAc (263 mg, 2.68 mmol) and Pin₂B₂ (CAS 73183-34-3, 681 mg, 2.68 mmol) in 1,4dioxane (10 mL) was heated to 55 °C under N₂ for 12 h. The mixture was concentrated and the residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (3:1) to afford 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (900 mg, 98%). ¹H NMR (CDCh.400 MHz): δ 8.74 (s, 1H), 8.71 (s, 1H), 8.03 (s, 1H), 7.13-7.16 (m, 1H), 7.09 (s, 1H), 6.98 (d, J= 8.4 Hz, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H). LCMS m/z = 512 [MH]⁺.

Préparation 3: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-(1 -((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (3.8 g, 95%) was prepared in an analogous manner to Préparation 1 using 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine (Préparation 4, 4.0 g, 7.6 mmol) which was used without further purification.

Préparation 4: 3-(3-((tert-butyldimethylsilyl)oxy)-1 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)-1 -(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)prop-1en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (7.5 g, 97%) was prepared in an analogous manner to Préparation 2 using 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(35 ethoxy-4-methoxyphenyl)pyridine (Préparation 38, 7.0 g, 14.6 mmol). ¹H NMR (CDCH, 400MHz): δ 8.69-8.73 (m, 2H), 8.03 (s, 1H), 7.14 (dd, J = 2.0, 8.4 Hz, 1H), 7.10 (s, 1H), 6.97 (d, J= 8.4 Hz, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.93 (s, 1H), 1.51 (t, J= 7.2 Hz, 3H), 1.33 (s, 12H), 0.83 (s, 9H), 0.08 (s, 6H).

Préparation 5: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 8, 4.00 g, 7.41 mmol) in EtOAc (100 mL) was added Pd/C (1.0 g, 10% loading) under N₂. The mixture was stirred under H₂ (14 psig) at about 25 °C for about 3 h. The mixture was filtered and concentrated to afford 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (3.44 g, 86%), which was used without further purification.

Préparation 6: (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronic acid

Method A:

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 50, 50.00 g, 120.9 mmol), [lr(COD)CI]₂ (CAS 12112-67-3,

2.03 g, 3.02 mmol) and (S,S)-[2-(4'-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine (CAS

163169-29-7, 3.20 g, 6.65 mmol) was added anhydrous THF (403 mL). The mixture was stirred for about 15 min at about 20 °C under N₂. The flask was chilled in an ice water bath until the solution température was about 0 °C. Catecholborane (181.48 mL, 181 mmol, 1.0 M in THF) was added dropwise over 1 h. Once the catecholborane was added the flask was removed from the cooling bath and stirred at about 20 °C for about 3 h. The mixture was quenched with a dropwise addition of methanol (25 mL) at about 0 °C (ice bath). The solution was removed from the ice bath and stirred about 30 min. The solution was concentrated to afford (R)-(3-((tertbutyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (88 g), which is used directly without further purification. LCMS m/z = 460 [MH]⁺.

Method B:

To a solution of Turbo Grignard (180 mL, 117 mmol, 1.3 M in THF) was added 1,4dioxane (19 mL) and stirred at about 20 °C for about 1 h. To the mixture was added slowly a solution of (R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 42, 46.8 g, 86.5 mmol) in anhydrous THF (270 mL), which was stirred at about 20 °C for about 20 min. A solution of trimethyl borate (96.4 mL, 865 mmol) in THF (107 mL) was added drop wise and stirred at about 20 °C for about 30 min. The mixture was concentrated and partitioned between water (500 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined EtOAc layers were washed with brine, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptanes/EtOAc (80:20 to 0:100) followed by EtOAc/MeOH (100:0 to 90:10) to afford (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronic acid (29.0 g, 73%). ¹H NMR (CD₃OD, 400 MHz): δ 8.51 (d, J = 2.3 Hz, 1H), 8.30 (d, J= 2.0 Hz, 1H), 7.85 (br s, 1H), 7.14-7.17 (m, 2H), 7.03 (d, J = 7.8 Hz, 1 H), 4.00 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 3.70-3.80 (m, 2H), 3.27 (br s, 2H), 3.07-3.14 (m, 1H), 1.76-1.85 (m, 2H), 1.10-1.33 (m, 2H), 1.03 (t, J= 7.81 Hz, 3H), 0.79 (s, 9H), -0.08 (d, J = 12.9 Hz, 6H). LCMS m/z = 460 [MH]⁺.

Préparation 7: (S)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronic acid

OH

I

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyndine (Préparation 50, 1.0 g, 2.42 mmol), [lr(COD)CI]₂ (CAS 12112-67-3, 44.2 mg, 0.06 mmol) and (R,R)-[2-(4'-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine (CAS 541540-70-9, 58.2 mg, 0.12 mmol) was added anhydrous THF (8.1 mL). The mixture was stirred at about 20 °C for about 10 min. The reaction was cooled to about 0 °C and catecholborane (6.04 mL, 6.04 mmol, 1.0 M in THF) was added dropwise. The reaction was warmed to about 20 °C and stirred for about 8 h. The reaction was cooled to about 5 °C and quenched with MeOH. The mixture was concentrated and purified by column chromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) to afford (S)-(3-((tertbutyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (889 mg, 80%). ¹H NMR (CD₃OD, 400 MHz): δ 8.51 (d, J = 2.3 Hz, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 7.85 (brs, 1H), 7.14-7.17 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 4.00 (t, J= 6.6 Hz, 2 H), 3.85 (s, 3H), 3.70-3.80 (m, 2H), 3.27 (brs, 2H), 3.07-3.14 (m, 1H), 1.76-1.85 (m, 2H), 1.10-1.33 (m, 2H), 1.03 (t, J = 7.81 Hz, 3H), 0.79 (s, 9H), -0.08 (d, J= 12.9 Hz, 6H). LCMS m/z = 460 [MH]⁺.

Préparation 8: 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

3-(1-Bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 39, 5.60 g, 11.37 mmol), Pd(dppf)CI₂ (415.98 mg, 568.50 umol), Pin₂B₂ (4.33 g, 17.06 mmol) and KOAc (2.23 g, 22.74 mmol) in dioxane (100 mL) was heated to about 60 °C under N₂for about 16 h. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to afford 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (6.10 g, 99%). ¹H NMR (CDCI₃, 400MHz): δ 8.70-8.73 (m, 2H), 8.03 (t, J = 2.0 Hz, 1H), 7.14 (dd, J = 2.0, 8.4 Hz, 1H), 7.10 (s, 1H), 6.97 (d, J = 8.4 Hz, 1 H), 5.90 (s, 1 H), 4.97 (s, 2H), 4.06 (t, J = 6.8 Hz, 2H), 3.93 (s, 1 H), 1.87-1.96 (m, 2H), 1.33 (s, 12H), 1.08 (t, J = 7.6 Hz, 3H), 0.83 (s, 9H), 0.07 (s, 6H).

Préparation 9: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine

Bis(1,5-cyclooctadiene)di-p-methoxydiiridium(l) (CAS 12148-71-9, 96 mg, 0.15 mmol) and ethylenebis(diphenylphosphine) (CAS, 1663-45-2, 116 mg, 0.29 mmol) in anhydrous DCE (10 mL) were stirred for about 15 min under N2 at about 15 °C. 3-(3-((tert5 butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine (Préparation 51,600 mg, 1.45 mmol) was added to the mixture under N₂ at about 15 °C. After stirring for about 5 min, 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (CAS 25015-63-9, 913 mg, 7.13 mmol) was added at about 70 °C and stirred for an additional 15 min. The reaction was quenched with MeOH and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 85:15) to give afford 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-isopropoxy-4methoxyphenyl)pyridine (750 mg, 96%). LCMS m/z = 542 [MH]⁺.

Préparation 10: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (750 mg, 95%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3cyclopropoxy-4-methoxyphenyl)pyridine (Préparation 52, 600 mg, 1.46 mmol). LCMS m/z = 540

[MH]⁺.

Préparation 11: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

3-(1 -((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine (2.0 g, 81%) was prepared in an analogous manner to Préparation 9 using 3-(3-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2yl)pyridine (Préparation 53, 2.0 g, 3.8 mmol). LCMS m/z = 658 [MH]⁺.

Préparation 12: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12.0 g, 97%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Préparation 54, 10.0 g, 18.4 mmol). LCMS m/z = 671 [MH]⁺.

Préparation 13: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (700 mg, 89%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(320225 (2-fluoroethoxy)-4-methoxyphenyl)pyridine (Préparation 55, 600 mg, 1.4 mmol). LCMS m/z =

433 [MH] .

Préparation 14: tert-butyl(2-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilane

tert-butyl(2-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilane was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(3-(3-fluoropropoxy)-4methoxyphenyl)pyridine (Préparation 56).

Préparation 15: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (300 mg, 46%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Préparation 57, 361 mg, 1.13 mmol). LCMS m/z = 578 [MH]⁺.

Préparation 16: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine (650 mg, 75%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3ethoxy-5-fluoro-4-methoxyphenyl)pyridine (Préparation 58, 660 mg, 1.58 mmol). LCMS m/z = 546 [MH]⁺.

Préparation 17: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine (800 mg, 77%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3chloro-5-ethoxy-4-methoxyphenyl)pyridine (Préparation 59, 800 mg, 1.8 mmol). LCMS m/z = 562 [MH]⁺.

Préparation 18: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (2.0 g, 85%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2fluoro-4-methoxyphenyl)pyridine (Préparation 60, 1.80 g, 4.31 mmol). ¹H NMR (CDCh, 400MHz): δ 8.56 (t, J = 1.7 Hz, 1 H), 8.44 (d, J = 2.0 Hz, 1 H), 7.71 (m, 1 H), 6.88 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 11.5 Hz, 1H), 4.10 (q, J= 7.0 Hz, 2H), 3.90 (s, 3H), 3.68-3.75 (m, 2H), 3.073.14 (m, 1H), 1.47 (t, J= 7.0 Hz, 3H), 1.22-1.29 (m, 2H), 1.09 (d, J= 13.1 Hz, 12H), 0.81 (s, 9H), -0.06 (d, J = 6.5 Hz, 6H). LCMS m/z = 546 [MH]⁺.

Préparation 19: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine (2.05 g, 73%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2chloro-5-ethoxy-4-methoxyphenyl)pyridine (Préparation 61,2.17 g, 5.0 mmol). ¹H NMR (CDCI₃, 400MHz): δ 8.44 (m, 2H), 7.63 (t, J = 2.0 Hz, 1 H), 6.95 (s, 1 H), 6.77 (s, 1 H), 4.06 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 3.64-3.74 (m, 2H), 3.06-3.13 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.23-1.29 (m, 2H), 1.08 (d, J = 13.6 Hz, 12H), 0.79 (s, 9H), -0.08 (d, J= 6.8 Hz, 6H).

Préparation 20: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (4.0 g, 86%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2fluoro-4-methoxy-5-propoxyphenyl)pyridine (Préparation 62, 6 g, 8.3 mmol). LCMS m/z = 560 [MH]⁺.

Préparation 21: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine (2.25 g, 88%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyIdimethylsilyl)oxy)prop-1-en-2-yl)-5-(4(difluoromethoxy)-3-propoxyphenyl)pyridine (Préparation 63, 2.0 g, 4.5 mmol). ¹H NMR (CDCh, 400MHz): δ 8.61 (d, J= 2.2 Hz, 1H), 8.57 (d, J= 2.1 Hz, 1H), 7.73 (t, J= 2.1 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.09-7.12 (m, 2H), 6.61 (t, J= 75.3 Hz, 1H), 4.05 (t, J= 6.5 Hz, 2H), 3.67-3.77 (m, 2H), 3.09-3.16 (m, 1H), 2.16 (s, 2H), 1.84-1.93 (2H), 1.06-1.11 (m, 15H), 0.81 (s, 9H), -0.07-0.05 (d, J = 5.8 Hz, 6H). LCMS m/z = 578 [MH]⁺.

Préparation 22: 5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine

5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (4.02 g, quant.) was prepared in an analogous manner to Préparation 9 using 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (Préparation 64, 3.1 g, 7.17 mmol). ¹H NMR (CDCh, 400MHz): δ 9.03 (s, 1H), 8.45 (d, J=2.3Hz, 1H), 8.13-8.15 (m, 1H), 6.95 (d, J= 11.3 Hz, 1H), 4.12 (t, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.68-3.76 (m, 2H), 3.09-3.16 (m, 1H), 1.85-1.94 (m, 2H), 1.22-1.29 (m, 2H), 1.10 (d, J = 11.5 Hz, 12H), 1.05 (t, J= 7.5 Hz, 3H), 0.81 (s, 9H), -0.07-0.06 (d, J = 7.5Hz, 6H). LCMS m/z = 561 [MH]⁺

Préparation 23: 5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine

5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine (2.55 g, 81%) was prepared in an analogous manner to Préparation 9 using 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy3,3'-bipyridine (Préparation 65, 2.4 g, 5.8 mmol). LCMS m/z = 543 [MH]⁺.

Préparation 24: 5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine

5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan5 2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine (700 mg, 91%) was prepared in an analogous manner to Préparation 9 using 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3ethoxy-4-methoxyphenyl)-2-methylpyridine (Préparation 66, 590 mg, 1.43 mmol). LCMS m/z = 542 [MH]⁺.

Préparation 25: 4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-210 yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (0.94 g, 59%) was prepared in an analogous manner to Préparation 9 using 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)15 2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (Préparation 67, 1.27 g, 2.63 mmol). Ή NMR (CDCh, 400MHz): δ 8.17-8.19 (m, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.42 (s, 1H), 6.97 (d, J= 8.6 Hz, 1H), 4.12-4.16 (m, 2H), 3.95 (s, 3H), 3.79-3.89 (m, 2H), 3.31-3.37 (m, 1H), 1.90-1.99 (m, 2H), 1.23-1.29 (m, 2H), 1.13 (s, 6H), 1.10 (t, J= 7.5 Hz, 3H), 1.05 (s, 6H), 0.800.82 (s, 9H), -0.04 (t, J = 3.1 Hz, 3H), -0.08 (t, J = 3.1 Hz, 3H). LCMS m/z = 611 [MH]⁺

Préparation 26: 2-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propan2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine (720 mg, 43%) was prepared in an analogous manner to Préparation 9 using 2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-45 methoxyphenyl)pyrazine (Préparation 68, 1.26 g, 3.1 mmol). LCMS m/z = 529 [MH]⁺.

Préparation 27: 2-(6-(1-borono-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)acetic acid

Ethyl 2-(6-(1 -((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-210 yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Préparation 28, 758 mg, 1.21 mmol) was dissolved in MeCN (10 mL) and water (10 mL). To the solution was added LiOHH₂O (101 mg, 2.41 mmol) in portions. The mixture was stirred at about 25 °C for about 1 h. The mixture was concentrated. The reaction mixture was used directly in the next step without further purification. LCMS m/z = 519 [MH]⁺.

Préparation 28: ethyl 2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

101

Ethyl 2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pynmidin-4-yl)acetate (437 mg, 70%) was prepared in an analogous manner to Préparation 9 using ethyl 2-(6-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Préparation 69, 500 mg, 0.99 mmol). LCMS m/z = 629 [MH]⁺.

Préparation 29: 4-(1 -((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)propan-2-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan2-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (1.0 g, 58%) was prepared in an analogous manner to Préparation 9 using 4-(((tertbutyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3propoxyphenyl)pyrimidine (Préparation 70, 1.4 g, 2.5 mmol). LCMS m/z = 687 [MH]⁺.

Préparation 30: methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate

A mixture of methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3(((trifluoromethyl)sulfonyl)oxy)acrylate (Préparation 40, 15.00 g, 30.03 mmol), Pd(dppf)Cl2 (1.10 g, 1.50 mmol), Pin₂B2 (11.44 g, 45.05 mmol) and KOAc (4.42 g, 45.05 mmol) in 1,4-dioxane (200 mL) was stirred at about 80 °C for about 2 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to afford methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,T-biphenyl]-3-yl)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (13.6 g, 94%). ¹H NMR (CDCI₃, 400MHz):

102 δ 7.52 (s, 1Η), 7.49-7.47 (m, 1H), 7.42-7.40 (m, 2H), 7.14-7.11 (m, 2H), 6.30 (s, 1H), 4.18-4.14 (m, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 1.90-1.81 (m, 2H), 1.25 (s, 12H), 1.06 (t, J= 3.6 Hz, 3H).

Préparation 31: 2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)butan-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2yl)-6-(4-methoxy-3-propoxyphenyl)pyridine (140 mg, 12%) was prepared in an analogous manner to Préparation 9 using 2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3propoxyphenyl)pyridine (Préparation 71, 900 mg, 2.10 mmol). LCMS m/z = 556 [MH]⁺.

Préparation 32: (E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

A solution of 2,2,6,6-tetramethylpiperidine (CAS 768-66-1, 1.08 mL, 6.41 mmol) in THF (2.5 mL) was cooled to about 0 °C (ice bath) under N₂. N-BuLi (2.56 mL, 6.41 mmol, 2.5 M in hexanes) was added dropwise to the solution and stirred for about 30 min at about 0 °C. A solution of 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (Préparation 149, 1810 mg, 6.41 mmol) in THF (2 mL) was added dropwise, which was stirred for about 5 min before cooling to about -78 °C. A solution of 2-((tert-butyldimethylsilyl)oxy)-1-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)ethan-1-one (Préparation 75, 666 mg, 1.60 mmol) in THF (3.0 mL) added dropwise and stirred under N₂ at about -78 °C for about 1 h. The reaction was placed in an ice bath and stirred for an additional hour. The reaction was quenched with water and diluted with EtOAc. The EtOAc was separated, washed with brine and dried over MgSO4. The solution was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (9:1) to afford (E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (400 mg, 45%). LCMS m/z = 554 [MH]⁺.

103

Préparation 33: ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate

To a mixture of ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)propanoate (Préparation 110, 249 mg, 0.625 mmol) and 2-(4-methoxy-3propoxyphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Préparation 114, 357 mg, 1.22 mmol) in 1,4-dioxane (8.5 mL) was added a solution of K3PO4 in water (2.0 M, 0.625 mL, 1.25 mmol).

The mixture was degassed using N₂ at about 20 °C for about 10 min. Bis(tri-tbutylphosphine)palladium(O) (CAS 53199-31-8, 16.0 mg, 0.03 mmol) was added and the mixture was allowed to stir at about 20 °C for 2 h. The mixture was diluted with EtOAc, dried over Na₂SO4, filtered, and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to afford ethyl 2-(5-(4-methoxy-315 propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propanoate (134 mg, 44%). ¹H NMR (CDCI3, 400MHz,): δ 7.40-7.56 (m, 1H), 7.23-7.38 (m, 4H), 7.07-7.13 (m, 4H), 6.96 (d, J = 8.6 Hz, 2H), 5.33 (s, 1 H), 4.02-4.22 (m, 7H), 3.93 (s, 6H), 1.83-2.08 (m, 4H), 1.71 (s, 4H), 1.49-1.67 (m, 9H), 1.37 (s, 1H), 1.17-1.29 (m, 19H), 1.09 (t, J = 7 A Hz, 7H). LCMS m/z = 399 [MH]⁺.

Préparation 34: 5-(3-((tert-butyldimethylsilyl)oxy)-1 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butan-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)butan-2yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine (160 mg, 41%) was prepared in an analogous manner to Préparation 9 using 5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3propoxyphenyl)pyridazine (Préparation 72, 300 mg, 0.7 mmol). LCMS m/z = 557 [MH]⁺.

104

Préparation 35: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prOpan2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (0.28 g, 26%) was prepared in an analogous manner to Préparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3ethoxy-4-methoxyphenyl)-4-methylpyridine (Préparation 73, 0.8 g, 1.93 mmol). ¹H NMR (CDCh, 400MHz): δ 8.36 (s, 1 H), 8.22 (s, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 6.75-6.78 (m, 1 H), 6.73 (d, J = 2.0 Hz, 1 H), 4.08 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 3.74-3.78 (m, 1 H), 3.64-3.68 (m, 1 H), 3.383.46 (m, 1H), 2.29 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.22-1.29 (m, 2H), 1.03-1.08 (m, 12H), 0.79 (s, 9H), -0.11-0.08 (m, 6H). LCMS m/z = 542 [MH]⁺

Préparation 36: 4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole (0.41 g, 39%) was prepared in an analogous manner to Préparation 9 using 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4methoxyphenyl)thiazole (Préparation 74, 0.8 g, 1.97 mmol). ¹H NMR (CDCh, 400MHz): δ 7.53 (d, J = 2.0 Hz, 1 H), 7.46 (dd, J = 2.0, 8.5 Hz, 1 H), 6.91 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 4.20 (q, J = 7.0 Hz, 2H), 3.88-3.92 (s, 4H), 3.77-3.81 (m, 1 H), 3.27-3.34 (m, 1 H), 1.51 (t, J = 7.0Hz, 3H), 1.27-1.30 (m, 2H), 1.15 (d, J = 13.6, 12 H), 0.85 (s, 9H), -0.03 (s, 6H). LCMS m/z = 534 [MH]⁺.

Préparation 37: 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4dimethoxyphenyl)pyridine

105

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4dimethoxyphenyl)pyridine (Préparation 48, 30.00 g, 77.81 mmol) in DCM (500 mL) was added pyridinium tribromide (CAS 39416-48-3, 24.9 g, 77.8 mmol) in portions at about 0 °C. The mixture was stirred at about 20 °C for about 1 h and poured into cold aqueous Na₂SÜ3 (100 mL). The mixture was extracted with DCM (3 x 50 mL). The combined DCM extracts were washed with brine (50 mL), dried over Na₂SO₄ and concentrated. DBU (CAS 6674-22-2, 58.64 mL, 389.1 mmol) was added to the above mixture in DCM (500 mL) at about 20 °C. The mixture was stirred at about 20 °C for about 16 h and poured into aqueous NH₄CI (500 mL). The mixture was extracted with DCM (3 x 200 mL). The combined DCM extracts were washed with brine (200 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (15:1) to afford 3-(1-bromo-3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (27.0 g, 75%). ¹H NMR (CDCI₃,400 MHz): δ 8.74 (d, J = 2.4 Hz, 1 H), 8.55 (d, J = 3.0 Hz, 1 H), 7.88 (t, J = 2.0 Hz, 1 H), 7.13-7.15 (m, 1H), 7.08 (d, J = 3.0 Hz, 1H), 6.97 (d, J= 7.2 Hz, 1H), 6.57 (s, 1H), 4.76 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 0.82 (s, 9H), 0.07 (s, 6H).

Préparation 38: 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine

A mixture of 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine (Préparation 47a, 11.0 g, 19.66 mmol) and DBU (CAS 6674-22-2, 5.99 g, 39.33 mmol, 5.93 mL) in DCM (150 mL) was stirred at about 25 °C for about 16 h. The mixture was washed with 1N HCl (300 mL), brine (300 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3ethoxy-4-methoxyphenyl)pyridine (7.0 g, 74%). ¹H NMR (CDCI3, 400MHz): δ 8.74 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.14 (dd, J= 1.6, 8.0 Hz, 1H), 7.09 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 4.77 (s, 2H), 4.18 (q, J = 6.8 Hz, 2H), 3.94 (s, 3H), 1.51 (t, J = 6.8 Hz, 3H), 0.82 (s, 9H), 0.08 (s, 6H).

Préparation 39: 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

106

To a mixture of 3-(1,2-ibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 47b, 10.0 g, 17.44 mmol) in DCM (150 mL) was added

DBU (CAS 6674-22-2, 5.26 mL, 34.88 mmol), which was stirred at about 25 °C for about 16 h under N₂. The mixture was washed with 1N HCl (400 mL), brine (400 mL), dried over Na₂SO4 and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4methoxy-3-propoxyphenyl)pyridine (5.60 g, 65%). ¹H NMR (CDCh, 400MHz): δ 8.74 (d, J= 2.0 Hz, 1H), 8.55 (d, J= 1.6 Hz, 1H), 7.87 (s, 1H), 7.13 (dd, J= 1.6, 8.4 Hz, 1H), 7.09 (s, 1H), 6.98 (d, J = 8.0 Hz, 1 H), 6.57 (s, 1 H), 4.77 (s, 2H), 4.06 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.87-1.96 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H), 0.82 (s, 9H), 0.08 (s, 6H).

Préparation 40: methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3(((trifluoromethyl)sulfonyl)oxy)acrylate

To a solution of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-315 hydroxyacrylate (Préparation 41, 14.5 g, 39.47 mmol) in toluene (500 mL) was added LiOH (11.59 g, 276.27 mmol) in water (30 mL). To the mixture was added Tf₂O (CAS 358-23-8, 15.63 mL, 94.72 mmol) dropwise at about 0 °C. The mixture was stirred at about 0 °C for about 1 h. The reaction was quenched with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined EtOAc extracts were washed with brine (2 x 300 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (15:1) to afford methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,Tbiphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate (15.00 g, 74%). ¹H NMR (CDCI₃, 400MHz): δ 7.56-7.59 (m, 1H), 7.48-7.52 (m, 2H), 7.39-7.41 (m, 1H), 7.13-7.18 (m, 3H), 4.19 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.83-1.92 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H).

Préparation 41: methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,T-biphenyl]-3-yl)-3hydroxyacrylate

107

To a mixture of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1 ,T-biphenyl]-3-yl)acetate (Préparation 85, 12.0 g, 35.36 mmol) and ethyl formate (11.39 mL, 141.43 mmol) in DCM (150 mL) was added TiCU (13.41 g, 70.72 mmol, 7.62 mL) and Et₃N (8.59 g, 84.86 mmol, 11.76 mL) slowly at about 0 °C. The mixture was stirred at about 20 °C for about 1 h. Water (150 mL) was added and the mixture was extracted with DCM (2 x 150 mL). The combined DCM extracts were washed with brine (150 mL), dried over Na2SO4 and concentrated to afford methyl 2-(2'cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-hydroxyacrylate (14.50 g), which was used directly without further purification. Ή NMR (CDCh, 400MHz): δ 12.09 (d, J = 12.4 Hz, 1H), 7.43-7.44 (m, 3H), 7.38-7.41 (m, 1H), 7.29-7.34 (m, 1H), 7.15 (s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 1.84-1.93 (m, 2H), 1.07-1.11 (m, 3H).

Préparation 42: (R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

A mixture of (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin3-yl)propyl methanesulfonate (Préparation 43, 45.5 g, 89.28 mmol) and lithium iodide (38.2 g, 286 mmol) in acetone (446 mL) was stirred at about 30 °C for 3 days. The reaction was heated to about 50 °C for about 45 min. The mixture was cooled to about 20 °C and concentrated to remove acetone. The residue was diluted with DCM and washed with water (2 x 100 mL). The DCM extract was dried over MgSO4, filtered and concentrated. The residue was triturated in heptanes/EtOAc (1:1, 100 mL) for about 45 min. The solid material was filtered and purified by column chromatography (silica) and eluted with heptanes/EtOAc (85:15 to 30:70) to afford (R)3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (41.2 g, 85%). 1H NMR (CDCh, 400 MHz): δ 8.71 (d, J = 2.3 Hz, 1 H), 8.43 (d, J = 2.0 Hz, 1 H), 7.71 (t, J = 2.0 Hz, 1H), 7.09-7.15 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 4.06 (t, J= 7.0 Hz, 2H), 3.98-4.02 (m, 1H), 3.93 (s, 3H), 3.84-3.88 (m, 1H), 3.68-3.72 (m, 1H), 3.43-3.47 (m, 1H), 3.093.15 (m, 1H), 1.87-1.96 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.05 (d, J= 7.4 Hz, 6H). LCMS m/z = 542 [MH]⁺.

Préparation 43: (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl methanesulfonate

108

To an ice cold solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propan-1-ol (Préparation 44, 42.8 g, 99.2 mmol) in DCM (600 mL) was added Et₃N (25.1 mL, 178 mmol) and stirred for about 30 min. MsCI (9.98 mL, 129 mmol) was added dropwise and allowed to warm and stir at about 20 °C overnight. The mixture was washed with water, dried over MgSO₄, filtered, passed through a silica gel plug and concentrated to afford (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl methanesulfonate (45.5 g), which was used in Préparation 42. LCMS m/z = 510 [MH]⁺.

Préparation 44: (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propan-1-ol

To an ice cold solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl acetate (Préparation 45, 45.7 g, 96.5 mmol) in THF (400 mL) was added aqueous NaOH (154 mL, 1 N). The mixture was allowed to warm and stir at about 20 °C for 2 days. The organic phase was separated and concentrated. The residue was dissolved in DCM (300 mL). The aqueous layer was extracted with DCM. The combined DCM extracts were washed with water, brine, dried over Na2SO₄, filtered and concentrated to afford (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol (42.8 g), which was used in Préparation 43. LCMS m/z = 432 [MH]⁺.

Préparation 45: (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl acetate

To an ice cold solution of (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl acetate (Préparation 46, 43.4 g, 121 mmol) in 2-MeTHF (1400 mL) was added DCM (800 mL), imidazole (41.1 g, 604 mmol) and TBS-CI (91.0 g, 604 mmol). The reaction mixture

109 was warmed to about 20 °C and stirred overnight. The mixture was filtered and the solids washed with EtOAc. The combined filtrâtes were washed with water, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40) to afford (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (48.3 g, 85%). ¹H NMR (CDCh, 400 MHz): δ 8.70 (d, J = 2.0 Hz, 1 H), 8.45 (d, J = 2.3 Hz, 1 H), 7.74 (t, J = 2.3 Hz, 1 H), 7.08-7.14 (m, 2H), 6.98 (d, J= 8.2 Hz, 1H), 4.40-4.49 (m, 2H), 4.06 (t, J= 7.0 Hz, 2H), 3.86-3.95 (m, 5H), 3.173.23 (m, 1 H), 2.04 (s, 3H), 1.67-1.96 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H), 0.87 (s, 9H), 0.01 (d, J = 2.3 Hz, 6H). LCMS m/z = 474 [MH]⁺.

Préparation 46: (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate

To a mixture of 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol (Préparation 82, 38.3 g, 121 mmol) in 2-MeTHF (1088 mL) was added immobilized Rhizomucor miehei lipase (1.53 g, Lipozyme® RM IM, Novozymes A/S, Denmark). The mixture was stirred at about 20 °C for about 5 min. Vinyl acetate (89.0 mL, 965 mmol) was added to the mixture followed by 2-MeTHF (100 mL). The mixture was stirred at about 20 °C for about 39 h. The mixture was filtered and the filter cake was washed with 2-MeTHF (50 mL). The combined filtrâtes were concentrated to afford (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl acetate (36.0 g, 83%), which was used in Préparation 45. Préparation 47a: 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine (Préparation 49, 8.00 g, 20.02 mmol) in DCM (150 mL) was added pyridinium tribromide (CAS 39416-48-3, 7.68 g, 24.02 mmol) in one portion at about 0 °C under N₂. The mixture was stirred at about 25 °C for about 3 h. The DCM mixture was washed with aqueous Na₂SO₃ (100 mL), brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (11.00 g) which was used directly for the next step. ¹H NMR (CDCh, 400MHz): δ 8.72-8.74 (m,

110

2H), 7.99 (t, J = 2.0 Hz, 1H), 7.14 (dd, J= 2.0, 8.4 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.00 (d, J = .0 Hz, 1H), 4.37-4.40 (m, 2H), 4.28 (d, J= 11.2 Hz, 1H), 4.21-4.26 (m, 3H), 3.93 (s, 3H), 1.52 (t, J = 7.2 Hz, 3H), 0.94 (s, 9H), 0.14 (d, J = 9.6 Hz, 6H).

Préparation 47b: 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 50, 7.00 g, 16.92 mmol) in DCM (150 mL) was added pyridinium tribromide (CAS 39416-48-3, 6.49 g, 20.30 mmol) in one portion at about 0 °C under N₂. The mixture was stirred at about 25 °C for about 3 h. The DCM mixture was washed with aqueous Na₂SO₃ (100 mL), brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (10.00 g), which was used directly for the next step. ¹H NMR (CDCI₃, 400MHz): δ 8.72-8.75 (m, 2H), 7.99 (t, J= 2.0 Hz, 1H), 7.14 (dd, J= 2.0, 8.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 4.39 (d, J = 10.8 Hz, 2H), 4.28 (d, J = 10.8 Hz, 1H), 4.20 (d, J= 10.4 Hz, 1H), 4.07 (t, J= 6.8 Hz, 2H), 3.93 (s, 3H), 1.97-1.87 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.14 (d, J = 9.6 Hz, 6H).

Préparation 48: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4dimethoxyphenyl)pyridine

A mixture of 3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine (Préparation 91a, 2.0 g, 5.86 mmol), 2-bromoallyloxy-tert-butyl-dimethyl-silane (Préparation 227, 1.47 g, 5.86 mmol), Pd(dppf)CI₂ DCM (239.34 mg, 293 umol), Na₂CO₃(621.26 mg, 5.86 mmol) and KOAc (1.15 g, 11.72 mmol) in 1,4-dioxane (50 mL) and water (5 mL) were heated to about 90 °C for about 12 h. The mixture was filtered and the filtrate concentrated. The residue was purified by column chromatography (silica) and eluted with DCM/MeCN (5:1) to afford 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4dimethoxyphenyl)pyridine (2.10 g, 5.45 mmol, 93%). ¹H NMR (CDCI₃, 400 MHz): δ 8.72 (d, J =

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2.0 Hz, 1H), 8.61 (d, J= 2.0 Hz, 1H), 7.85 (t, J= 2.0 Hz, 1H), 7.14-7.16 (m, 1H), 7.08 (d, J = 2.0

Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 5.52 (d, J = 12.0 Hz, 2H), 4.56 (s, 2H), 3.97 (s, 3H), 3.95 (s,

3H), 0.93 (s, 9H), 0.12 (s, 6H).

Préparation 49: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine

A mixture of 3-bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine (Préparation 92, 20 g, 64.9 mmol), tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Préparation 146, 23.23 g, 77.88 mmol), Pd(dppf)CI₂ (1.42 g, 1.95 mmol), K₂CO₃ (17.94 g, 129.8 mmol) and KOAc (9.55 g, 97.35 mmol) in 1,4-dioxane (300 mL) and water (10 mL) was degassed and heated to about 90 °C for about 16 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (3:1) to afford 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4methoxyphenyl)pyridine (18.0 g, 69%). ¹H NMR (CDCI₃, 400MHz): δ 8.71 (d, J = 2.0 Hz, 1H), 8.60 (d, J= 2.0 Hz, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.14 (dd, J= 2.0, 8.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.99 (d, J=8.0Hz, 1H), 5.54 (s, 1H), 5.50 (s, 1H),4.56 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.52 (t, J= 7.2 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

Préparation 50: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

A mixture of 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 93a, 15.0 g, 46.55 mmol), tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Préparation 146, 18.05 g, 60.51 mmol), Pd(dppf)CI₂ (1.70 g, 2.33 mmol), K₂CO₃ (12.87 g, 93.10 mmol) and KOAc (6.85 g, 69.83 mmol) in 1,4-dioxane (250 mL) and water (5 mL) was degassed and heated to about 90 °C for about 16 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (3:1) to afford 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (13.50 g, 70%). ¹H NMR (CDCI₃, 400MHz): δ 8.71 (d, J = 2.4 Hz, 1H), 8.60 (d, J= 2.0 Hz, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.13 (dd, J= 2.4, 8.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 5.53 (d, J= 1.2 Hz, 1H), 5.50 (d, J= 1.2 Hz, 1H), 4.56 (s, 2H),

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W 4.06 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.87-1.96 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H),

0.13 (s, 6H).

Préparation 51: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(3-isopropoxy-4 methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4methoxyphenyl)pyridine (1.1 g, 75%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (Préparation 94, 1.15 g, 3.6 mmol) at 10 about 90 °C for about 2 h. LCMS m/z = 414 [MH]⁺.

Préparation 52: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4methoxyphenyl)pyridine (730 mg, 76%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (Préparation 95, 0.75 g, 2.34 mmol). Ή NMR (CDCh, 400 MHz): δ 8.74 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.85 (t, J = 2.3 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.14-7.22 (m, 1H), 6.98 (d, J= 8.5 Hz, 1H), 5.53 (dd, J =

1.3, 10.3 Hz, 2H), 4.50-4.62 (m, 2H), 3.92 (s, 3H), 3.84 (tt, J = 3.2, 6.1 Hz, 1H), 0.81-0.96 (m,

13H), 0.11-0.14 (m, 6H). LCMS m/z = 412 [MH]⁺.

Préparation 53: 3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine

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3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (6.7 g, 62%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4methoxyphenyl)pyridine (Préparation 96, 9.3 g, 21 mmol). ¹H NMR (CDCh, 400 MHz): δ 8.71 (d, J= 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 7.83 (t, J= 2.0 Hz, 1H), 7.13-7.18 (m, 2H), 6.96-7.01 (m, 1H), 5.52 (dd, J= 1.3, 10.3 Hz, 2H), 4.56 (s, 2H), 4.16-4.22 (m, 2H), 4.02-4.07 (m, 2H), 3.92 (s, 3H), 0.92-0.95 (m, 9H), 0.90 (s, 9H), 0.12 (s, 6H), 0.10 (s, 6H). LCMS m/z = 530 [MH]⁺.

Préparation 54: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(3-(3-((tertbutyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tertbutyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12.9 g, 99%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(3-(3-((tertbutyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Préparation 97, 10.8g, 23.8 mmol). Ή NMR (CDCh, 400 MHz): δ 8.71 (d, J= 2.5 Hz, 1H), 8.60 (d, J= 2.0 Hz, 1H), 7.83 (t, J= 2.2 Hz, 1H), 7.11-7.16 (m, 2H), 6.98 (d, J= 8.3 Hz, 1H), 5.49-5.54 (m, 2H), 4.56 (t, J = 1.5 Hz, 2H), 4.21 (t, J = 6.4 Hz, 2H), 3.92 (s, 3H), 3.85 (t, J = 5.9 Hz, 2H), 2.05-2.13 (m, 2H), 0.92-0.94 (m, 9H), 0.89 (s, 9H), 0.12 (s, 6H), 0.05 (s, 6H). LCMS m/z = 544 [MH]⁺.

Préparation 55: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(3-(2-fluoroethoxy)-4methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4methoxyphenyl)pyridine (1.6 g, 78%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (Préparation 98, 1.4 g, 4.7 mmol). Ή NMR (CDCI₃,400 MHz): δ 8.92 (d, J = 2.5 Hz, 1 H), 8.70-8.73 (m, 1 H), 7.73 (t, J = 8. 6 Hz, 1 H), 6.84-6.90 (m, 1 H), 6.07 (d, J = 1.5 Hz, 1 H), 5.76 (d, J = 1.5 Hz, 1 H), 4.76 (t, J = 1.7 Hz, 2H), 4.06 (t, J = 6.9 Hz, 2H), 3.94 (s, 3H), 1.81-1.86 (m, 2H), 1.03-1.09 (m, 3H), 0.95 (s, 9H), 0.14 (s, 6H). LCMS m/z = 433 [MH]⁺.

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Préparation 56: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(3-(3-fluoropropoxy)-4methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-45 methoxyphenyl)pyridine was prepared in an analogous manner to Préparation 50 using 3bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine (Préparation 99).

Préparation 57: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy4-methoxyphenyl)pyridine

A solution of 2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1ol (Préparation 76, 321 mg, 0.71 mmol) and imidazole (97.2mg, 1.43 mmol) in DCM (20 mL) was added TBS-CI (129 mg, 0.86 mmol) at about 0 °C. The reaction mixture was stirred at about 20 °C for about 15 h. Additional TBS-CI (129 mg, 0.86 mmol) was added and the reaction mixture was stirred at about 20 °C for about 20 h. The reaction mixture was concentrated and purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 60:40) to afford 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridine (361 mg, 75%). ¹H NMR (CDCI₃,400 MHz): δ 8.66 (d, J = 2.0 Hz, 1H),

8.51 (d, J=2.0Hz, 1H), 7.71 (t, J=2.3Hz, 1 H), 7.05-7.10 (m, 1 H), 6.78-7.03 (m, 2H), 5.51 (dd,

J = 1.5, 14.1 Hz, 2H), 4.55 (t, J = 1.5 Hz, 2H), 4.17 (q, J =7.0 Hz, 2H), 3.93 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.88-0.94 (m, 9H), 0.09-0.13 (m, 6H). LCMS m/z = 450 [MH]⁺.

Préparation 58: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridine

115

P To a mixture of 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (Préparation 86, 795 mg, 2.42 mmol), 2-(3-ethoxy-5-fluoro-4-methoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Préparation 132, 652 mg, 2.2 mmol), Pd(dppf)Cl2 DCM and K₂CO₃ (760 mg, 5.5 mmol) was suspended in 1,4-dioxane (20 mL) and water (0.7 mL). The 5 mixture was degassed and heated to about 85 °C under N₂ for about 9 h. The mixture was concentrated and MTBE (50 mL) was added, stirring for about 20 min. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford 3-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine (660 mg, 10 72%). Ή NMR (CDCI3, 400 MHz): δ 8.66 (dd, J = 2.2, 15.4 Hz, 2H), 7.82 (t, J = 2.0 Hz, 1H), .94 (dd, J = 2.2, 11.0 Hz, 1 H), 6.88 (t, J = 1.7 Hz, 1 H), 5.50-5.57 (m, 2H), 4.54-4.57 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 1.50 (t, J= 7.1 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). LCMS m/z = 418 [MH]⁺.

Préparation 59: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-415 methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridine (840 mg, 61%) was prepared in an analogous manner to Préparation 58 using 2-(3-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 133, 1.0 g, 3.2 mmol). ¹H NMR (CDCI₃,400 MHz): δ 8.66 (dd, J = 2.2, 11.5 Hz, 2H), 7.83 (t, J= 2.2 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 6.99 (d, J= 2.0 Hz, 1H), 5.53 (dd, J= 1.5, 12.2 Hz, 2H), 4.52-4.63 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.51 (t, J = 6.9 Hz, 3H), 0.90-0.97 (m, 9H), 0.08-0.15 (m, 6H).

Préparation 60: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-425 methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridine (400 mg, 89%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (Préparation 101, 350 mg,

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1.07 mmol). Ή NMR (CDCI₃, 400MHz): δ 8.66 (t, J = 1.7 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 7.847.86 (m, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 6.75 (d, J = 11.7 Hz, 1 H), 5.50-5.53 (m, 2H), 4.56 (t, J =

1.3 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 1.48 (t, J= 7.0 Hz, 3H), 0.92 (s, 9H), 0.11 (s,

6H). LCMS m/z = 418 [MH]⁺.

Préparation 61: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(2-chloro-5-ethoxy-4methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-chloro-5-ethoxy-410 methoxyphenyl)pyridine (2.1 g, 48%) was prepared in an analogous manner to Préparation 58 using 2-(2-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Préparation 135, 3.13 g, 10.0 mmol). LCMS m/z = 434 [MH]⁺.

Préparation 62: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-5-(2-fluoro-4-methoxy-5propoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5propoxyphenyl)pyridine (5.0 g, 99%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (Préparation 102, 7.0 g, 9.0 mmol). Ή NMR (CDCI₃,400 MHz): δ 8.66 (s, 1 H), 8.62 (d, J = 2.0 Hz, 1 H), 7.85 (d, J = 1.5 Hz, 20 1 H), 6.92 (d, J = 7.3 Hz, 1 H), 6.76 (d, J = 11.7 Hz, 1 H), 5.52 (d, J = 9.8 Hz, 2H), 4.55 (s, 2H), .00 (t, J = 6.8 Hz, 2H), 3.91 (s, 3H), 1.84-1.93 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H), 0.94 - 0.92 (m, 9H), 0.12 - 0.11 (m, 6H). LCMS m/z = 432 [MH]⁺.

Préparation 63: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3propoxyphenyl)pyridine

117

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3propoxyphenyl)pyridine (2.1 g, 62%) was prepared in an analogous manner to Préparation 58 using 2-(4-(difluoromethoxy)-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 142, 2.46 g, 7.5 mmol). Ή NMR (CDCh, 400MHz): δ 8.66-8.71 (m, 2H), 7.85 (d, J =2.1 Hz, 1 H), 7.27-7.29 (m, 1H), 7.12-7.14 (m, 2H) 6.63 (t, J = 75.3 Hz, 1H), 5.53 (d, J = 12.0

Hz, 2H), 4.56 (s, 2H), 4.07 (t, J = 6.4 Hz, 2H), 1.85-1.94 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). LCMS m/z = 450 [MH]⁺.

118

Préparation 64: 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy2,3'-bipyndine

To a mixture of 5'-chloro-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (Préparation 103, 3.0 g, 10.11 mmol) and tert-butyldimethyl((2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)allyl)oxy)silane (Préparation 146, 12.1 g, 40.4 mmol) in 1,4-dioxane (300 mL) was added Xphos Pd G2 (CAS 1310584-14-5, 0.64 g, 0.81 mmol), Pd(dppf)-tBu (0.66 g, 1.01 mmol), K₂CO₃ (2.79 g, 20.2 mmol) and KOAc (0.50 g, 5.06 mmol). The mixture was degassed, heated to about 70 °C for about 16 h under N₂. The mixture was diluted with EtOAc (50 mL), dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to afford 5'-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (3.1 g, 71%). ¹H NMR (CDCh, 400MHz): δ 9.13-9.14 (m, 1H), 8.62 (d, J= 2.1 Hz, 1H), 8.28 (t, J= 2.1 Hz, 1H), 6.97 (d, J= 11.4 Hz, 1H), 5.51-5.54 (m, 2H), 4.57 (t, J = 1.5 Hz, 2H), 4.44 (t, J= 7.0 Hz, 2H), 3.93 (s, 3H), 1.86-1.95 (m, 2H), 1.06 (t, J= 7.5 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H). LCMS m/z = 433 [MH]⁺

Préparation 65: 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy-3,3'bipyridine

5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine (4.85 g, 87%) was prepared in an analogous manner to Préparation 58 using 2-methoxy-3propoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (Préparation 124, 3.95 g, 13.5 mmol). Ή NMR (CDCh, 400 MHz): δ 8.67 (dd, J =2.2, 16.9 Hz, 2H), 7.9 (d, J= 2.2 Hz, 1H), 7.83 (t, J = 2.2 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 5.47-5.60 (m, 2H), 4.56 (t, J = 1.3 Hz, 2H), 4.034.08 (m, 5H), 1.90-1.99 (m, 2H), 1.04-1.13 (m, 3H), 0.92 (s, 9H), 0.10-0.13 (m, 6H).

119

Préparation 66: 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)2-methylpyridme

3-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine (Préparation 87, 1.28 g, 3.7 mmol) and 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (Préparation 113, 1.25 g, 4.49 mmol), Pd(dppf)Cl2 (274 mg, 0.374 mmol) and K2CO3 (1.29 g, 9.35 mmol) was suspended in 1,4-dioxane (60 mL) and water (2 mL). The mixture was degassed and heated to about 80 °C under N2 for about 5 h. The mixture was concentrated and to the residue was added MTBE (100 mL), which was stirred for about 20 min. The mixture was filtered and the filter cake was washed with MTBE (50 mL). The combined filtrâtes were dried and concentrated. The residue was purified column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to afford 5-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine (640 mg, 41 %). Ή NMR (CDCh, 400 MHz): δ 8.54 (d, J = 2.5 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 6.94-6.97 (m, 1H), 6.85-6.88 (m, 1H), 6.83-6.84 (m, 1H), 5.48 (d, J= 1.5 Hz, 1H), 5.43-5.45 (m, 1H), 4.52 (t, J= 1.5 Hz, 2H), 4.12 (q, J= 7.0 Hz, 2H), 3.93 (s, 3H), 2.51 (s, 3H), 1.49 (t, J= 7.0 Hz, 3H), 0.90-0.93 (m, 9H), 0.09-0.11 (m, 6H). LCMS m/z = 414 [MH]⁺.

Préparation 67: 4-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-2-(4-methoxy-3propoxyphenyl)-6-(trifluoromethyl)pyrimidine

To a mixture of 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6(trifluoromethyl)pyrimidine (Préparation 90, 1.33 g, 3.77 mmol) in 1,4-dioxane (40 mL) was added 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 114, 1.32 g, 4.52 mmol), K₃PO₄(3.01 g, 11.3 mmol) and Pd(dppf)CI₂ (0.41 g, 0.57 mmol). The mixture was degassed and heated to about 90 °C for about 5 h under N2. The mixture was concentrated and the residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to afford 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (1.27 g, 70%). ¹H NMR (CDCh, 400MHz): δ 8.13-8.16 (m, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 6.99 (d, J= 8.6 Hz, 1H),

120 φ 6.31 (d, J = 1.1 Hz, 1H), 5.95 (d, J = 1.0 Hz, 1H), 4.65 (t, J= 1.6 Hz, 2H), 4.13 (t, J= 6.9 Hz, 2H), 3.96 (s, 3H), 1.90-1.99 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H), 0.97 (s, 9H), 0.13 (s, 6H). LCMS m/z = 483 [MH]⁺

Préparation 68: 2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-45 methoxyphenyl)pyrazine

2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine (1.26 g, 65%) was prepared in an analogous manner to Préparation 50 using 2-bromo-6-(3ethoxy-4-methoxyphenyl)pyrazine (Préparation 104, 1.5 g, 4.9 mmol). ¹H NMR (CDCh, 400

MHz): δ 8.77-8.90 (m, 1H), 8.68 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 2.1, 8.44 Hz,

H), 6.99 (d, J = 8.3 Hz, 1 H), 6.07 (q, J = 1.4 Hz, 1 H), 5.77 (q, J = 1.9 Hz, 1 H), 4.80 (t, J = 1.7 Hz, 2H), 4.23 (q, J= 7.0 Hz, 2H), 3.96 (s, 3H), 1.53 (t, J = 7.0 Hz, 3H), 0.90-0.98 (m, 9H), 0.130.18 (m, 6H). LCMS m/z = 401 [MH]⁺.

Préparation 69: ethyl 2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-315 propoxyphenyi)pyrimidin-4-yl)acetate

Ethyl 2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)acetate (5.6 g, 82%) was prepared in an analogous manner to Préparation 50 using ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Préparation 105, 5 g, 13.7 mmol). ’H NMR (CD3OD, 400 MHz): δ 8.05 (dd, J = 2.1, 8.4 Hz, 1 H), 8.01-8.03 (m, 1H), 7.46 (s, 1H), 7.05 (d, J= 8.6 Hz, 1H), 6.24 (d, J = 1.2 Hz, 1H), 5.81 (d, J = 1.5 Hz, 1 H), 4.81 (t, J = 1.6 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 2H), 1.80-1.92 (m, 2H), 1.26-1.31 (m, 3H), 1.08 (t, J = 7.5 Hz, 3H), 0.95 (s, 9H), 0.13-0.16 (m, 6H). LCMS m/z = 501 [MH]⁺.

121

Préparation 70: 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-25 (4-methoxy-3-propoxyphenyl)pyrimidine (1 g, 77%) was prepared in an analogous manner to

Préparation 58 using 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine (Préparation 89, 2.0 g, 5.2 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 114, 0.817 g, 2.8 mmol) at about 90 °C and substituting K₃PO₄ (1.55 g, 5.80 mmol) for K₂CO₃. ¹H 10 NMR (CDCh, 400 MHz): δ 8.02-8.08 (m, 2H), 7.52 (s, 1H), 6.94-6.99 (m, 1H), 6.20 (d, J= 1.5

Hz, 1H), 5.84 (d, J= 1.5 Hz, 1H), 4.80-4.86 (m, 4H), 4.09-4.15 (m, 2H), 3.93-3.96 (m, 3H), 1.911.98 (m, 2H), 1.09 (t, J= 7.5 Hz, 3H), 1.00 (s, 9H), 0.97 (s, 9H), 0.17 (s, 6H), 0.15 (s, 6H).

LCMS m/z = 559 [MH]⁺.

Préparation 71: 2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-315 propoxyphenyl)pyridine

2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine (900 mg, 68%) was prepared in an analogous manner to Préparation 50 using 2-bromo-6-(4methoxy-3-propoxyphenyl)pyridine (Préparation 93b, 1000 mg, 3.10 mmol) and tert20 butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (Préparation 148, 969 mg, 3.10 mmol). LCMS m/z = 428 [MH]⁺.

Préparation 72: 5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3propoxyphenyl)pyridazine

122

5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine (3.0 g, 89%) was prepared in an analogous manner to Préparation 50 using 5-chloro-3-(4methoxy-3-propoxyphenyl)pyridazine (Préparation 107, 2.2 g, 7.9 mmol) and tert5 butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane (Préparation 147, 4.9 g, 15.8 mmol). ¹H NMR (CDCh, 400 MHz): δ 9.14 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.53 (dd, J= 2.0, 8.3 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1 H), 5.58 (s, 1 H), 5.53 (s, 1 H), 4.08-4.18 (m, 3H), 3.95 (s, 3H), 1.86-1.99 (m, 2H), 1.29 (d, J = 6.9 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H), 0.93 (s, 9H), 0.12 (d, J = 19.6 Hz, 6H). LCMS m/z = 429

[MH]⁺.

Préparation 73: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)4-methylpyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4- methylpyridine (0.8 g, 77%) was prepared in an analogous manner to Préparation 50 using 3bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (Préparation 108, 0.81 g, 3.28 mmol) and tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Préparation 146, 0.98 g, 3.28 mmol). ¹H NMR (CDCh, 400MHz): δ 8.35 (s, 1H), 8.26 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.83-6.86 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 5.61-5.63 (m 1H), 5.10-

5.12 (m, 1H), 4.31-4.32 (m, 2H), 4.12 (q, J= 7.0 Hz, 2H), 3.93 (s, 3H), 2.21 (s, 3H), 1.48 (t, J =

7.0 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 6H). LCMS m/z = 414 [MH]⁺.

Préparation 74: 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4methoxyphenyl)thiazole

4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole was prepared (0.8 g, 91%) in an analogous manner to Préparation 50 using 4-bromo-2-(325

123 ethoxy-4-methoxyphenyl)thiazole (Préparation 109, 0.68 g, 2.16 mmol) and tertbutyldimethyl((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Préparation 146, 0.84 g, 2.81 mmol). Ή NMR (CDCh, 400MHz): δ 7.57 (d, J = 2.3Hz, 1H), 7.58 (dd, J = 2.3, 8.3Hz, 1H), 7.17 (s, 1H), 6.91 (d, J = 8.3Hz, 1H), 6.07-6.08 (m, 1H), 5.50-5.52 (m, 1H), 4.604.61 (m, 1H), 4.22 (q, J = 7.0Hz, 2H), 3.93 (s, 3H), 1.52 (t, J = 7.0Hz, 3H), 0.99 (s, 1H), 0.95 (s, 9H), 0.13 (s, 6H). LCMS m/z = 406 [MH]⁺.

Préparation 75: 2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3-propoxyphenyl)pyridin-2yl)ethan-1-one

To a mixture of 1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one (Préparation 88, 1270 mg, 4.36 mmol), K2CO3 (1000 mg, 7.27 mmol), KOAc (357 mg, 3.63 mmol), Pd(dppf)CI₂ DCM (151 mg, 0.182 mmol) and a solution of 2-(4-methoxy-3propoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 114, 1200 mg, 3.633 mmol) in 1,4-dioxane (24 mL) was added water (2.4 mL). The mixture was degassed and heated to about 90 °C for about 16 h under N₂. The reaction was filtered through a pad of MgSO₄ and silica gel, washing with DCM and EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 95:5) to afford 2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3-propoxyphenyl)pyridin-2yl)ethan-1-one (1.21 g, 80%). Ή NMR (CDCh, 400 MHz): δ 7.84-7.93 (m, 3H), 7.72 (d, J= 2.0 Hz, 1H), 7.58 (dd, J = 2.0, 8.6 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.42 (s, 2H), 4.12 (t, J= 6.8 Hz, 2H), 3.95 (s, 3H), 1.90-2.00 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H), 1.00 (s, 9H), 0.16-0.20 (m, 6H). LCMS m/z = 416 [MH]⁺.

Préparation 76: 2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol

2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol (321 mg, 61%) was prepared in an analogous manner to Préparation 50 using 3-bromo-5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Préparation 100, 558 mg, 1.56 mmol) at about 100 °C for about 15 h. Ή NMR (CDCh, 400 MHz): δ 8.70 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 7.76-7.79 (m, 1H), 7.07 (d, J= 8.6 Hz, 1H), 7.01 (d, J= 8.6 Hz, 1H), 6.96 (t, J =

124 • 54.4 Hz, 1H), 5.60(s, 1H), 5.49 (s, 1H), 4.58 (s, 2H), 4.12-4.22 (m, 2H), 3.93 (s, 3H), 1.75 (br s,

H), 1.43 (t, J = 7.0 Hz, 3H,). LCMS m/z = 336 [MH]⁺.

125

Préparation 77: 3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

To a solution of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan5 5-yl)methyl methanesulfonate (Préparation 78, 140 mg, 0.30 mmol) in acetone (1.20 mL) was added lithium iodide (201 mg, 1.50 mmol). The solution was stirred at about 50 °C for about 16 h. The reaction was cooled to about 50 °C, diluted with EtOAc, washed with water, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to afford 3-(5-(iodomethyl)-2,2-dimethyl-1,310 dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (138 mg, 92%). ¹H NMR (CDCb, 400MHz): δ 8.74 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.66 (t, J= 2.0 Hz, 1H), 7.08-7.17 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 4.25-4.37 (m, 2H), 4.14-4.23 (m, 2H), 4.07 (t, J= 6.8 Hz, 2H), 3.93 (s, 3H), 3.81 (s, 2H), 1.92 (qd, J = 7.2, 14.3 Hz, 2H), 1.49 (d, J= 18.3 Hz, 6H), 1.08 (t, J= Ί A Hz, 3H). LCMS m/z = 498 [MH]⁺.

Préparation 78: (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5yl)methyl methanesulfonate

To a mixture of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan20 5-yl)methanol (Préparation 79, 128 mg, 0.33 mmol) in DCM (7.0 mL) was added Me₃N (84 pL, 0.60 mmol), followed by MsCI (33 pL, 0.43 mmol). The solution was stirred at about 20 °C for about 3.5 h. The mixture was concentrated and the residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to afford (5-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (144 mg, 94%). Ή NMR (CDCb, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1H), 8.47 (d, J= 2.0 Hz, 1H),

7.72 (t, J= 2.1 Hz, 1H), 7.08-7.17 (m, 2H), 6.99 (d, J= 8.2 Hz, 1H), 4.78 (s, 2H), 4.20-4.28 (m, 2H), 4.03-4.18 (m, 4H), 3.93 (s, 3H), 2.92-3.01 (m, 3H), 1.87-1.96 (m, 2H), 1.51 (d, J = 4.3 Hz, 6H), 1.08 (t, J= ΊΑ Hz, 3H).

126

Préparation 79: (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5yl)methanol

To a solution of 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-35 yl)propane-1,3-diol (Préparation 80, 406 mg, 1.17 mmol) in DCM (12 mL) was added 2,2dimethoxypropane (0.43 mL, 3.51 mmol) and pTSOH (33 mg, 0.18 mmol). The solution was stirred at about 40 °C for about 24 h and about 20 °C for about 4 days. The solution wasconcentrated and the residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100 gradient) to afford (5-(5-(4-methoxy-310 propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol (129 mg, 28%). ¹H NMR (CDCh, 400MHz): δ 8.71 (d, J= 2.3 Hz, 1H), 8.50 (d, J= 2.0 Hz, 1H), 7.75 (t, J = 2.1 Hz, 1H), 7.05-7.15 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 4.19 (d, J= 5.5 Hz, 3H), 4.12-4.17 (m, 3H), 4.06 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.91 (qd, J = 7.2, 14.4 Hz, 2H), 1.62-1.64 (m, 1H), 1.49 (d, J= 5.1 Hz, 6H), 1.08 (t, J= 7.4 Hz, 3H). LCMS m/z = 388 [MH]⁺.

Préparation 80: 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3diol

To a solution of methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-320 propoxyphenyl)pyridin-3-yl)propanoate (Préparation 81,250 mg, 0.67 mmol) in methanol (2.0 mL) was added LiBH₄ (17.5 mg, 0.80 mmol). The solution was stirred at about 20 °C for about 21 h. The mixture was treated with saturated aqueous NH₄CI and extracted with DCM. The DCM extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 2(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol (55 mg, 24%).

Ή NMR (CDCh, 400MHz): δ 8.49 (br s, 1 H), 8.28 (br s, 1 H), 7.90 (br s, 1 H), 6.83-7.00 (m, 2H), 6.77 (d, J = 8.6 Hz, 1 H), 4.78 (br s, 2H), 4.04 (br s, 5H), 3.74-3.99 (m, 6H), 1.74-1.91 (m, 2H), 1.26 (s, 1 H), 1.00 (t, J = 7.4 Hz, 3H). LCMS m/z = 348 [MH]⁺.

127

Préparation 81: methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin3-yl)propanoate

To a solution of methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (Préparation 84, 65 g, 210 mmol) in DMSO (200 mL) was added paraformaldéhyde (6.81 g, 227 mmol), followed by DMSO (300 mL). NaOMe (2.23 g, 41.2 mmol) was added, followed by another 100 mL of DMSO. The mixture was stirred at about 20 °C for about 18 h. The mixture was diluted with water (1200 mL) and extracted with diethyl ether and EtOAc. The diethyl ether and EtOAc combined extracts were washed with water, brine, dried over MgSO₄, filtered and concentrated. The residue was stirred with EtOH (200 mL) at about 65 °C until the residue was dissolved. The solution was cooled to about 20 °C with stirring for about 2 h. The mixture was cooled to about 0 °C (ice water bath) for an additionall h. The mixture was filtered, and the filter cake was washed with ice-cold EtOH. The combined EtOH filtrâtes were concentrated and the residue purified by column chromatography (silica) eluting with EtOAc/MeOH (95:5) to afford methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propanoate (5.46 g, 7%). ¹H NMR (CDCb, 400MHz): δ 8.64 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.25 (s, 1H), 6.98 -7.10 (m, 2H), 6.94 (t, J = 7.3 Hz, 1 H), 4.36 (d, J = 11.3 Hz, 2H), 4.24 (d, J = 11.3 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.03 (s, 1H), 1.78-1.97 (m, 2H), 1.05 (t, J= 7.4 Hz, 3H).

Préparation 82: 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol

To an ice cold solution of methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propanoate (Préparation 83, 26.4 g, 73.5 mmol) in MeOH (350 mL) was added LiBH₄ (3.2 g, 147 mmol) in 3 portions. The mixture was stirred for about 1 h. The mixture was concentrated and diluted with DCM. The mixture was washed with 2N NaOH. The DCM layer was separated, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) to afford 2-(5-(4-methoxy3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol (20.3 g, 87%). ¹H NMR (DMSO-de, 400 MHz): δ 8.68 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.84 (t, J= 2.3 Hz, 1H), 7.21-7.25 (m, 2H),

128

7.06 (d, J = 8.2 Hz, 1 H), 4.64 (t, J = 5.4 Hz, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 3.65-3.79 (m, 4H), 2.89-2.95 (m, 1H), 1.72-1.80 (m, 2H), 1.00 (t, J =7.4 Hz, 3H). LCMS m/z = 318 [MH]⁺.

Préparation 83: methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate

A mixture of methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (Préparation 84, 30.0 g, 95 mmol), paraformaldéhyde (3.14 g, 105 mmol) and NaOMe (1.03 g, 19.0 mmol) in anhydrous DMSO (317 mL) was stirred at about 20 °C for about 16 h. The mixture was diluted with water (1200 mL) and extracted with diethyl ether and EtOAc. The combined diethyl ether and EtOAc extracts were washed with water, brine, dried over MgSO₄, filtered and concentrated. The residue was dissolved in hot EtOH (120 mL). The solution was cooled to about 20 °C with stirring. Further cooling, to about 0 °C (ice bath) affording a precipitate which was filtered to afford methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propanoate (15.6 g). The filtrate was concentrated and purified by column chromatography (silica) to provide additional solid (10.8 g). The solids were combined to afford methyl 3-hydroxy2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (26.4 g, 78%). ¹H NMR (CDCh, 400 MHz): δ 8.72 (d, J= 2.0 Hz, 1H), 8.45 (d, J= 2.3 Hz, 1H), 7.76 (t, J= 2.0 Hz, 1H), 7.07-7.12 (m, 2H), 6.97 (d, J= 8.6 Hz, 1 H),4.16-4.22 (m, 1H), 4.05 (t, J= 7.0 Hz, 2H), 3.91-3.99 (m, 5H), 3.76 (s, 3H), 2.66-2.70 (m, 1 H), 1.67-1.95 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). LCMS m/z = 346 [MH]⁺.

Préparation 84: methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate

A mixture of methyl 2-(5-bromopyridin-3-yl)acetate (55.5 g, 241.0 mmol), 2-(4-methoxy3-propoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 114, 84.7 g, 290 mmol) and anhydrous Na₂CO₃ (51.1 g, 482 mmol) in 1,4-dioxane (700 mL) and water (180 mL) was degassed and stirred at about 20 °C for about 20 min under N₂. Pd(dppf)CI₂ (9.85 g, 12.1 mmol) was added to the mixture, which was heated to about 85 °C for about 18 h under N₂. The reaction was cooled to about 20 °C and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) eluting with heptane/EtOAc (85:15 to 40:60) to afford

129 methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (75.4 g, 88%). ¹H NMR (CDCI₃,

400MHz): δ 8.72 (d, J= 2.0 Hz, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.3, 8.6 Hz, 1 H), 7.09 (d, J = 2.3 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1 H), 4.06 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.70 (s, 2H), 2.94 (s, 3H), 1.86-1.95 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). LCMS m/z = 316 [MH]⁺.

Préparation 85: methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)acetate

To a solution of 6-bromo-3-methoxy-2-propoxybenzonitrile (Préparation 171, 10.0 g, 37.02 mmol), (3-(2-methoxy-2-oxoethyl)phenyl)boronic acid (7.18 g, 37.02 mmol), Pd(dppf)CI₂(1.35 g, 1.85 mmol), KOAc (3.63 g, 37.02 mmol) and Na₂CO₃ (7.85 g, 74.04 mmol) in 1,4dioxane (100 mL) and water (5 mL) was degassed and heated to about 90 °C for about 5 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (4:1) to afford methyl 2-(2'-cyano-4'methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)acetate (12.0 g, 96%). ¹H NMR (CDCI3, 400MHz): δ 7.40-7.44 (m, 3H), 7.33 (d, J = 6.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 4.18 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.71 (d, J= 5.6 Hz, 5H), 1.83-1.92 (m, 2H), 1.09 (t, J= 7.2 Hz, 3H).

Préparation 86: 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine

A mixture of tert-butyldimethyl((2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)allyl)oxy)silane (Préparation 146, 14.9 g, 50 mmol), 3,5-dibromopyridine (12.4 g, 52.5 mmol), Pd(dppf)CI₂ (1.83 g, 2.5 mmol) and K₂CO₃ (20.7 g, 150 mmol) were suspended in 1,4-dioxane (300 mL) and water (20 mL). The mixture was degassed and heated to about 85 °C for about 5 h under N₂. The mixture was removed from heat and allowed to stand over the weekend. The mixture was concentrated, MTBE (100 mL) was added and stirred for about 20 min. The mixture was filtered and the filter cake was washed with MTBE (50 mL). The combined MTBE filtrâtes were dried and concentrated. The residue was purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:0 to 95:5) to afford 3-bromo-5-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (8.5 g, 51.8%). ¹H NMR (CDCI3, 400 MHz): δ 8.5520225

130

8.63 (m, 2H), 7.84-7.93 (m, 1H), 5.44-5.55 (m, 2H), 4.49 (t, J= 1.5 Hz, 2H), 0.91 (s, 9H), 0.10 (s, 6H). LCMS m/z = 329 [MH]⁺.

Préparation 87: 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine

Br. Æ./ ίγ ¹

A mixture of tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)allyl)oxy)silane (Préparation 146, 4.2 g, 14.08 mmol), 3,5-dibromo-2-methylpyridine (3.71 g, 14.8 mmol), Pd(dppf)CI₂ (1030 mg, 1.41 mmol) and K₂CO₃ (5.84 g, 42.2 mmol) were suspended in 1,4-dioxane (150 mL) and water (5 mL). The mixture was degassed and heated to about 80 °C for about 5 h under N₂. The mixture was concentrated and MTBE (100 mL) was added, stirring for about 20 min. The mixture was filtered and the filter cake was washed with MTBE (50 mL). The combined MTBE filtrâtes were concentrated and the residue was purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:0 to 95:5) to afford 3-bromo-5-(3((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine (930 mg, 19.3%). ¹H NMR (CDCI₃, 400 MHz): δ 8.46-8.53 (m, 1H), 7.86 (d, J= 2.0 Hz, 1H), 5.41-5.50 (m, 2H), 4.43-4.54 (m, 2H), 2.66 (s, 3H), 0.92 (s, 9H), 0.10 (s, 6H).

Préparation 88: 1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one

A solution of 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one (Préparation 237, 977 mg, 4.52 mmol) and DCM (30 mL) cooled to about 0 °C, was added imidazole (770 mg, 11.3 mmol) and TBS-CI (750 mg, 4.97 mmol). The mixture was stirred at about 0 °C for about 2.5 h. The reaction was quenched with water and the layers were separated. The DCM layer was washed with water and brine. The DCM layer was passed through through a pad of MgSO₄ and silica gel. The filtrate was concentrated to afford 1-(6-bromopyridin-2-yl)-2-((tertbutyldimethylsilyl)oxy)ethan-1-one (1.35 g, 90%). ¹H NMR (CDCI₃, 400 MHz): δ 7.93-8.04 (m, 1H), 7.62-7.78 (m, 2H), 5.21 (s, 2H), 0.97 (s, 9H), 0.15 (s, 6H).

131

Préparation 89: 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1en-2-yl)-2-chloropyrimidme

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2chloropyrimidine (0.9 g, 34%) was prepared in an analogous manner to Préparation 50 using 4(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine (Préparation 230, 1.65 g, 5.5 mmol) and K3PO4 as base. Ή NMR (CDCh, 400 MHz): δ 7.63 (s, 1 H), 6.23 (d, J = 1.5 Hz, 1 H), 5.87 (d, J = 1.5 Hz, 1 H), 4.76 (d, J = 1.0 Hz, 2H), 4.62-4.66 (m, 2H), 0.97-0.99 (m, 9H), 0.94 (s, 9H), 0.12-0.16 (m, 12H). LCMS m/z = 429 [MH]⁺.

Préparation 90: 4-(3-((tert-butyldimethylsilyl)oxy)prop-1 -en-2-yl)-2-chloro-6(trifluoromethyl)pyrimidine

4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine (1.33 g, 66%) was prepared in an analogous manner to Préparation 50 using 2,4-dichloro-6(trifluoromethyl)pyrimidine (CAS 16097-64-6, 1.24 g, 5.72 mmol) and substituting K3PO4 (4.57 g, 17.1 mmol) for K₂CO₃. Ή NMR (CDCh, 400MHz): δ 7.77 (s, 1H), 6.38-6.39 (m, 1H), 5.99-6.00 (m, 1H), 4.65 (t, J = 1.5Hz, 2H), 0.92-0.94 (m, 9H), 0.13 (s, 6H). LCMS m/z = 353 [MH]⁺.

Préparation 91a: 3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine

A mixture of 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (Préparation 91b, 12.20 g, 41.48 mmol), Pin₂B₂ (21.07 g, 82.96 mmol), KOAc (8.14 g, 82.96 mmol) and Pd(dppf)CI₂ (607 mg, 830 umol) in 1,4-dioxane (500 mL) was degassed and stirred at about 110 °C for about 4 h under

132

N₂. The mixture was concentrated and the residue was purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:1 to 10:1) to afford 3-(3,4-dimethoxyphenyl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.00 g, 42%). ¹H NMR (CDCh, 400 MHz):

8.97 (d, J = 2.3 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.14 (s, 1H), 7.27 (s, 1 H), 7.22-7.26 (m, 1H),

7.06 (d, J= 8.3 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 1.33 (s, 13H).

Préparation 91b: 3-bromo-5-(3,4-dimethoxyphenyl)pyridine

A mixture of 3,5-dibromopyridine (17.90 g, 75.56 mmol), (3,4-dimethoxyphenyl) boronic acid (CAS 122775-35-3, 12.50 g, 68.69 mmol), Na₂CO₃ (10.92 g, 103.0 mmol), KOAc (10.11 g, 103.03 mmol) and Pd(dppf)CI₂ (1.01 g, 1.37 mmol) in 1,4-dioxane (20 mL) was degassed and stirred at about 90 °C for about 8 h under N₂. The mixture was filtered and concentrated The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (20:1 to 1:1) to afford 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (20.2 g, 59%). ¹H NMR (DMSO-ch, 400 MHz): 5 8.88 (d, J = 1.8 Hz, 1 H), 8.61 (d, J = 1.8 Hz, 1 H), 8.35 (t, J = 2.0 Hz, 1 H), 7.28-7.35 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H). LCMS m/z = 294 [MH]⁺.

Préparation 92: 3-Bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine

A mixture of 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 113, 20.0 g, 71.9 mmol), 3,5-dibromopyridine (34.07 g, 143.8 mmol), K₂CO₃ (19.87 g, 143.8 mmol), KOAc (10.58 g, 107.9 mmol) and Pd(dppf)CI₂ (2.10 g, 2.88 mmol) in 1,4dioxane (600 mL) and water (10 mL) was degassed and heated to about 100 °C for about 5 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to afford 3-bromo-5-(3-ethoxy-4methoxyphenyl)pyridine (20 g, 90%). ¹H NMR (CDCh, 400MHz): 5 8.71 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.11 (dd, J = 2.0, 8.4 Hz, 1H), 7.05 (s, 1H), 6.97 (t, J = 4.0 Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H), 3.92 (s, 3H), 1.49 (t, J = 6.8 Hz, 3H).

133 ‘ Préparation 93a: 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine \ JL^L^^/Br ^ilT

LL

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 114, 28.00 g, 95.83 mmol), 3,5-dibromopyridine (45.40 g, 191.66 mmol), K2CO3 (19.87 g, 5 143.75 mmol), KOAc (14.11 g, 143.75 mmol) and Pd(dppf)CI₂ (3.51 g, 4.79 mmol) in 1,4dioxane (600 mL) and water (10 mL) was degassed and heated to about 100 °C for about 5 h under N2. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to afford 3-bromo-5-(4-methoxy3-propoxyphenyl)pyridine (15.00 g, 49%). ¹H NMR (CDCh, 400MHz): δ 8.72 (d, J = 2.0 Hz, 1H), 10 8.61 (d, J= 2.0 Hz, 1H), 7.97 (t, J= 2.0 Hz, 1H), 7.12 (dd, J= 2.0, 8.4 Hz, 1H), 7.06 (d, J= 2.4

Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.06 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.87-1.96 (m, 2H), 1.08 (t, J= 7.2 Hz, 3H).

Préparation 93b: 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation

114, 10.6 g, 36.3 mmol), 2,6-dibromopyridine (9.0 g, 38.0 mmol), K3PO4 (16.1 g, 76.0 mmol) and Pd(dppf)CI₂ (1.55 g, 1.90 mmol) in dioxane (6 mL) and water (1.5 mL) was degassed and heated to about 80 °C overnight. The mixture was diluted with brine (150 mL) and EtOAc (150 mL). The layers were separated and the EtOAc layer was washed with brine (75 mL), dried over 20 Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 3:1) to afford 2-bromo-6-(4-methoxy-3propoxyphenyl)pyridine (5.34 g, 44%). ¹H NMR (CDCh, 400MHz): δ 7.81-8.72 (m, 2H), 7.517.57 (m, 2H), 7.35 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.11 (t, J= 6.6 Hz, 2H), 3.93 (s, 3H), 1.86-1.97 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H).

Préparation 94: 3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine

3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (1.15 g, 52%) was prepared in an analogous manner to Préparation 93a using 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,520225

134 tetramethvl-1,3,2-dioxaborolane (Préparation 115, 2 g, 6.8 mmol) at about 120 °C for about 2 h.

Ή NMR (CDCh, 400 MHz): δ 8.71 (d, J= 1.5 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.95-7.98 (m, 1H), 7.12-7.16 (m, 1H), 7.09 (d, J =2.5 Hz, 1H), 6.99 (d, J =8.5 Hz, 1H), 4.58-4.67 (m, 1H), 3.92 (s, 3H), 1.42 (d, J = 6.0 Hz, 6H). LCMS m/z = 323 [MH]⁺.

Préparation 95: 3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (860 mg, 52%) was prepared in an analogous manner to Préparation 93a using 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Préparation 117, 1.5 g, 5.2 mmol) at about 120 °C for about 2 h. ¹H NMR (CDCh, 400 MHz): δ 8.74 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.5 Hz, 1H), 7.99 (t, J = 2.2 Hz, 1H), 7.43 (d, J =2.0 Hz, 1H), 7.14 (dd, J = 2.5, 8.3 Hz, 1H), 6.97 (d, J= 8.3 Hz, 1H), 3.92 (s, 3H), 3.81-3.87 (m, 1H), 0.83-0.96 (m, 4H). LCMS m/z = 321 [MH]⁺.

Préparation 96: 3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine 3-bromo5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine (6.8 g, 32%) was prepared in an analogous manner to Préparation 93a using tert-butyl(2-(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)dimethylsilane (Préparation 120, 20 g, 49 mmol) at about 120 °C for about 3 h. ¹H NMR (CDCh, 400 MHz): δ 8.69-8.78 (m, 1H), 8.61 (d, J= 2.2 Hz, 1H), 7.97 (t, J = 2.1 Hz, 1H), 7.13 (qd, J = 2.2, 4.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 1H), 4.16-4.23 (m, 2H), 4.02-4.09 (m, 2H), 3.92 (s, 3H), 0.88-0.93 (m, 9H), 0.10 (s, 6H). LCMS m/z = 439 [MH]⁺.

135

Préparation 97: 3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4methoxyphenyl)pyridine

3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12.4 g, 5 64%) was prepared in an analogous manner to Préparation 93a using tert-butyl(3-(2-methoxy-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane (Préparation 121, 18 g, 42.6 mmol). Ή NMR (CDCh, 400 MHz): δ 8.68 (d, J = 2.0 Hz, 1H), 8.58 (d, J= 2.5 Hz, 1H), 7.94-8.01 (m, 1H), 7.10 (dd, J = 2.5, 8.3 Hz, 1H), 7.07 (d, J = 2.0Hz, 1 H), 6.96 (d, J=8.3 Hz, 1H), 4.19 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.80-3.86 (m, 2H), 2.03-2.11 (m, 2H), 0.85-0.90 (m, 9H), 0.04 (s, 6H). LCMS m/z = 454 [MH]⁺.

Préparation 98: 3-bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-Bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (1.8 g, 74%) was prepared in an analogous manner to Préparation 93a using 2-(3-(2-fluoroethoxy)-4-methoxyphenyl)-4,4,5,515 tetramethyl-1,3,2-dioxaborolane (Préparation 122, 2.2 g, 7.4 mmol) at about 120 °C for about 2 h. Ή NMR (CDCh, 400 MHz): δ 8.68-8.76 (m, 1H), 8.58-8.65 (m, 1H), 7.97 (t, J= 2.3 Hz, 1H), 7.18 (dd, J = 2.0, 8.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.00 (d, J= 8.5 Hz, 1H), 4.83-4.92 (m, 1 H), 4.72-4.81 (m, 1 H), 4.37-4.44 (m, 1 H), 4.25-4.36 (m, 1 H), 3.88-3.97 (m, 3H). LCMS m/z = 325 [MH]⁺.

Préparation 99: 3-bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine

3-Bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared in an analogous manner to Préparation 93a using 2-(3-(3-fluoropropoxy)-4-methoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Prpeartion 123).

136

Préparation 100: 3-bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

3-Bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (1000 mg, 28%) was prepared in an analogous manner to Préparation 93a using 2-(2-(difluoromethyl)-3-ethoxy-45 methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 127, 4.09g, 12.46 mmol) heated to about 100 °C for about 15 h. ¹H NMR (400 MHz, CDCI₃): δ 8.67 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 1.5 Hz, 1H), 7.86 (t, J= 2.0 Hz, 1H), 6.84-7.13 (m, 4H), 4.17 (q, J = 7.4 Hz, 2H), 3.93 (s, 3H), 1.42 (t, J =7.0 Hz, 3H). LCMS m/z = 359 [MH]⁺.

Préparation 101: 3-bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-Bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (350 mg, 27%) was prepared as in an analogous manner to Préparation 93a using 2-(5-ethoxy-2-fluoro-4-methoxyphenyl)4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Préparation 134, 1.2 g, 4.05 mmol). ¹H NMR (CDCh, 400MHz): δ 8.68 (t, J= 1.7 Hz, 1H), 8.63 (d, J= 2.1 Hz, 1H), 7.98-8.00 (m, 1H), 6.88 (d, J= 7.3 15 Hz, 1H), 6.75 (d, J= 11.7 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 1.49 (t, J= 7.0 Hz, 3H). LCMS m/z = 327 [MH]⁺.

Préparation 102: 3-bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-Bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (3.4 g, 31%) was prepared as 20 in an analogous manner to Préparation 93a using 2-(2-fluoro-4-methoxy-5-propoxyphenyl)4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 138, 10 g, 32 mmol). ¹H NMR (CDCI3, 400MHz): δ 8.68 (t, J = 1.5 Hz, 1 H), 8.63 (d, J = 2.4 Hz, 1 H), 7.99 (q, J = 2.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1H), 6.75 (d, J= 11.7 Hz, 1H), 4.00 (t, J= 6.8 Hz, 2H), 3.91 (s, 3H), 1.84-1.93 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H). LCMS m/z = 339 [MH]⁺.

137

Préparation 103: 5'-chloro-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine

5'-Chloro-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (3.11 g, 78%) was prepared in an analogous manner to Préparation 93a using 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine (Préparation 220, 4.18 g, 13.44 mmol) and (5-chloropyridin-3-yl)boronic acid (2.11 g, 13.4 mmol) at about 90 °C for about 16 h. ¹H NMR (CDCb, 400MHz): δ 9.13 (s, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.27 (t, J= 2.1 Hz, 1H), 6.97 (d, J= 11.5 Hz, 1H), 4.43 (t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 1.86-1.95 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). LCMS m/z = 328 [MH]⁺.

Préparation 104: 2-bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-Bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine (2.9 g, 52%) was prepared in an analogous manner to Préparation 93a using 2-(3-ethoxy-2-fluoro-4-methoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Préparation 113, 5 g, 18 mmol) and 2,6-dibromopyrazine (6.4 g, 27 mmol) at about 110 °C for about 16 h. ¹H NMR (CDCb, 400MHz): δ 8.86-8.92 (m, 1H),

8.53 (s, 1H), 7.61 (d, J= 2.0 Hz, 1H), 7.57 (dd, J= 2.2, 8.3 Hz, 1H), 6.98 (d, J= 8.3 Hz, 1H),

4.23 (q, J = 6.9 Hz, 2H), 3.95 (s, 3H), 1.53 (t, J = 7.0 Hz, 3H). LCMS m/z = 309 [MH]⁺.

Préparation 105: ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

POCb(253 mL, 2716 mmol) was added to ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-620 oxo-1,6-dihydropyrimidin-4-yl)acetate (Préparation 106, 42.98 g, 124.08 mmol), followed by pyridine hydrochloride (14.3 g, 124 mmol) at about 25 °C. The resulting mixture was heated to about 80 °C for about 0.5 h. The mixture was diluted with EtOAc (200 mL) and added into water dropwise. The EtOAc layer was treated with NaHCO₃. The EtOAc layer was washed with brine,

138 f dried with Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on a reversed-phase column eluting with MeCN/water (0:100 to 100:0) to afford ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (22.07 g, 49%). ¹H

NMR (CDCh, 400MHz): δ 8.08 (dd, J = 2.1, 8.4 Hz, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.20 (s, 1H),

6.95 (d, J = 8.6 Hz, 1 H), 4.24 (q, J = 7.2 Hz, 2H), 4.11 (t, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.85 (s,

2H), 1.89-1.96 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H). LCMS m/z = 365 [MH]⁺.

Préparation 106: ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4yl)acetate

A mixture of 4-methoxy-3-propoxybenzimidamide (Préparation 233, 25.3 g, 121 mmol),

NaHCO₃(12.2 mg, 146 mmol) and diethyl 1,3-acetonedicarboxylate (CAS 105-50-0, 29.4 g, 146 mmol) in EtOH (500 mL) was stirred at about 100 °C for about 24 h. The mixture was filtered, and the filter cake was washed with MTBE (200 mL), MeOH (100 mL) and DCM (50 mL) to afford ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate (34.34 g,

82%). Ή NMR (CDCh, 400MHz): δ 12.44 (br s, 1H), 7.73-7.86 (m, 2H), 6.99 (d, J= 8.3 Hz, 1H),

6.33 (s, 1H), 4.23 (q, J= 7.3 Hz, 2H), 4.16 (t, J= 6.9 Hz, 2H), 3.96 (s, 3H), 3.66 (s, 2H), 1.921.97 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.10 (t, J= 7.5 Hz, 3H). LCMS m/z = 346 [MH]⁺.

Préparation 107: 5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (2.9 g, 52%) was prepared in an analogous manner to Préparation 93a using 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Préparation 114, 4.3 g, 14.7 mmol) and 3,5-dichloropyridazine (2.3 g, 15.5 mmol). Ή NMR (CDCh, 400 MHz): δ 9.08 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 2.5 Hz, 2H), 7.51 (dd, J = 2.2, 8.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.95 (s,

3H), 1.92-1.97 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). LCMS m/z = 278 [MH]⁺.

139

Préparation 108: 3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (0.82 g, 35%) was prepared in an analogous manner to Préparation 93a using 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (Préparation 113, 2.0 g, 7.19 mmol) and 3,5-dibromo-4methylpyridine (2.71 g, 10.8 mmol) at about 120 °C for about 2 h. ¹H NMR (CDCh, 400MHz): δ 8.61 (s, 1H), 8.32 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.81-6.83 (m, 1H), 6.78 (d, J = 2.3 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 2.34 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H). LCMS m/z = 323 [MH]⁺.

Préparation 109: 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole

To a mixture of Pd(OAc)₂ (CAS 3375-31-3, 40.4 mg, 0.18 mmol) and Xantphos (CAS 161265-03-8, 208.0 mg, 0.36 mmol), stirring for about 10 min., was added 2-(3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Préparation 113, 1.0 g, 3.60 mmol), 2,4-dibromothiazole (0.83 g, 3.42 mmol) and K₃PO₄ (2.44 g, 11.5 mmol). The combined mixture was degassedand heated to about 60 °C for about 16 h. The mixture was concentrated and the residue was purified by column chromatography (silica) eluting with pet. ether:EtOAc (100:0 to 85:15) to afford 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (0.68 g, 60%). ¹H NMR (CDCh, 400MHz): δ 7.51 (d, J = 2.3 Hz, 1H), 7.45 (dd, J= 2.3, 8.3 Hz, 1H), 7.14 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 1.51 (t, J= 7.0 Hz, 3H). LCMS m/z = 315 [MH]⁺.

Préparation 110: ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)propanoate

To a mixture of sodium iodide (1.05 g, 6.98 mmol) and acetone (1.50 mL) was added 2(chloromethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (187 mg, 1.06 mmol) and was stirred at about 20 °C for about 30 min. The mixture was filtered through a pad of Celite® and the filtrate

140 concentrated. The residue was dissolved and concentrated with anhydrous THF (3x5 mL). The residue was dissolved in THF (6.0 mL) and added to a cold suspension of NaH (60% dispersion in minerai oil, 349 mg, 8.73 mmol) and ethyl 2-(6-bromopyridin-2-yl)propanoate (Préparation 111,1.502 g, 5.819 mmol) in THF (13.0 mL), which had been degassed under N₂. The combined mixture was stirred at about 20 °C for about 18 h. The mixture was treated with saturated aqueous NH₄CI and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was dissolved in DMSO (5 mL) and was purified by préparative HPLC (Biotage C18 RP column, 60 g) eluting with MeCN (0.1% NH₄CO₂H)/water (0:100 to 100:0) to afford ethyl 2-(6-bromopyridin-2-yl)-2methyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propanoate (339 mg, 14%). ¹H NMR (CDCh, 500MHz): δ 7.44-7.48 (m, 1H), 7.31 (m, 1H), 7.25-7.29 (m, 2H), 4.15 (q, J= 7.1 Hz, 2H), 1.67-1.70 (m, 3H), 1.54 (s, 2H), 1.23-1.25 (m, 7H), 1.20 (d, J= 3.9 Hz, 13H). LCMS m/z = 399 [MH]⁺.

Préparation 111: ethyl 2-(6-bromopyridin-2-yl)propanoate

To a solution of ethyl 2-(6-bromopyridin-2-yl)acetate (Préparation 112, 5.72 g, 23.4 mmol) in THF (117 mL) cooled to about -78 °C was added a solution of LiHMDS in THF (1.0 M, 29.3 mL, 29.3 mmol). The solution was stirred for about 1 h and iodomethane (3.33 g, 23.4 mmol, 1.46 mL) was added dropwise. The reaction was allowed to warm to about 20 °C over about 19 h. The reaction mixture was diluted with EtOAc. The mixture was washed with saturated aqueous NH₄CI, brine, dried over MgSO₄ and Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 80:20) to afford ethyl 2-(6-bromopyridin-2-yl)acetate (5.06 g, 84%). ¹H NMR (CDCh, 400MHz,): δ 7.50-7.57 (m, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.26-7.31 (m, 1H), 4.19 (q, J= 7.0 Hz, 2H), 3.93 (q, J = 7.0 Hz, 1 H), 1.57 (d, J = 7A Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS m/z = 259 [MH]⁺.

Préparation 112: ethyl 2-(6-bromopyridin-2-yl)acetate

To a solution of 2-bromo-6-methylpyridine (CAS 5315-25-3, 10.2 g, 59.1 mmol) in THF (62 mL) was cooled to about -78 °C under N₂ was added a solution of LDA in THF (2.0 M, 59 mL, 118 mmol) slowly while stirring. The solution was stirred at about -78 °C for about 30 min. To the mixture was added diethyl carbonate (8.6 mL, 70.9 mmol) at about -78 °C. The mixture

141 was allowed to warm to about 20 °C over overnight. The reaction was cooled to about 0 °C and diluted with saturated aqueous NH₄CI solution. The aqueous layer was extracted with DCM and the combined DCM extracts were washed with water, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40) to afford ethyl 2-(6-bromopyridin-2-yl)acetate (7.7 g, 53%). ¹H NMR (CDCI_3i 400MHz,): δ 7.55 (t, J = 7.8 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.28-7.34 (m, 1 H), 4.21 (q, J = 7.2 Hz, 2H), 3.85 (s, 2H), 1.26-1.34 (m, 3H). LCMS m/z = 245 [MH]⁺.

Préparation 113: 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-bromo-2-ethoxy-1-methoxybenzene (Préparation 150, 48.0 g, 207.7 mmol), Pd(dppf)CI₂ (4.56 g, 6.23 mmol), Pin₂B₂ (58.0 g, 228.5 mmol) and KOAc (40.8 g, 415.4 mmol) in 1,4-dioxane (500 mL) was degassed and heated to about 90 °C for about 16 h under N₂. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 2-(3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 g, 86%). ¹H NMR (CDCI3, 400MHz): δ 7.41 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.16 (q, J =7.2 Hz, 2H), 3.90 (s, 3H), 1.47 (t, J= 7.2 Hz, 3H), 1.34 (s, 12H).

Préparation 114: 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-bromo-1-methoxy-2-propoxybenzene (Préparation 151,43.00 g, 175.43 mmol), KOAc (34.43 g, 350.86 mmol), Pin₂B₂ (49.00 g, 192.97 mmol) and Pd(dppf)CI₂ DCM (4.30 g, 5.26 mmol) in 1,4-dioxane (500 mL) was degassed and stirred at about 80 °C for about 16 h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 2(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51.0 g, 99%). ¹H NMR (CDCI3,400 MHz): δ 7.40-7.42 (m, 1 H), 7.30 (d, J = 1.2 Hz, 1 H), 6.89 (d, J = 8.0 Hz, 1 H), 4.03 (t, J = 7.0 Hz, 2H), 3.89 (s, 3H), 1.84-1.93 (m, 2H), 1.34 (s, 12H), 1.05 (t, J = ΊΑ Hz, 3H).

The following compounds were prepared using the appropriate bromide and 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane), following the procedure described in Préparation 114.

142

Préparation No.	Structure/Name	Source	Analytical Data
115	o>O_B-°_Z ⁰ n 2-(3-isopropoxy-4-methoxyphenyl)- 4,4,5,5-tetramethyl-l ,3,2- dioxaborolane	Préparation 152	¹H NMR (CDCb, 400 MHz): δ 7.40-7.44 (m, 1H), 7.33 (d, J= 1.5 Hz, 1H), 6.87-6.91 (m, 1H), 4.62 (td, J = 6.1, 12.2 Hz, 1H), 3.88 (s, 3H), 1.36-1.39 (m, 6H), 1.34 (s, 12H). LCMS m/z = 293 [MH]⁺.
116	oXXb'⁰^ xJ °~7x 2-(3-isobutoxy-4-methoxyphenyl)- 4,4,5,5-tetramethyl-l ,3,2dioxaborolane	Préparation 153	¹H NMR (CDCb, 400 MHz): δ 7.41 (dd, J = 1.2, 8.1 Hz, IH), 7.29 (d, J = 1.0 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.82 (d, J = 6.9 Hz, 2H), 2.16-2.23 (m, 1H), 1.331.37 (m, 12H), 1.05 (d, J = 6.4 Hz, 6H). LCMS m/z = 307 [MH]⁺.
117	oXX-%/ Λ 2-(3-cyclopropoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 154	¹H NMR (CDCb, 400 MHz): δ 7.62 (d, J =1.0 Hz, 1H), 7.40-7.48 (m, 1H), 6.83-6.91 (m, 1H), 3.87 (s, 3H), 3.81-3.86 (m, 1H), 1.33-1.36 (m, 12H), 0.80-0.88 (m, 4H). LCMS m/z = 291 [MH]⁺.

143

118	o-O^_B-o '—s 2-(4-methoxy-3- ((tetrahydrothiophen-3yl)oxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 155	¹H NMR (CDCh, 400 MHz): δ 7.43-7.51 (m, 1H), 7.37 (d, J= 1.5 Hz, 1H), 6.88-6.92 (m, 1H), 5.135.15 (m, 1H), 3.87 (s, 3H), 3.09-3.18 (m, 3H), 2.89-2.96 (m, 1H), 2.392.47 (m, 1H), 2.04-2.07 (m, 1H), 1.34 (s, 12H). LCMS m/z = 337 [MH]⁺.
119	ύ A 2-(4-methoxy-3-((tetra hyd ro-2 Hthiopyran-4-yl)oxy)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane	Préparation 156	¹H NMR (CDCh, 400 MHz): 6 7.41-7.48 (m, 1H), 7.32 (d, J= 1.5 Hz, 1H), 6.86-6.93 (m, 1H), 4.264.37 (m, 1H), 3.86 (s, 3H), 2.87-3.01 (m, 2H), 2.512.62 (m, 2H), 2.13-2.25 (m, 2H), 1.98-2.10 (m, 2H), 1.29-1.36 (m, 12H).
120	Ο—/ tert-butyl(2-(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)ethoxy)dimethylsilane	Préparation 157	Ή NMR (CDCh, 400 MHz): δ 7.42 (dd, J= 1.5, 7.8 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 6.86-6.90 (m, 1H), 4.10-4.18 (m, 2H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 1.34 (s, 12H), 0.900.92 (m, 9H), 0.09-0.11 (m, 6H). LCMS m/z = 409 [MH]⁺.

144

121	>u. Y । ο-/ tert-butyl(3-(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)propoxy)dimethylsilane	Préparation 158	^XH NMR (CDCh, 400 MHz): δ 7.40-7.43 (m, 1H), 7.33 (d, J= 1.5 Hz, 1H), 6.86-6.89 (m, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 3.81-3.85 (m, 2H), 2.05-2.09 (m, 2H), 1.34 (s, 12H), 0.90 (s, 9H), 0.050.06 (m, 6H). LCMS m/z = 423 [MH]⁺.
122	o-/ 2-(3-(2-fluoroethoxy)-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 159	Ή NMR (CDCh, 400 MHz): δ 7.46 (dd, J= 1.5, 7.8 Hz, 1H), 7.32 (d, J = 1.0 Hz, 1H), 6.89-6.93 (m, 1H), 4.83-4.88 (m, 1H), 4.71-4.75 (m, 1H), 4.344.38 (m, 1H), 4.27-4.31 (m, 1H), 3.90 (s, 3H), 1.34 (s, 12H). LCMS m/z = 297 [MH]⁺.
123	O-/ 2-(3-(3-fluoropropoxy)-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 160	Ή NMR (CDCh, 400 MHz): δ 7.44 (dd, J = 1.5, 7.8 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.74 (t, J = 5.9 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 2.27-2.30 (m, 1H), 2.202.23 (m, 1H), 1.32-1.37 (m, 12H). LCMS m/z = 311 [MH]⁺.

145

124	N l /\ o-Z 2-methoxy-3-propoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)pyridine	Préparation 215	¹H NMR (CDCh, 400 MHz): δ 8.12 (d, J= 1.5 Hz, 1H), 7.34 (d, J= 1.5 Hz, 1H), 4.03 (s, 3H), 3.98-4.02 (m, 2H), 1.851.94 (m, 2H), 1.35 (s, 12H), 1.05 (t, J = 7.5 Hz, 3H). LCMS m/z = 294 [MH]⁺.
125	CN O— 2,3-dimethoxy-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile	Préparation 162	1H NMR (CDCh, 400 MHz): δ 7.57 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 4.00-3.96 (m, 3H), 3.93-3.89 (m, 3H), 1.37 (s, 12H).
126	F °~Tx 2-(3-ethoxy-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 170a	¹H NMR (CDCh, 400 MHz): δ 7.35-7.44 (m, 1H), 6.69 (dd, J= 0.9, 8.4 Hz, 1H), 4.07-4.16 (m, 2H), 3.88 (s, 3H), 1.33-1.40 (m, 15H).
127	Β-'θγ^ ' z\ A. o—z F F 2-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 168	Ή NMR (CDCh,400 MHz): δ 7.15-7.18 (m, 1H), 7.11 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.96 (d, J= 1.3 Hz, 3H), 1.46 (t, J= 7.0 Hz, 3H), 1.34 (s, 12H). ¹⁹F NMR (CDCh, 376 MHz): δ -114.25 (brs, 1F). LCMS m/z = 296 [MH]⁺.

146

128	I ' F °-Z 2-(2-fluoro-4-methoxy-3- propoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 170b	LCMS m/z = 311 [MH]⁺.
129	ί II θηχ N ί 3-methoxy-2-propoxy-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile	Préparation 171	Ή NMR (CDCb,400 MHz): δ 7.54 (d, J= 8.1 Hz, 1H), 7.05 (d, J= 8.3 Hz, 1H), 4.06-4.11 (m, 2H), 3.89 (s, 3H), 1.79-1.90 (m, 2H), 1.35-1.38 (m, 12H), 1.031.08 (m, 3H). LCMS m/z = 318 [MH]⁺.
130	/ό^Ρ'β·'⁰ ^ °\ o—2^ 2-(2,4-dimethoxy-3-propoxyphenyl)- 4,4,5,5-tetramethyl-l ,3,2dioxaborolane	Préparation 210	¹H NMR (CDCb, 400 MHz): δ 7.42 (d, J =8.5 Hz, 1H), 6.69 (d, J= 8.3 Hz, 1H), 3.92-3.99 (m, 2H), 3.823.87 (m, 6H), 1.73-1.84 (m, 2H), 1.33-1.38 (m, 12H), 1.00-1.08 (m, 3H). LCMS m/z = 345 [M+Na]⁺.
131	οΑ'_Β·χ CN 2-(cyclopentyloxy)-3-methoxy-6(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)benzonitrile	Préparation 207	¹H NMR (CDCb,400 MHz): δ 7.52 (d, J= 8.3 Hz, 1H), 7.00-7.10 (m, 1H), 4.985.11 (m, 1H), 3.88 (s, 3H), 1.91-2.01 (m, 4H), 1.651.76 (m, 2H), 1.53-1.64 (m, 2H), 1.37 (s, 12H). LCMS m/z = 344 [MH]⁺.

147

132	F I ζ\ °--Ζ 2-(3-ethoxy-5-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 172	¹H NMR (CDCh,400 MHz): δ 7.17 (dd, J= 1.0, 10.5 Hz, 1H), 7.11 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.96 (d, J= 1.0 Hz, 3H), 1.56 (s, 6H), 1.46 (t, J= 7.0 Hz, 3H), 1.34 (s, 12H). LCMS m/z = 297 [MH]⁺.
133	Cl '0·^ l /\ o-Z 2-(3-chloro-5-ethoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 177	¹H NMR (CDCh,400 MHz): δ 7.44 (d, J= 1.0 Hz, 1H), 7.22 (d, J= 1.0 Hz, 1H), 4.10-4.17 (m, 2H), 3.91 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.34 (s, 12H). LCMS m/z = 312 [MH]⁺.
134	l Z\ °-Z 2-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 182	¹H NMR (CDCh, 400 MHz): δ 7.14 (d, J= 5.5 Hz, 1H), 6.59 (d, J = 10.0 Hz, 1H), 4.02-4.16 (m, 2H), 3.86 (s, 3H), 1.40-1.52 (m, 3H), 1.34 (s, 12H). LCMS m/z = 297 [MH]⁺.
135	I z\ o-Z 2-(2-chloro-5-ethoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 183	Ή NMR (CDCh,400 MHz): δ 7.18 (s, 1H), 6.86 (s, 1H), 4.12 (q, J= 7.0 Hz, 2H), 3.87 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.36 (s, 12H). LCMS m/z = 312 [MH]⁺.

148

136	'''θ^Υ-B··⁰ I /\ o-Z 2-(5-ethoxy-4-methoxy-2- methylphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 187	¹H NMR (CDCh,400 MHz): δ 7.28 (s, 1H), 6.69 (s, 1H), 4.13 (q, J = 6.9 Hz, 2H), 3.88 (s, 3H), 2.50 (s, 3H), 1.46 (t, J= 7.1 Hz, 3H), 1.33 (s, 12H). LCMS m/z = 292 [MH]⁺.
137	F ^B θΥ- I । /\ F °< 2-(3-ethoxy-2,6-difluoro-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 193	Ή NMR (CDCh,400 MHz): δ 6.34-6.48 (m, 1H), 4.04 (q, J= 7.0 Hz, 2H), 3.85 (s, 3H), 1.32-1.42 (m, 15H). LCMS m/z = 315 [MH]⁺.
138	o-/ 2-(2-fluoro-4-methoxy-5- propoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane	Préparation 188	Ή NMR (CDCh, 400MHz): δ 7.15 (d, J= 5.9 Hz, 1H), 6.59 (d, J= 10.8 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 1.81-1.90 (m, 2H), 1.25-1.30 (m, 12H), 1.05 (t, J = 7.6 Hz, 3H).
139	ο·'Ο_Βο l /\ ο—Z 2-(4-ethoxy-3-methoxyphenyl)4,4,5,5-tetramethyl-1,3,2dioxaborolane	Préparation 198	Ή NMR (CDCh,400 MHz): δ 7.41 (dd, J= 1.2, 8.1 Hz, 1H), 7.29 (d, J= 1.5 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 1.48 (t, J = 6.9 Hz, 3H), 1.34-1.36 (m, 12H). LCMS m/z = 279 [MH]⁺.

149

140	o'^Qb·⁰ I । z\ F ° K 2-(4-ethoxy-2-fluoro-3- methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 199	¹H NMR (CDCh,400 MHz): δ 7.37 (dd, J= 6.4, 8.3 Hz, 1H), 6.64-6.73 (m, 1H), 4.07-4.18 (m, 2H), 3.90 (d, J= 1.0 Hz, 3H), 1.46 (t, J = 6.9 Hz, 3H), 1.35 (s, 12H). LCMS m/z = 297 [MH]⁺.
141	o-Z 2-(3,4-diethoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane	Préparation 197	¹H NMR (400 MHz, CDCh) δ 7.39 (dd, J= 1.2, 8.1 Hz, 1H), 7.30 (d, J = 1.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.08-4.17 (m, 4H), 1.41-1.49 (m, 6H), 1.33 (s, 12H). LCMS m/z = 293 [MH]⁺.
142	F^F ' z\ O—Z 2-(4-(difluoromethoxy)-3propoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane	Préparation 223	¹H NMR (CDCh,400 MHz): δ 7.40 (d, J = 1.2 Hz, 1H), 7.38 (s, 1H), 7.15 (dd, J = 0.7, 7.6 Hz, 1H), 6.41-6.82 (m, 1H), 4.04 (t, J= 6.5 Hz, 2H), 1.80-1.91 (m, 2H), 1.33-1.37 (m, 12H), 1.06 (t, J= 7.3 Hz, 3H).
143	B-⁰ - I z\ 0—/ 2-(3-methoxy-4-(methylthio)phenyl)4,4,5,5-tetramethyl-l ,3,2dioxaborolane	Préparation 203	Ή NMR (CDCh. 400 MHz): δ 7.43 (dd, J= 1.1, 7.7 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H), 1.35 (s, 12H). LCMS m/z = 281 [MH]⁺.

150

144	I /\ o-Z 2-(3-ethoxy-4-(methylthio)phenyl)- 4,4,5,5-tetramethyl-1,3,2dioxaborolane	Préparation 204	¹H NMR (MeOD-ch, 400 MHz): δ 7.34 (dd, J = 0.7, 7.6 Hz, 1H), 7.19 (s, 1H), 7.12-7.16 (m, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.39 (d, J = 1.0 Hz, 3H), 1.39-1.44 (m, 3H), 1.34 (s, 12H). LCMS m/z = 295 [MH]⁺.
145	_o/O_B·⁰. o % 2-(3-(cyclopentyloxy)-4(methylthio)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane	Préparation 205	Ή NMR (CDCh. 400 MHz): δ 7.39 (dd, J= 1.0, 7.8 Hz, 1H), 7.22 (s, 1H), 7.067.11 (m, 1H), 4.94-4.98 (m, 1H), 2.41 (s, 3H), 1.821.96 (m, 6H), 1.61-1.67 (m, 2H), 1.32-1.37 (m, 12H). LCMS m/z = 335 [MH]⁺.

Préparation 146: tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)allyl)oxy)silane

Method A:

Five reactions were carried out in parallel. A mixture of ((2-bromoallyl)oxy)(tertbutyl)dimethylsilane (Préparation 227, 300 g, 1.19 mol), KOAc (234 g, 2.39 mol), 4,4,4',4^,,5,5,5',5'-octa_methyl-2,2'-bi(1,3,2-dioxaborolane) (333 g, 1.31 mol) and Pd(PPh3)2Ch (16.7 g, 0.023 mol) in 1,4-dioxane (1.5 L) was degassed and stirred at about 80 °C for about 16

h. The solids were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (1:0) to afford tertbutyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (520 g, 30%). GC (Column: Agilent J&W HP-5MS 30M x 0.25 mm ID x 0.25 um film thickness; injector temp. 250 °C; split ratio 100:1 ; ion source temp 230 °C; interface temp. 250 °C; Column temp. 50 °C 1 min to 100 °C @ 30 °C/min to 250 °C @ 10 °C/min.; run time 17.67 min.; Flow rate 1.5 mL/min; RT = 11.67 min. ¹H NMR (CDCh, 400MHz): δ 5.97 (d, J = 1.3 Hz, 1H), 5.88 (td, J = 1.8, 3.9 Hz, 1H), 4.29 (t, J= 2.0 Hz, 2H), 1.21-1.30 (m, 12H), 0.93 (s, 9H), 0.07 (s, 6H).

151

Method B:

To a mixture of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (250 mg, 1.47 mmol), sodium t-butoxide (21.2mg, 0.220mmol), copper (I) chloride (14.5 mg, 0.10 mmol) and 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (410 mg, 1.61 mmol) under N₂ was added dropwise a solution of tBu₃P (1.0M solution in toluene, 0.176 mL, 0.12 mmol) in anhydrous toluene (2.5 mL). MeOH (94 mg, 2.94 mmol) was added to the mixture dropwise and the mixture was stirred at about 20 °C overnight. The reaction was quenched with MeOH (20 mL) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford tert-butyldimethyl((2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)allyl)oxy)silane (2.2 g, 50%). Ή NMR (CDCI₃, 400MHz): δ 5.97 (br s, 1 H), 5.88 (d, J = 1.6 Hz, 1H), 4.29 (s, 2H), 1.25-1.33 (m, 12H), 0.93 (s, 9H), 0.08 (s, 6H).

Préparation 147: tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)but-3-en-2yl)oxy)silane

To a mixture of (but-3-yn-2-yloxy)(tert-butyl)dimethylsilane (CAS 193812-02-1, 10 g, 54.24 mmol), sodium t-butoxide (782 mg, 8.41 mmol), copper (I) chloride (537 mg, 5.42 mmol) and Pin₂B₂ (15.2 g, 59.7 mmol) in toluene (120 mL) under N₂ was added a solution of tBu₃P (13.2 g, 6.51 mmol) in anhydrous toluene (10 mL) drop-wise. MeOH (3.48g, 108 mmol) was added dropwise and the mixture was stirred at about 20 °C for about 16 h. The reaction was quenched with MeOH (10 mL) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 97:3) to afford tertbutyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane (8.2g, 48.4%). Ή NMR (CDCh, 400 MHz): δ 5.88-6.02 (m, 1 H), 5.79 (dd, J = 1.5, 3.5 Hz, 1 H), 4.404.56 (m, 1H), 1.27 (d, J= 3.5 Hz, 12H), 1.24 (d, J= 6.5 Hz, 3H), 0.91 (s, 9H), 0.05 (d, J =5.5 Hz, 6H).

Préparation 148: tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)but-3-en-1yl)oxy)silane

B

I

O o'^Si

152

A mixture of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (Préparation 229, 2.0 g, 7.54 mmol), Pin₂B₂ (2.87 g, 11.3 mmol) and KOAc (0.74g, 7.54mmol) was suspended in anhydrous 1,4-dioxane (10 mL). The mixture was degassed for about 10 min at about 18 °C under N₂. Pd(PPh₃)₂Cl2 (106 mg, 0.15 mmol) was added and the mixture was heated to about 90 °C for 16 h. The reaction was cooled to about 20 °C and filtered. The filter cake was washed with 1,4-dioxane and the combined filtrâtes were concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 80:20) to afford tertbutyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (1.15 g, 49%). LCMS m/z = 313 [MH]⁺.

Préparation 149: 2,2'-(ethane-1,1 -diyl)bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolane)

A mixture of 1,1-dibromoethane (14.9 g, 58.6 mmol), lithium methoxide (3.03 g, 79.8 mmol) and copper (I) iodide (5.07 g, 26.6 mmol) was suspended in DMF (150 mL) under N₂. Additional lithium methoxide (5.0 g, 2.43 mL) in DMF (10 mL) was added to the mixture. The reaction mixture was warmed to about 40 °C and stirred for about 48 h under N₂. The solution was cooled to to about 20 °C and extracted with heptane (3 x 300 mL). The heptane extracts were washed with water (100 mL), brine (100 mL) and passed through a pad of MgSO₄ and silica gel. The pad was washed with DCM (100 mL). The combined filtrâtes were concentrated. The residue was purified by column chromatography (silica) and eluted with DCM to afford 2,2'(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.6 g, 48%). ¹H NMR (CDCI₃, 400 MHz): δ 1.23 (d, J = 3.1 Hz, 24H), 1.05 (d, J = 7.4 Hz, 3H), 0.72 (q, J = 7.0 Hz, 1H).

Préparation 150: 4-bromo-2-ethoxy-1-methoxybenzene

A mixture of 5-bromo-2-methoxyphenol (40.0 g, 197.0 mmol), iodoethane (23.6 mL, 295.5 mmol) and Cs₂CO₃ (96.3 g, 295.5 mmol) in DMF (350 mL) was stirred at about 25 °C for about 16 h. The mixture was filtered and water (500 mL) was added to the filtrate. The mixture was extracted with EtOAc (2 x 400 mL). The combined EtOAc extracts were washed with brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 4-bromo-2-ethoxy-1methoxybenzene (48.0 g), which was used directly in the next step. ¹H NMR (CDCb, 400MHz):

153 δ 7.02 (dd, J = 2.4, 8.4 Hz, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 6.76-6.73 (m, 1 H), 4.08 (q, J = 7.2 Hz,

2H), 3.88 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H).

Préparation 151: 4-bromo-1-methoxy-2-propoxybenzene

To a solution of 5-bromo-2-methoxyphenol (40.0 g, 197.0 mmol) and K2CO3 (54.5 g, 394 mmol) in DMF (200 mL) was added 1-iodopropane (28.9 mL, 295 mmol) in portions at about 20 °C. The mixture was stirred at about 20 °C for about 1 h. The mixture was poured into ice water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined EtOAc extracts were washed with brine (200 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (40:1) to afford 4-bromo-1-methoxy-2propoxybenzene (43.0 g, crude). ¹H NMR (CDCI3, 400 MHz): δ 7.27 (s, 1H), 6.99-7.03 (m, 1H), 6.74 (d, J = 8.4 Hz, 1 H), 3.96 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 1.83-1.92 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H).

Préparation 152: 4-bromo-2-isopropoxy-1-methoxybenzene

4-bromo-2-isopropoxy-1-methoxybenzene (16 g, 95%) was prepared in an analogous manner to Préparation 150 using 2-bromopropane (12.7 g, 103.4 mmol). ¹H NMR (CDCI₃, 400 MHz): δ 7.00-7.05 (m, 2H), 6.75 (d, J = 8.3 Hz, 1 H), 4.50-4.54 (m, 1 H), 3.83 (s, 3H), 1.35-1.40 (m, 6H). LCMS m/z = 245 [MH]⁺.

Préparation 153: 4-bromo-2-isobutoxy-1-methoxybenzene

To a solution of 5-bromo-2-methoxyphenol (25 g, 120 mmol), 2-methylpropan-1-ol (11.0 g, 148 mmol), PPh₃ (48.4 g, 185 mmol) in anhydrous DCM (400 mL) at about 0 °C was added DIAD (37.3 g, 185 mmol) dropwise under N₂. The mixture was stirred at about 0 °Cfor about 2 h. Additional DIAD (2.53 g, 12.5 mmol) and 2-methylpropan-1-ol (1.03 g, 13.9 mmol) were added and the mixture was stirred at about 10 °C for about 5 days then filtered. The filtrate was concentrated under reduced pressure. MTBE (500 mL) was added and the mixture was stirred at about 10 °C for about 20 min. A white precipitate was filtered. The filtrate was concentrated.

154

The residue was dissolved in water (200 mL) and extracted with MTBE (2 x 300 mL). The combined MTBE extracts were concentrated and the residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:1 to 90:10) to afford 4-bromo-2isobutoxy-1-methoxybenzene (22 g, 69%). ¹H NMR (CDCh, 400 MHz): δ 6.99-7.03 (m, 1H), 6.96-6.99 (m, 1H), 6.74 (d, J= 8.5 Hz, 1H), 3.84 (s, 3H), 3.75 (d, J = 7.0 Hz, 2H), 2.11-2.22 (m, 1H), 1.04 (d, J = 6.5 Hz, 6H).

Préparation 154: 4-bromo-2-cyclopropoxy-1-methoxybenzene

4-bromo-2-cyclopropoxy-1-methoxybenzene (6.15 g, 64%) was prepared in an analogous manner to Préparation 150 using bromocyclopropane (8.0 g, 39 mmol). ¹H NMR (CDCh, 400 MHz): δ 7.36 (d, J = 2.5 Hz, 1 H), 7.05 (dd, J = 2.5, 8.5 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 3.70-3.77 (m, 1H), 0.80-0.90 (m, 4H).

Préparation 155: 3-(5-bromo-2-methoxyphenoxy)tetrahydrothiophene

To a solution of 5-bromo-2-methoxyphenol (1.6 g, 7.88 mmol), tetrahydrothiophen-3-ol (0.903 g, 8.67 mmol), PPh₃ (3.10 g, 11.8 mmol) in anhydrous DCM (20 mL) at about 0 °C was added DIAD (2.39 g, 11.8 mmol) dropwise under N₂. The mixture was stirred at about 0 °C for about 2 h. The mixture was stirred for about 3 days. The mixture was filtered and the filtrate was concentrated. To the residue was added MTBE (50 mL) and stirred at about 10 °C for about 20 min. A white precipitate was filtered. The filtrate was concentrated again. The residue was dissolved in water (20 mL) and extracted with MTBE (2 x 30mL). The combined MTBE extracts were concentrated and the residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:1 to 90:10) to afford 3-(5-bromo-2methoxyphenoxy)tetrahydrothiophene (2.0 g, 88%). ¹H NMR (CDCh, 400 MHz): δ 7.05-7.11 (m, 2H), 6.74-6.79 (m, 1H), 5.06-5.09 (m, 1H), 3.82 (s, 3H), 3.04-3.15 (m, 3H), 2.93 (ddd, J = 3.7,

7.3, 10.5 Hz, 1H), 2.38-2.47 (m, 1H), 2.03-2.05 (m, 1H).

155

Préparation 156: 4-(5-bromo-2-methoxyphenoxy) tetrahydro-2H-thiopyran

4-(5-bromo-2-methoxyphenoxy) tetrahydro-2H-thiopyran (5.1 g, 68%) was prepared in an analogous manner to Préparation 155 using tetrahydro-2H-thiopyran-4-ol (3.2 g, 27.1 mmol). Ή NMR (CDCI₃, 400 MHz): δ 7.03-7.08 (m, 1H), 7.01 (d, J= 2.5 Hz, 1H), 6.73-6.77 (m, 1H), 4.21-4.29 (m, 1H), 3.81-3.84 (m, 3H), 2.87-2.96 (m, 2H), 2.52-2.62 (m, 2H), 2.15-2.25 (m, 2H), 1.98-2.08 (m, 2H).

Préparation 157: (2-(5-bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane . 0..-C1 \ .Si O Br

X ¹ (2-(5-bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane (60 g, 86%) was prepared in an analogous manner to Préparation 155 using 2-((tert-butyldimethylsilyl)oxy)ethan1-ol (34 g, 190 mmol). Ή NMR (CDCI3, 400 MHz): δ 7.07 (d, J= 2.2 Hz, 1H), 7.00-7.05 (m, 1H), 6.71-6.76 (m, 1H), 4.06-4.11 (m, 2H), 3.96-4.02 (m, 2H), 3.81-3.85 (m, 3H), 0.88-0.93 (m, 9H), 0.08-0.12 (m, 6H).

Préparation 158: (3-(5-bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane

Ai, Xa (3-(5-bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane (19.8 g, 86%) was prepared in an analogous manner to Préparation 155 using 3-((tertbutyldimethylsi!yl)oxy)propan-1-ol (Préparation 236, 12.5 g, 61.6 mmol). ¹H NMR (CDCI₃, 400 MHz): δ 6.99-7.03 (m, 2H), 6.71-6.75 (m, 1H), 4.08-4.13 (m, 2H), 3.83 (s, 3H), 3.81 (t, J= 5.9 Hz, 2H), 2.00-2.07 (m, 2H), 0.88-0.91 (m, 9H), 0.04-0.07 (m, 6H).

Préparation 159: 4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene

156

4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene (12 g, 98%) was prepared in an analogous manner to Préparation 155 using 2-fluoroethan-1-ol (3.79 g, 59 mmol). ¹H NMR (CDCb, 400 MHz): δ 7.08 (dd, J = 2.5, 8.8 Hz, 1 H), 7.03 (d, J = 2.5 Hz, 1 H), 6.75-6.79 (m, 1 H), 4.82-4.87 (m, 1H), 4.71-4.74 (m, 1H), 4.27-4.31 (m, 1H), 4.20-4.24 (m, 1H), 3.86 (s, 3H).

Préparation 160: 4-bromo-2-(3-fluoropropoxy)-1-methoxybenzene

4-bromo-2-(3-fluoropropoxy)-1-methoxybenzene (10 g, 100%) was prepared in an analogous manner to Préparation 155 using 3-fluoropropan-1-ol (3.69 g, 47.3 mmol). ¹H NMR (CDCb, 400 MHz): δ 7.03-7.07 (m, 1 H), 7.01-7.03 (m, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 4.72 (t, J = 5.6 Hz, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.13 (t, J = 6.1 Hz, 2H), 3.84 (s, 3H), 2.26-2.28 (m, 1H), 2.19-2.22 (m, 1H).

Préparation 161: 1-bromo-2-fluoro-3,4-dimethoxybenzene

F

A mixture of 1-fluoro-2,3-dimethoxybenzene (35.0 g, 224.1 mmol) and NBS (43.9 g, 246.6 mmol) in DCM (300 mL) was degassed and stirred at about 15 °C for about 12 h under N₂. The reaction mixture was quenched with water (300 mL) and extracted with DCM (2 x 300 mL). The combined DCM extracts were washed with brine (2 x 100 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 1-bromo-2-fluoro-3,4-dimethoxybenzene (35.0 g, 66%). Ή NMR (CDCb, 400MHz): δ 7.17-7.21 (m, 1H), 6.60-6.63 (m, 1H), 3.93 (s, 3H), 3.87 (s, 3H).

Préparation 162: 6-bromo-2,3-dimethoxybenzonitrile

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde oxime (Préparation 163, 30.0 g, 115 mmol) in DCM (500 mL) was added TFAA (24.0 mL, 173 mmol) and Et₃N (48.0 mL, 346.0

157

F mmol). The mixture was stirred at about 20 °C for about 2 h. The mixture was quenched with water (200 mL) at about 0 °C and extracted with DCM (300 mL). The combined DCM extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1 to 3:1) to afford 65 bromo-2,3-dimethoxybenzonitrile (25.0 g, 90%). ¹H NMR (CDCb, 400MHz): δ 7.34-7.29 (m, 1H), 6.99 (d, J = 8.8 Hz, 1 H), 4.04-4.01 (m, 3H), 3.90-3.88 (m, 3H).

Préparation 163: 6-bromo-2,3-dimethoxybenzaldehyde oxime ^O^y^Br

Ή OH

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde (Préparation 164, 15.0 g, 61.2 mmol) in EtOH (150 mL) was added NaHCO₃ (7.7 g, 91.8 mmol) and NH₂OH HCI (6.4 g, 91.8 mmol). The mixture was stirred at about 20 °C for about 2 h. The mixture was quenched by the addition of water (300 mL) at about 0 °C and extracted with EtOAc (200 mL). The EtOAc layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 6-bromo-2,3dimethoxybenzaldehyde oxime (15.0 g), which was used in Préparation 162. ¹H NMR (CDCb,

400MHz): δ 7.27-7.34 (m, 1H), 6.99 (d, J= 9.2 Hz, 1H), 4.00-4.03 (m, 3H), 3.87-3.90 (m, 3H).

Préparation 164: 6-bromo-2,3-dimethoxybenzaldehyde

O'^T^Br । L

6-bromo-2,3-dimethoxybenzaldehyde (35.0 g, 82.5%) was prepared in an analogous manner to Préparation 172 using 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Préparation 165, 20 40 g, 173.1 mmol) and iodomethane (36.8 g, 259.7 mmol). ¹H NMR (CDCb, 400MHz): δ 10.35 (s, 1H), 7.33-7.37 (m, 1H), 6.97 (d, J= 8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H).

Préparation 165: 6-bromo-2-hydroxy-3-methoxybenzaldehyde

158

To a solution of 3-bromo-2-formyl-6-methoxyphenyl acetate (Préparation 166, 40.0 g,

146.5 mmol) in MeOH (400 mL) and water (50 mL) was added NaHCO₃ (13.5 g, 161.1 mmol) and LiOH (12.3 g, 293.0 mmol). The mixture was stirred at about 20 °C for about 12 h. The reaction was adjusted to pH 5-6 and extracted with DCM. The DCM layer was concentrated to afford 6-bromo-2-hydroxy-3-methoxybenzaldehyde (40.0 g), which was used in Préparation 164. ¹H NMR (CDCh, 400MHz): δ 12.21 (s, 1H), 10.22 (s, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.81-3.85 (m, 3H).

Préparation 166: 3-bromo-2-formyl-6-methoxyphenyl acetate

To a solution of 2-formyl-6-methoxyphenyl acetate (Préparation 167, 50.0 g, 257.5 mmol) in water (500 mL) was added Br₂ (53.5 g, 334.7 mmol) and KBr (46.0 g, 386.2 mmol). The mixture was stirred at about 20 °C for about 10 h. The precipitate was filtered, rinsed with ethyl acetate and recrystallized from EtOAc/pet. ether to afford 3-bromo-2-formyl-6methoxyphenyl acetate (40.0 g, 57%). Ή NMR (CDCh, 400MHz): δ 10.28 (s, 1H), 7.53 (d, J = 8.8 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 3.87 (s, 3H), 2.40 (s, 3H).

Préparation 167: 2-formyl-6-methoxyphenyl acetate

To a solution of 2-hydroxy-3-methoxybenzaldehyde (50.0 g, 328.6 mmol) in DCM (200 mL) was added Ac₂O (33.5 g, 329 mmol), DMAP (4.0 g, 32.8 mmol) and Et₃N (33.2 g, 329 mmol). The mixture was stirred at about 20 °C for about 2 h. The reaction mixture was quenched with saturated aqueous NH4CI (100 mL) and extracted with DCM (2 x 100 mL). The combined DCM extracts were washed with HCl (100 mL, 1 M), brine (300 mL), dried over Na₂SO₄, filtered and concentrated to afford 2-formyl-6-methoxyphenyl acetate (60.0 g, 94%). ¹H NMR (CDCh, 400MHz): δ 10.12-10.17 (m, 1H), 7.46 (dd, J= 1.6, 7.8 Hz, 1H), 7.34 (t, J= 8.0 Hz, 1H), 7.22 (dd, J = 1.6, 8.2 Hz, 1H), 3.88 (s, 3H), 2.41 (s, 3H).

159

Préparation 168:1 -bromo-2-(difluoromethyl)-3-ethoxy-4-methoxybenzene

To a mixture of DAST (CAS 38078-09-0, 17.8 mL, 143.0 mmol) in DCM (100 mL) was added a solution of 6-bromo-2-ethoxy-3-methoxybenzaldehyde (Préparation 169, 4.64 g, 17.9 mmol) in DCM (20 mL) at about -20 °C. The reaction mixture was warmed to about 25 °C over 0.5 h and then at about 25 °C for about 15 h. The reaction was quenched with saturated aqueous NaHCO₃ (200 mL) at about 0 °C and the mixture was extracted with DCM (2 x 100 mL). The combined DCM extracts were concentrated and the residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 97:3) to afford 1-bromo-2(difluoromethyl)-3-ethoxy-4-methoxybenzene (4.77 g, 95%). ¹H NMR (CDCI₃, 400MHz): δ 7.31 (d, J= 8.8 Hz, 1H), 7.10 (t, J = 54.0 Hz, 1H), 6.87 (d, J= 8.8 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

Préparation 169: 6-bromo-2-ethoxy-3-methoxybenzaldehyde

To a mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Préparation 165, 5 g, 21.64 mmol) and K₂CO₃ (5.98 g, 43.3 mmol) in MeCN (100 mL) was added iodoethane (16.9 g, 108 mmol). The mixture was warmed to 60 °C and stirred for 4 h, followed by heating to 100 °C for 19 h. The mixture was cooled to r.t and condensed under reduced pressure. The residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to afford 6-bromo-2-ethoxy-3-methoxybenzaldehyde (5.1 g, 92%) as a light yellow oil. ¹H NMR (CDCh, 400MHz): δ 10.37 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). Préparation 170a: 1-bromo-3-ethoxy-2-fluoro-4-methoxybenzene

1-bromo-3-ethoxy-2-fluoro-4-methoxybenzene (25 g, 58%) was prepared in an analogous manner to Préparation 155 using 3-bromo-2-fluoro-6-methoxyphenol (38 g, 170 mmol) and iodoethane (40.2 g, 258 mmol). ¹H NMR (CDCh, 400MHz): δ 7.14-7.20 (m, 1H), 6.58-6.63 (m, 1H), 4.02 (t, J= 6.7 Hz, 2H), 3.86 (s, 3H), 1.75-1.80 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H).

160

Préparation 170b: 1-bromo-2-fluoro-4-methoxy-3-propoxybenzene

F

1-bromo-2-fluoro-4-methoxy-3-propoxybenzene (10.2 g 57%) was prepared in an analogous manner to Préparation 155 using 3-bromo-2-fluoro-6-methoxyphenol (15 g, 68.2 mmol) and 1-bromopropane (10.8 g, 88.6 mmol). ¹H NMR (CDCh, 400MHz): δ 7.14-7.20 (m, 1 H), 6.58-6.63 (m, 1 H), 4.02 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 1.75-1.80 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H).

Préparation 171: 6-bromo-3-methoxy-2-propoxybenzonitrile

II N

6-bromo-3-methoxy-2-propoxybenzonitrile (10.9 g 92%) was prepared in an analogous manner to Préparation 155 using 6-bromo-2-hydroxy-3-methoxybenzonitrile (10 g, 44 mmol) and 1-bromopropane (7 g, 57 mmol). ¹H NMR (CDCh, 400MHz): δ 7.27-7.30 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.15 (t, J= 6.6 Hz, 2H), 3.86 (s, 3H), 1.78-1.87 (m, 2H), 1.06 (t, J= 7.5 Hz, 3H). LCMS m/z = 270 [MH]⁺.

Préparation 172: 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene F

To a mixture of 5-bromo-3-fluoro-2-methoxyphenol (Préparation 173, 2.21 g, 10.0 mmol) and iodoethane (3.12 g, 20.0 mmol) dissolved in MeCN (30 mL) was added K₂CO₃ (2.07 g, 15 mmol). The mixture was warmed to about 50 °C and stirred for about 5 h. The mixture was cooled to about 20 °C and was filtered. The filtrate was concentrated and the residue was triturated with MTBE (20 mL) for about 20 min. The mixture was filtered and the filtrate was concentrated to afford 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene (1.85 g, 74%). ¹H NMR (CDCh, 400MHz): δ 6.88-6.91 (m, 1 H), 6.82-6.83 (m, 1 H), 4.07 (q, J = 7.0 Hz, 2H), 3.90 (d, J = 0.7 Hz, 3H), 1.46 (t, J = 7.0 Hz, 3H).

161

Préparation 173: 5-bromo-3-fluoro-2-methoxyphenol

To a mixture 5-bromo-3-fluoro-2-methoxyphenyl formate (Préparation 174, 4.98 g, 20.0 mmol) in MeOH (30 mL) and water (30 mL) was added LiOH (1.68 g, 40.0 mmol) in portions. The mixture was stirred at about 25 °C for about 16 h. The mixture was concentrated. The resulting aqueous phase was diluted with water and NaHCOs was added until pH 8. The aqueous phase was washed with MTBE (2 x 30 mL) and the combine MTBE extracts were concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to afford 5-bromo-3-fluoro-2-methoxyphenol (2.4 g, 54% over 2 steps). ¹H NMR (CDCh, 400MHz): δ 6.91-6.92 (m, 1H), 6.81-6.84 (m, 1H), 5.82 (s, 1H), 4.00 (d, J = 1.8 Hz, 3H).

Préparation 174: 5-bromo-3-fluoro-2-methoxyphenyl formate

F

To a mixture of 5-bromo-3-fluoro-2-methoxybenzaldehyde (Préparation 175, 3.50 g, 15.0 mmol) in DCM (50 mL) was added m-CPBA (4.85 g, 22.5 mmol). The resulting mixture was stirred at about 25 °C for about 16 h. The reaction was concentrated to afford 2-(5-bromo-3fluoro-2-methoxyphenyl)acetaldehyde (3.74 g), which was used in Préparation 173.

Préparation 175: 5-bromo-3-fluoro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (Préparation 176, 18.6 g, 85.0 mmol) in MeCN (150 mL) was added K2CO3 (17.6 g, 128.0 mmol) and iodomethane (24.1 g, 170.0 mmol). The mixture was warmed to about 50 °C for about 16 h. The reaction was filtered and the filtrate was concentrated. The residue was triturated in MTBE (50 mL) and the resulting solid was filtered to afford 5-bromo-3-fluoro-2-methoxybenzaldehyde (4.9 g, 25%). ¹H NMR (CDCh, 400MHz): δ 10.33 (s, 1H), 7.73-7.74 (m, 1 H), 7.47-7.51 (m, 1 H), 4.10 (d, J = 3.0 Hz, 3H).

162

Préparation 176: 5-bromo-3-fluoro-2-hydroxybenzaldehyde

To a mixture of 4-bromo-2-fluorophenol (20.0 g, 104.7 mmol) dissolved in TFA (100 mL) was added HMTA (CAS 100-97-0, 29.4 g, 209.0 mmol) in portions. The mixture was heated at about 90 °C for about 16 h. The mixture was poured into water (800 mL) and a solid formed which was filtered. The cake was washed with water (2 x 150 mL) and dried to afford 5-bromo3-fluoro-2-hydroxybenzaldehyde (18.9 g, 82%). ¹H NMR (CDCh, 400MHz): δ 10.90 (s, 1H), 9.88 (d, J = 2.0 Hz, 1 H), 7.49-7.53 (m, 2H).

Préparation 177: 5-bromo-1-chloro-3-ethoxy-2-methoxybenzene

Cl

5-bromo-1-chloro-3-ethoxy-2-methoxybenzene (1.25 g, 86%) was prepared in an analogous manner to Préparation 172 using 5-bromo-3-chloro-2-methoxyphenol (Préparation 178, 1.3 g, 5.47 mmol). Ή NMR (CDCh, 400MHz): δ 7.12 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 4.06 (q, J= 7.0 Hz, 2H), 3.86 (s, 3H), 1.46 (t, J= 7.0 Hz, 3H).

Préparation 178: 5-bromo-3-chloro-2-methoxyphenol

Cl

To a mixture of 5-bromo-3-chloro-2-methoxyphenyl formate (Préparation 179, 15.6 g, 58.76 mmol) in MeOH (100 mL) and water (100 mL) was added LiOH (4.93 g, 118.0 mmol) in portions. The mixture was stirred at about 25 °C for about 16 h. The mixture was concentrated and the resulting aqueous phase was diluted with aqueous NaHCO₃ (50 mL). The solution was extracted with MTBE (2 x 30 mL) and the combined MTBE extracts were dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to afford 5-bromo-3-chloro-2-methoxyphenol (1.3 g, 7% over 2 steps). Ή NMR (CDCh, 400MHz): δ 7.07 (d, J = 2.3 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 5.79 (s, 1H), 3.92 (s, 3H).

163

Préparation 179: 5-bromo-3-chloro-2-methoxyphenvl formate

Cl

To a mixture of 5-bromo-3-chloro-2-methoxybenzaldehyde (Préparation 180, 20.0 g, 80.16 mmol) in DCM (200 mL) was added m-CPBA (25.9 g, 120 mmol). The mixture was stirred at about 25 °C for about 16 h. The white solid was filtered and the filtrate was concentrated to afford 5-bromo-3-chloro-2-methoxyphenyl formate (15.0 g, 70%), which was used in Préparation 178. LCMS m/z = 266 [MH]⁺.

Préparation 180: 5-bromo-3-chloro-2-methoxybenzaldehyde

Cl

To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (Préparation 181, 10 g, 42.5 mmol) dissolved in MeCN (150 mL) was added iodomethane (24.1 g, 170 mmol) and K₂CO₃(11.7 g, 84.9 mmol). The mixture was warmed to about 50 °C and stirred for about 24 h. The mixture was cooled to about 20 °C, filtered. The filtrate was concentrated and the residue was triturated with MTBE (30 mL) for about 20 min. before filtering. The filtrate was concentrated and the residue was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were concentrated to afford 5-bromo-3-chloro-2methoxybenzaldehyde (8.9 g, 84%), which was used in Préparation 179. ¹H NMR (CDCh, 400MHz): δ 10.30 (s, 1H), 7.87 (d, J = 2.5 Hz, 1 H), 7.77 (d, J = 2.5 Hz, 1 H), 4.01 (s, 3H).

Préparation 181: 5-bromo-3-chloro-2-hydroxybenzaldehyde

Cl

To a mixture of 4-bromo-2-chlorophenol (20.0 g, 94.41 mmol) in TFA (150 mL) was added HMTA (CAS 100-97-0, 27.0 g, 193 mmol) in portions. The mixture was stirred at about 90 °C for about 16 h. The mixture was poured into water (800 mL) forming a precipitate. The precipitate was filtered, washed with water (2 x 150 mL) and dried to afford 5-bromo-3-chloro-2hydroxybenzaldehyde (22.7 g), which was used in Préparation 180. ¹H NMR (CDCh, 400MHz): δ 11.40 (br s, 1 H), 9.86 (s, 1 H), 7.75 (d, J = 2.3Hz, 1 H), 7.63 (d, J = 2.3Hz, 1 H).

164

Préparation 182: 1-bromo-5-ethoxy-2-fluoro-4-methoxybenzene

1-bromo-5-ethoxy-2-fluoro-4-methoxybenzene (7.1 g, 90%) was prepared in an analogous manner to Préparation 172 using 5-bromo-4-fluoro-2-methoxyphenol (Préparation 192, 7.0 g, 32.0 mmol). ¹H NMR (CDCb, 400MHz): δ 6.96-6.98 (m, 1H), 6.69-6.71 (m, 1H), 4.02-4.07 (m, 2H), 3.84 (s, 3H), 1.41-1.52 (m, 3H).

Préparation 183: 1-bromo-2-chloro-5-ethoxy-4-methoxybenzene

1-bromo-2-chloro-5-ethoxy-4-methoxybenzene (5.7 g, 98%) was prepared in an analogous manner to Préparation 172 using 5-bromo-4-chloro-2-methoxyphenol (Préparation 184, 5.2 g, 21.9 mmol). ¹H NMR (CDCb, 400MHz): δ 7.05 (s, 1H), 6.94 (s, 1H), 4.06 (q, J= 7.0 Hz, 2H), 3.86 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H).

Préparation 184: 5-bromo-4-chloro-2-methoxyphenol

To a mixture of 5-bromo-4-chloro-2-methoxyphenyl formate (Préparation 185, 3.2 g, 12.05 mmol) in MeOH (50 mL) and water (50 mL) was added NaOH (0.72 g, 18.1 mmol). The mixture was stirred at about 20 °C for about 1 h. The mixture was acidified using 1N HCl to pH 3. The mixture was concentrated and the remaining aqueous phase was extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated to afford 5-bromo-4-chloro-2-methoxyphenol (2.8 g, 98%). Ή NMR (CDCb, 400MHz): δ 7.16 (s, 1H), 6.93 (s, 1H), 5.58 (s, 1H), 3.28 (s, 3H).

Préparation 185: 5-bromo-4-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-4-chloro-2-methoxybenzaldehyde (Préparation 186, 12.2 g, 48.9 mmol) in DCM (300 mL) was added m-CPBA (21.1 g, 97.8 mmol). The mixture was stirred at about 18 °C for about 16 h. The mixture was partitioned between DCM (400 mL) and saturated sodium metabisulfite solution (200 mL). The separated DCM layer was washed with

165 water (400 mL), brine (400 mL), dried over MgSO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 5bromo-4-chloro-2-methoxyphenyl formate (3.2 g, 25%). ¹H NMR (CDCh, 400MHz): δ 8.22 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 3.85 (s, 3H).

Préparation 186: 5-bromo-4-chloro-2-methoxybenzaldehyde

To a mixture of 1-bromo-2-chloro-4-methoxybenzene (15.0 g, 67.73 mmol) in TFA (100 mL) was added HMTA (CAS 100-97-0, 14.2 g, 102 mmol) in portions. The mixture was stirred at about 80 °C for about 12 h. The mixture was poured into water (1000 mL) and stirred at about 20 °C for about 1 h, forming a precipitate. The precipitate was filtered, dissolved in EtOAc (200 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 5-bromo-4chloro-2-methoxybenzaldehyde (6.7 g, 40%). ¹H NMR (CDCh, 400MHz): δ 10.33 (s, 1H), 8.03 (s, 1H), 7.12 (s, 1H), 3,94 (s, 3H).

Préparation 187: 1-bromo-5-ethoxy-4-methoxy-2-methylbenzene

1-bromo-5-ethoxy-4-methoxy-2-methylbenzene (8.0 g, 99%) was prepared in an analogous manner to Préparation 172 using 5-bromo-2-methoxy-4-methylphenol (Préparation 189, 7.16 g, 33.0 mmol). Ή NMR (CDCh, 400MHz): δ 7.01 (s, 1H), 6.74 (s, 1H), 4.05 (q, J= 7.0 Hz, 2H), 3.85 (s, 3H), 2.33 (s, 3H) 1.46 (t, J = 7.0 Hz, 3H).

Préparation 188: 1-bromo-2-fluoro-4-methoxy-5-propoxybenzene

1-bromo-2-fluoro-4-methoxy-5-propoxybenzene (13.5 g, 95%) was prepared in an analogous manner to Préparation 172 using 5-bromo-4-fluoro-2-methoxyphenol (Préparation 192, 12 g, 109 mmol) and 1-iodopropane (18.5 g, 109 mmol). ¹H NMR (CDCh, 400MHz): δ 6.98 (d, J = 6.8 Hz, 1 H), 6.70 (d, J = 9.8 Hz, 1 H), 3.93 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 1.81-1.90 (m 2H), 1.04 (t, J= 7.6 Hz, 3H).

166

Préparation 189: 5-bromo-2-methoxy-4-methylphenol

To a mixture of 5-bromo-2-methoxy-4-methylphenyl formate (Préparation 190, 19.3 g, 78.58 mmol) in MeOH (100 mL) and water (100 mL) was added NaOH (4.72 g, 118.1 mmol). The mixture was stirred at about 20 °C for about 1 h. The mixture was acidified using 1N HCl to pH 3. The mixture was concentrated and the remaining aqueous phase was extracted with EtOAc (3 x 150 mL). The combined EtOAc extracts were dried, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford 5-bromo-2-methoxy-4-methylphenol (10.25 g, 60% over 2 steps). ¹H NMR (CDCh, 400MHz): δ 7.10 (s, 1H), 6.72 (s, 1H), 5.46 (br s, 1H), 3.87 (s, 3H), 2.33 (s, 3H).

Préparation 190: 5-bromo-2-methoxy-4-methylphenyl formate

To a mixture of 5-bromo-2-methoxy-4-methylbenzaldehyde (Préparation 191, 18.0 g, 78.58 mmol) in DCM (200 mL) was added m-CPBA (33.9 g, 157.0 mmol). The mixture was stirred at about 18 °C for about 16 h. The mixture was filtered and the filtrate was concentrated. The residue was washed with aqueous sodium metabisulfite solution (1N, 200 mL), aqueous Na₂COs (1N, 100 mL) and water. The residue afforded 5-bromo-2-methoxy-4-methylphenyl formate (19.3 g), which was used in Préparation 189.

Préparation 191: 5-bromo-2-methoxy-4-methylbenzaldehyde

To a mixture of 1-bromo-4-methoxy-2-methyIbenzene (25.1 g, 125.0 mmol) in TFA (120 mL) was added HMTA (26.3 g, 188 mmol) in portions. The mixture was stirred at about 80 °C for about 12 h. The mixture was poured into water (500 mL) and stirred at about 20 °C for about 2 h, forming a precipitate. The precipitate was filtered, suspended in water at about 60 °C for about 20 min, cooled to about 20 °C and filtered. The precipitate was dissolved in EtOAc (300 mL), dried over Na₂SO₄, filtered and concentrated to afford 5-bromo-2-methoxy-4methylbenzaldehyde (18.0 g, 63%). ¹H NMR (CDCh, 400MHz): δ 10.34 (s, 1H), 7.95 (s, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 2.45 (s, 3H).

167

Préparation 192: 5-bromo-4-fluoro-2-methoxyphenol

To a solution of 4-fluoro-2-methoxyphenol (5 g, 40 mmol) and Fe powder (98.2 mg, 1.76 mmol) in DCM (230 mL) was added a solution of Br₂ (6.18 g, 38.7 mmol) in DCM (20mL). The solution was stirred for about 16 h at about 20 °C. The mixture was washed with water (3 x 200 mL) and NaOH (1N). The DCM layer was dried (Na₂SO4) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 5-bromo-4-fluoro-2-methoxyphenol (6.0 g, 77%). Ή NMR (CDCh, 400MHz): δ 7.07 (d, J = 6.8 Hz, 1 H), 6.68 (d, J = 9.6 Hz, 1 H), 5.47 (s, 1 H), 3.87 (s, 3H).

Préparation 193: 2-ethoxy-1,5-difluoro-3-methoxybenzene

To a mixture of 2-ethoxy-3,5-difluorophenol (6.0 g, 34.45 mmol) and iodomethane (Préparation 194, 24.5 g, 172.0 mmol) in MeCN (100 mL) was added K₂CO₃ (9.52 g, 68.9 mmol). The mixture was warmed to about 60 °C and stirred for about 5 h. The mixture was cooled to about 20 °C, filtered and concentrated. The residue was dissolved in EtOAc (200 mL). The EtOAc layer was washed with water (80 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to afford 2-ethoxy-1,5-difluoro-3-methoxybenzene (5.0 g, 77%), which was used in Préparation 137. ¹H NMR (CDCh, 400MHz): δ 6.43-6.50 (m, 2H), 4.07 (q, J= 7.0 Hz, 2H), 3.85 (s, 3H), 1.36 (t, J= 7.0 Hz, 3H).

Préparation 194: 2-ethoxy-3,5-difluorophenol

F

To a mixture of 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Préparation 195, 13.0 g, 45.76 mmol) in THF (100 mL) was added H₂O₂ (30%, 7.78 g, 68.6 mmol) and aqueous NaOH (1M, 48.0 mL, 48.0 mmol) at about 0 °C. The mixture was allowed to warm to about 25 °C for about 2 h. The mixture was acidified with 1N HCl to pH 5. Brine (100 mL) was added and the mixture was extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were dried over NaSO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 2-ethoxy-3,520225

168 difluorophenol (6.0 g, 75%). Ή NMR (CDCI₃, 400MHz): δ 6.49-6.52 (m, 1H), 6.37-6.43 (m, 1H),

5.95 (d, J= 1.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H).

Préparation 195: 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

F

A combined mixture of 1-bromo-2-ethoxy-3,5-difluorobenzene (Préparation 196, 11.0 g, 46.4 mmol), Pin₂B₂ (6.53 g, 51.0 mmol) Pd(dppf)CI₂ (1.7 g, 2.32 mmol) and KOAc (9.11 g, 92.8 mmol) in anhydrous 1,4-dioxane (200 mL) was degassed, heated and stirred at about 80 °C for about 24 h under N₂. The suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 70:30) to afford 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.0 g, 99%). Ή NMR (CDCI₃, 400MHz): δ 7.14-7.17 (m, 1H), 6.90-6.95 (m, 1H), 4.06 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H), 1.37 (s, 12H). LCMS m/z = 285 [MH]⁺.

Préparation 196: 1-bromo-2-ethoxy-3,5-difluorobenzene

To a mixture of 2-bromo-4,6-difluorophenol (10.0 g, 47.85 mmol) and iodoethane (14.9 g, 95.7 mmol) in MeCN (200 mL) was added K₂CO₃ (13.2 g, 95.7 mmol). The mixture was warmed to about 60 °C and stirred for about 16 h. The mixture was cooled to about 20 °C, filtered and the filtrate concentrated. The residue was dissolved in EtOAc (200 mL). The EtOAc layer was washed with water (80 mL), brine (50 mL), dried over MgSO₄, filtered and concentrated to afford 1-bromo-2-ethoxy-3,5-difluorobenzene (11.0 g, 97%), which was used in Préparation 195. Ή NMR (CDCI₃, 400MHz): δ 7.09-7.12 (m, 1H), 6.82-6.88 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

Préparation 197: 4-bromo-1,2-diethoxybenzene

169

4-bromo-1,2-diethoxybenzene (6.3 g, 97%) was prepared in an analogous manner to

Préparation 172 using 4-bromobenzene-1,2-diol (5.0 g, 26 mmol). ¹H NMR (CDCI₃, 400MHz): δ 6.96-7.01 (m, 2H), 6.71-6.76 (m, 1H), 4.06 (dq, J= 3.5, 7.0 Hz, 4H), 1.40-1.48 (m, 6H).

Préparation 198: 4-bromo-1-ethoxy-2-methoxybenzene

4-bromo-1-ethoxy-2-methoxybenzene (5.1 g, 98%) was prepared in an analogous manner to Préparation 172 using 4-bromo-2-methoxyphenol (4.57 g, 22.5 mmol). ¹H NMR (CDCh, 400MHz): δ 6.99-7.03 (m, 1 H), 6.97-6.99 (m, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 4.07 (q, J = 6.9 Hz, 2H), 3.86 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H). LCMS m/z = 231 [MH]⁺.

Préparation 199: 1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene

1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene was prepared as a yellow oil (6.3 g, 99%) in an analogous manner to Préparation 172 using 3-bromo-6-ethoxy-2-fluorophenol (Préparation 200, 6 g, 25.5 mmol) and iodomethane (10.9 g, 76.6 mmol). ¹H NMR (CDCh, 400MHz): δ 7.13-7.19 (m, 1H), 6.60 (dd, J = 2.0, 9.3 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.93 (d, J = 1.0 Hz, 3H), 1.46 (t, J= 7.1 Hz, 3H).

Préparation 200: 3-bromo-6-ethoxy-2-fluorophenol

To a solution of 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (Préparation 201, 15.2 g, 44.1 mmol) in THF (150 mL) was added H₂O₂ (30%, 7.49 g, 66.1 mmol) and aqueous NaOH (1M, 46.3 mL, 46.3 mmol) at about 0 °C. The mixture was allowed to warm to about 25 °C for about 1.5 h. The mixture was acidified with 1N HCl to pH 5. Brine (150 mL) was added and the mixture was extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were dried over Na₂S0₄, filtered and concentrated to afford 3-bromo20225

170

6-ethoxv-2-fluorophenol (10.0 g, 97%). ¹H NMR (CDCh, 400MHz): δ 6.99 (dd, J = 7.0, 9.0 Hz,

H), 6.53-6.62 (m, 1 H), 4.07-4.20 (m, 3H), 1.46 (t, J = 7.0 Hz, 3H).

Préparation 201: 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane

To a solution of 1-bromo-4-ethoxy-2-fluorobenzene (Préparation 202, 11.0 g, 50.2 mmol) in THF (250 mL) was added dropwise a solution of LDA (37.7 mL, 75.3 mmol, 2 M in THF) at about -78 °C. The solution was stirred at about -78 °C for about 1 h, PinBO-Pr (14.0 g, 75.3 mmol) was added dropwise. After stirring at about -78 °C for about 2 h, the solution was quenched with aqueous NH₄CI (1 M, 100 mL) and extracted with MTBE (3 x 300 mL). The combined MTBE extracts were washed with brine (200 mL), dried over Na2SO₄, and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-l ,3,2dioxaborolane (15.2 g, 88%). Ή NMR (CDCh, 400MHz): δ 7.43 (t, J = 8.6 Hz, 1 H), 6.51 (d, J = 8.8 Hz, 1H), 3.99 (q, J= 6.9 Hz, 2H), 1.35-1.45 (m, 16H).

Préparation 202: 1-bromo-4-ethoxy-2-fluorobenzene

1-bromo-4-ethoxy-2-fluorobenzene (11 g, 96%) was prepared in an analogous manner to Préparation 172 using 4-bromo-2-methoxyphenol (10 g, 52 mmol). ¹H NMR (CDCh, 400MHz): δ 7.33-7.45 (m, 1H), 6.69 (dd, J = 2.9, 10.8 Hz, 1H), 6.60 (ddd, J= 1.0, 2.9, 8.8 Hz, 1 H), 4.00 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 6.9 Hz, 3H).

Préparation 203: (4-bromo-2-methoxyphenyl)(methyl)sulfane

To a solution of dimethyl disulfide (35 g, 371 mmol) and isopentyl nitrite (57.9 g, 495 mmol) in THF (600 mL) was added 4-bromo-2-methoxybenzenamine (50 g, 247.46 mmol)

171 slowly. The mixture was stirred at about 70 °C for about 3 h. The reaction mixture was concentrated. The residue was purified by column chromatography (silica) and eluted with pet.

ether/EtOAc (100:0 to 90:10) to afford (4-bromo-2-methoxyphenyl)(methyl)sulfane (50 g, 87%).

Ή NMR (CDCh, 400MHz): δ 7.07-7.12 (m, 1H), 6.99-7.03 (m, 1H), 6.96 (d, J = 2.0 Hz, 1H),

3.90 (s, 3H), 2.42 (s, 3H). LCMS m/z = 233.0 [MH]⁺.

Préparation 204: (4-bromo-2-ethoxyphenyl)(methyl)sulfane

(4-bromo-2-ethoxyphenyl)(methyl)sulfane (35.0 g, 83%) was prepared in an analogous manner to Préparation 172 using 5-bromo-2-(methylthio)phenol (Préparation 20, 16 g, 73 mmol). Ή NMR (CDCh, 400MHz): δ 7.05-7.09 (m, 1H), 6.97-7.01 (m, 1H), 6.94 (d, J= 2.0 Hz, 1H), 4.09 (q, J= 7.1 Hz, 2H), 2.41 (s, 3H), 1.47 (t, J= 7.0 Hz, 3H).

Préparation 205: (4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane

IA ά (4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane (6.0 g, 92%) was prepared in an analogous manner to Préparation 153 using 5-bromo-2-(methylthio)phenol (5 g, 22.8 mmol) and cyclopentanol (2.36 g, 27.4 mmol). ¹H NMR (CDCh, 400MHz): δ 7.05 (dd, J = 2.0, 8.3 Hz, 1H), 6.93-6.98 (m, 2H), 4.80-4.84 (m, 1H), 2.38 (s, 3H), 1.79-1.95 (m, 6H), 1.60-1.68 (m, 2H).

Préparation 206: 5-bromo-2-(methylthio)phenol

To a solution of (4-bromo-2-methoxyphenyl)(methyl)sulfane (19.0 g, 81.5 mmol) in DCM (300 mL) at about -78 °C was added BBr₃ (179 mL, 179 mmol, 1 M in DCM) dropwise under N2 atmosphère. The reaction mixture was allowed to warm to about 20 °C and stirred for about 2 h. The mixture was quenched with MeOH at about 0 °C and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 70:30) to

172 afford 5-bromo-2-(methylthio)phenol (16.3 g, 91%). ^jH NMR (CDCh, 400MHz): δ 7.35 (d, J = 8.3

Hz, 1H), 7.17 (d, J= 2.2 Hz, 1H), 7.03 (dd, J = 2.2, 8.3 Hz, 1H), 6.67 (br s, 1H), 2.32 (s, 3H).

Préparation 207: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile

A mixture of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (Préparation 208, 7g, 22.3 mmol), TFAA (7.16 g, 33.45 mmol) and Et₃N (6.76 g, 66.9 mmol) in DCM (100 mL) was stirred at about 20 °C for about 16 h. Water (200 mL) was added to the mixture and extracted with DCM (2 x 200 mL). The combined DCM extracts were washed with brine (200 mL), dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to afford 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile (1.6 g, 24%). Ή NMR (CDCh, 400MHz): δ 7.26-7.30 (m, 1H), 6.96 (d, J= 8.8 Hz, 1H), 5.11-5.17 (m, 1H), 3.87 (s, 3H), 1.89-2.02 (m, 4H), 1.70-1.80 (m, 2H), 1.59-1.68 (m, 2H).

Préparation 208: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime

To a solution of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (Préparation 209, 6.8 g, 22.7 mmol) in EtOH (100 mL) was added NaHCO₃ (3.8 g, 45.4 mmol) and NH₂OHHCI (2.35 g, 34 mmol). The mixture was stirred at about 20 °C for about 2 h. The reaction mixture was concentrated to afford 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (7 g), which was used in Préparation 207.

Préparation 209: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde

173

6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (6.8 g, 90%) was prepared in an analogous manner to Préparation 172 using 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Préparation 165, 6 g, 30 mmol) and bromocyclopentane (4.26 g, 28.6 mmol) at about 60 °C for about 3 h. Ή NMR (CDCb, 400MHz): δ 10.31-10.38 (m, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1 H), 4.95-5.01 (m, 1 H), 3.87 (s, 3H), 1.70-1.93 (m, 7H), 1.62 (d, J = 5.4 Hz, 2H). LCMS m/z = 323 [M+Na]⁺.

Préparation 210: 1-bromo-2,4-dimethoxy-3-propoxybenzene

1-bromo-2,4-dimethoxy-3-propoxybenzene (10 g, 85%) was prepared in an analogous manner to Préparation 172 using 3-bromo-2,6-dimethoxyphenol (Préparation 211, 10 g, 43 mmol) and 1-iodopropane (14.6 g, 86 mmol). ¹H NMR (CDCb, 400MHz): δ 7.17-7.22 (m, 1H), 6.58 (d, J= 8.8 Hz, 1H), 3.95-3.99 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 1.73-1.85 (m, 2H), 1.011.07 (m, 4H). LCMS m/z = 276 [MH]⁺.

Préparation 211: 3-bromo-2,6-dimethoxyphenol

To a stirring solution of 2,6-dimethoxyphenol (1 g, 6.5 mmol) in CCI₄ (35 mL) at about10 °C was added Br2 (1.04 g, 6.5 mmol) and stirred for about 2 h. The reaction mixture was diluted with CCI₄ (20 mL), washed with water (3 x 60 mL) and the CCI₄ layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford 3-bromo-2,6dimethoxyphenol (1.46 g, 97%). ¹H NMR (CDCb, 400MHz): δ 7.02 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 5.66 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H).

Préparation 212: 6-iodo-3-methoxy-2-propoxypyridine

174

6-iodo-3-methoxy-2-propoxypyridine was (11 g, 95%) prepared in an analogous manner to Préparation 172 using 6-iodo-2-propoxypyridin-3-ol (Préparation 213, 11 g, 39 mmol) and 1iodomethane (57 g, 402 mmol) at about 15 °C for about 6 h. ¹H NMR (CDCh, 400MHz): δ 7.24 (d, J = 8.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 4.25 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.73-1.90 (m,

2H), 1.04 (t, J = 7.5 Hz, 3H). LCMS m/z = 293 [MH]⁺.

Préparation 213: 6-iodo-2-propoxypyridin-3-ol

Sodium propan-1-olate (21.8 g, 265 mmol) was added to 2-bromo-6-iodopyridin-3-ol (Préparation 214, 26.5 g, 88.4 mmol) in DMF (200 mL), and the reaction mixture was stirred for about 16 h at about 110 °C under N₂. After cooling to about 20 °C, the reaction mixture was partitioned between brine (200 mL) and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined EtOAc extracts were dried (Na₂SO4) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford 6-iodo-2-propoxypyridin-3-ol (11.2 g, 45%). Ή NMR (CDCh, 400MHz): δ 7.17 (d, J = 8.0 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 5.47 (s, 1 H), 4.31 (dt, J = 0.9, 6.7 Hz, 2H), 1.741.86 (m, 2H), 0.98-1.05 (m, 3H).

Préparation 214: 2-bromo-6-iodopyridin-3-ol

To a solution of 2-bromo-3-hydroxy pyridine (20.0 g, 114.95 mmol) in water (250 mL) was added K2CO3 (31.8g, 230 mmol) and l₂ (29.2 g, 115 mmol). The mixture was stirred at about 20 °C for about 5 h. The mixture was cooled to 0 °C and treated with concentrated HCl. The precipitate was filtered to afford 2-bromo-6-iodopyridin-3-ol (30 g, 87%). ¹H NMR (DMSOd_s, 400 MHz): δ 11.10 (br s, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H). LCMS m/z = 299 [MH]⁺.

Préparation 215: 5-bromo-2-methoxy-3-propoxypyridine

175

To a solution of 2-methoxy-3-propoxypyridine (Préparation 216, 5.68 g, 34 mmol) dissolved in DCM (60 mL) was added HOAc (2.04 g, 34mmol). To the mixture, NBS (6.35 g, 35.7 mmol) was added in portions while stirring. The mixture was stirred at about 12 °C for about 16 h. The mixture was concentrated. The residue was diluted with water (200 mL) and extracted with EtOAc (2 x 100 mL) The combined EtOAc extracts were dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to afford a mixture of 6-bromo-2-methoxy-3-propoxypyridine and 5-bromo-2methoxy-3-propoxypyridine. The mixture was chilled to about -10 °C overnight. A precipitate formed which was separated from the oil by centrifugation (3x5 min @ 3000 rpm) to afford 5bromo-2-methoxy-3-propoxypyridine (3 g, 53%). ¹H NMR (CDCb, 400MHz): δ 7.76 (d, J = 2.0 Hz, 1H), 7.13 (d, J= 2.0 Hz, 1H), 3.98 (s, 3H), 3.95 (t, J = 6.8 Hz, 2H), 1.85-1.94 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H).

Préparation 216: 2-methoxy-3-propoxypyridine

2-methoxy-3-propoxypyridine (5.7 g, 85%) was prepared in an analogous manner to Préparation 172 using 2-methoxypyridin-3-ol (5 g, 40 mmol) and 1-iodopropane (13.6 g, 80 mmol). Ή NMR (CDCb, 400MHz): δ 7.73 (dd, J = 1.5, 4.9 Hz, 1 H), 7.05 (dd, J = 1.5, 7.82 Hz, 1H), 6.83 (dd, J= 5.0, 7.7 Hz, 1H), 4.02 (s, 3H), 3.97 (t, J= 6.9 Hz, 2H), 1.86-1.93 (m, 2H), 1.05 (t, J =7.5 Hz, 3H).

Préparation 217: 2-bromo-5-methoxy-4-propoxypyridine

To a solution of 2-bromo-4-iodo-5-methoxypyridine (Préparation 218, 4.0 g, 13 mmol) in DMF (30 mL) was added NaH (765 mg, 19.1 mmol, 60%) and 1-propanol (1.53 g, 25.5 mmol) in DMF (25 mL) at about 20 °C. The mixture was heated to about 60 °C for about 1 h. The solution was quenched with aqueous NH₄CI (1 M, 30 mL) and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 89:11) to afford 2-bromo-5-methoxy-4-propoxypyridine (2 g, 64%). ¹H NMR (CDCb, 400MHz): δ 7.84 (s, 1 H), 6.91 (s, 1 H), 4.00 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 1.831.92 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H). LCMS m/z = 247.8 [MH]⁺.

176

Préparation 218: 2-bromo-4-iodo-5-methoxypyridine

Sodium hydride (1.27 g, 31.8 mmol, 60%) was suspended in MeOH (2.55 g, 79.5 mmol) and DMF (80 mL) at about 25 °C. The mixture was added to a solution of 2-bromo-5-fluoro-4iodopyridine (Préparation 219, 8 g, 26.50 mmol) in DMF (10 mL) at about 0 °C. The mixture was stirred at about 0 °C for about 1 h. The solution was quenched with aqueous NH₄CI (1 M, 60 mL) and extracted with MBTE (3 x 200 mL). The combined MTBE extracts were washed with brine (100 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 2-bromo-4iodo-5-methoxypyridine (4 g, 48.1%). Ή NMR (CDCh, 400MHz): δ 7.88 (s, 1H), 7.85 (s, 1H), 3.97 (s, 3H).

Préparation 219: 2-bromo-5-fluoro-4-iodopyridine

A solution of 2-bromo-5-fluoropyridine (24.6 g, 140 mmol) in THF (300 mL) was cooled to about -78 °C. LDA (2 M in THF, 90.9 mL, 182 mmol) was added dropwise and the mixture was stirred for about 20 min. To the mixture was added a solution of iodine (49.7 g, 196 mmol) in THF (100 mL) dropwise. The reaction mixture was warmed to about 0 °C and stirred for about 30 min. The reaction was quenched with 10% aq. Na₂S₂O₃ solution and was extracted with EtOAc (3 x 500 mL). The combined EtOAc extracts were washed with brine (500 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatograph (silica) and eluted with pet. ether/EtOAc (10:1) to afford 2-bromo-5-fluoro-4-iodopyridine (50 g, 67% purity). The material was further purified by préparative HPLC (Column: Phenomenex Synergi Max-RP 150 mm x 50 mm, 10 μ; Mobile Phase: [water (0.225% HCO₂H)-ACN]; B%: 30%-60%, 25 min. Flow rate 120 mL/min.) to afford 2-bromo-5-fluoro-4-iodopyridine (16.8 g, 40%). Ή NMR (CDCh, 400MHz): δ 8.15 (s, 1H), 7.92 (s, 1H). LCMS m/z = 303 [MH]⁺.

Préparation 220: 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine

177

To a solution of 5-fluoro-3-methoxy-2-propoxypyridine (Préparation 221, 2.80 g, 15.1 mmol) in EtOH (50 mL) was added Ag₂SO₄ (7.07 g, 22.7 mmol) and l₂ (5.76 g, 22.7 mmol). The reaction mixture was stirred at about 10 °C for about 16 h. The mixture was and the solution was partitioned between EtOAc (3 x 100 mL) and water (100 mL). The EtOAc extracts were dried with Na₂SO₄, filtered and concentrated to afford 3-fluoro-2-iodo-5-methoxy-6propoxypyridine (4.38 g, 93%). Ή NMR (CDCh, 400 MHz): δ 7.58-7.74 (m, 1H), 4.30 (t, J = 6.7 Hz, 2H), 3.92 (s, 3H), 1.75-1.91 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H). LCMS m/z = 311 [MH]⁺.

Préparation 221: 5-fluoro-3-methoxy-2-propoxypyridine

A mixture of tBuXPhos-Pd-G3 (CAS 14447963-75-8, 443 mg, 0.557 mmol), PrOH (803 mg, 13.4 mmol), 2-chloro-5-fluoro-3-methoxypyridine (Préparation 222, 1800 mg, 11.14 mmol) and Cs₂CO₃ (7260 mg, 22.3 mmol) was dissolved in PrOH (40 mL) under a N₂. The mixture was heated at about 90 °C for about 16 h. The mixture was dried and concentrated. The residue was purified by by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 5-fluoro-3-methoxy-2-propoxypyridine (1280 mg, 77%). ¹H NMR (CDCh, 400MHz): δ 7.57 (d, J = 2.5 Hz, 1 H), 6.87 (dd, J = 2.7, 9.3 Hz, 1 H), 4.31 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.77-1.93 (m, 2H), 0.98-1.08 (m, 3H). LCMS m/z = 185 [MH]⁺.

Préparation 222: 2-chloro-5-fluoro-3-methoxypyridine

2-chloro-5-fluoro-3-methoxypyridine (1.8 g, 72%) was prepared in an analogous manner to Préparation 153 using 2-chloro-5-fluoropyridin-3-ol (2.3 g, 16 mmol) and methanol (5 g, 156 mmol). Ή NMR (CDCh, 400MHz): δ 7.89 (d, J = 2.70 Hz, 1 H), 7.00 (dd, J = 2.5, 9.1 Hz, 1 H), 3.93 (s, 3H).

Préparation 223: 4-bromo-1-(difluoromethoxy)-2-propoxybenzene

178

Powdered KOH (1.34 g, 23.8 mmol) was added to a stirring solution of 4-bromo-2propoxyphenol (Préparation 224, 5.5 g, 23.8 mmol) in NMP (150 mL) at about 15 °C under N₂.

The mixture was heated at about 50 °C for about 45 min then cooled to about 15 C. Difluorochloromethane was bubbled through the reaction mixture (approximately 20 min) until saturation and the mixture was stirred for an additional 20 min. Potassium hydroxide (2.68 g in 3 mL of water) was added dropwise, maintaining the température below 33 °C. The mixture was stirred for an additional 40 min. Additional potassium hydroxide (1.34 g, in 3 mL of water) was added dropwise and the mixture was stirred for 1 h. N₂ was bubbled through the reaction and water was added. The pH ofthe resulting mixture was adjusted to 8 by the addition of potassium hydroxide (aqueous) and the mixture was extracted using MTBE (2 x 100 mL). The combined MBTE extracts were washed with water (50 mL), brine (3 x 100 mL), dried over Na₂SO4, filtered, and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 4-bromo-1-(difluoromethoxy)-2propoxybenzene (4.8 g, 72%). Ή NMR (CDCh, 400MHz): δ 7.09 (d, J= 1.3 Hz, 1H), 7.03-7.06 (m, 2H), 6.33-6.74 (m, 1 H), 3.93-4.01 (m, 2H), 1.80-1.92 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

Préparation 224: 4-bromo-2-propoxyphenol

To a solution of 4-bromo-2-propoxyphenyl formate (Préparation 225, 10.9 g, 42 mmol) in MeOH (75 mL) and water (75 mL) was added NaOH (4200 mg, 105 mmol). The mixture was stirred at about 10 °C for about 1h. The mixture was allowed to stand overnight. The mixture was acidified by HCl (1N) to pH 3. The mixture was concentrated and filtered. The filter cake was washed with water (20 mL). The cake was dissolved in MTBE (200 mL) and EtOAc (50 mL). The combined MTBE and EtOAc extracts were dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 75:25) to afford 4-bromo-2-propoxyphenol (6.11 g, 63%). ¹H NMR (CDCh, 400MHz): δ 6.94-7.06 (m, 2H), 6.81 (d, J = 8.5 Hz, 1 H), 3.99 (t, J = 6.8 Hz, 2H), 1.791.95 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H).

Préparation 225: 4-bromo-2-propoxyphenyl formate

179

To a solution of 4-bromo-2-propoxybenzaldehyde (Préparation 226, 10.2 g, 42 mmol) dissolved in DCM (150 mL) was added m-CPBA (18.1 g, 84 mmol). The mixture was stirred at about 18 °C for about 16 h, then allowed to stand over the weekend. The mixture was filtered and concentrated to afford 4-bromo-2-propoxyphenyl formate (10.9 g), which was used in

Préparation 224. LCMS m/z = 248 [MH]⁺.

180

Préparation 226: 4-bromo-2-propoxybenzaldehyde

4-bromo-2-propoxybenzaldehyde (11.5 g, 95%) was prepared in an analogous manner to Préparation 172 using 4-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol) and 1-iodopropane (11 g, 65 mmol). Ή NMR (CDCI₃, 400MHz): δ 10.45 (d, J= 0.7 Hz, 1H), 7.69 (d, J= 8.1 Hz, 1H), 7.11-7.22 (m, 2H), 4.04 (t, J = 6.5 Hz, 2H), 1.80-2.02 (m, 2H), 1.09 (t, J= 7.3 Hz, 3H).

Préparation 227: ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane

Five reactions were carried out in parallel. To a solution of 2-bromoprop-2-en-1-ol (Préparation 60, 150 g, 1.10 mol) and imidazole (Préparation 228, 74.6 g, 0.985 mol) in DMF (900 mL) was added TBS-CI (140 g, 0.93 mol) in portions at about 30 °C. Then the mixture was stirred at about 35 °C for 1 h. The mixture was poured into water (5.0 L). The combined mixtures were extracted with MTBE (3 x 2.5 L). The organic layer was washed with brine (2.0 L), dried over Na₂SO₄ and concentrated to afford ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane (1250 g, 92%). Ή NMR (CDCh, 400MHz): δ 5.96 (d, J= 1.8 Hz, 1H), 5.54 (d, J= 1.8 Hz, 1H), 4.22 (t, J= 1.5 Hz, 2H), 0.89-0.97 (m, 9H), 0.11 (s, 6H).

Préparation 228: 2-bromoprop-2-en-1-ol

Five reactions were carried out in parallel: To a solution of 2,3-dibromoprop-1-ene (300 g, 1.50 mol) in DMF (900 mL) was added KOAc (221 g, 2.25 mol) in portions with stirring at about 20 °C. The mixture was stirred at about 20 °C for about 12 h. A solution of LiOH (126 g, 3.01 mol) in MeOH (900 mL) and H₂O (300 mL) was added dropwise to the above mixture with stirring at about 20 °C. The mixture was stirred at about 20 °C for about 1 h. The mixture was concentrated and poured into ice-water (2.0 L). The mixture was extracted with EtOAc (3x1.5 L). The EtOAc extracts were washed with brine (1.0 L), dried over Na₂SO₄ and concentrated to afford 2-bromoprop-2-en-1-ol (750 g, 72%). ¹H NMR (CDCh, 400MHz): δ 5.87-6.02 (m, 1H), 5.45-5.62 (m, 1H), 4.17 (s, 2H), 3.70 (br s, 1H).

181

Préparation 229: ((3-bromobut-3-en-1 -yl)oxy)(tert-butyl)dimethylsilane

To a mixture of 3-bromobut-3-en-1-ol (CAS 76334-36-6, 10.0 g, 66.2 mmol) in anhydrous DCM (65 mL) was added imidazole (5.41 g, 79.5 mmol) and TBS-CI (9.98 g, 66.2 mmol). The mixture was stirred at about 18 °C for about 16 h. The reaction was poured into ice water and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO₄ and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether to afford ((3-bromobut-3-en-1yl)oxy)(tert-butyl)dimethylsilane (16.0 g, 91%). Ή NMR (CDCh, 400MHz): δ 5.64 (s, 1H), 5.46 (d, J = 1.6 Hz, 1 H), 3.80 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 6.2 Hz, 2H), 0.90 (s, 9H), -0.08 (s, 6H).

Préparation 230: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine

Cl

To a solution of 2,6-dichloropyrimidin-4-yl)methanol (Préparation 231, 3.5 g, 19.55 mmol) and imidazole (1.6 g, 23.5 mmol) in DMF (60 mL) was added TBS-CI (3.24 g, 22.4 mol) in portions at about 0 °C. The mixture was stirred at about 0 °C for about 2 h. The mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (2 x 30 mL), dried over Na2SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine (3.1 g, 54%). ¹H NMR (CDCh, 400MHz): δ 7.48-7.57 (m, 1H), 4.72-4.82 (m, 2H), 0.93-1.03 (m, 9H), 0.14 (s, 6H). LCMS m/z = 293 [MH]⁺.

Préparation 231: 2,6-dichloropyrimidin-4-yl)methanol

2,6-Dichloropyrimidine-4-carbonyl chloride (Préparation 232, 10 g, 47.3 mmol) was dissolved in a mixture of MeCN (60 mL) and THF (70 mL). The mixture was cooled to about -78 °C and treated with a solution of NaBH₄ (3.58 g, 94.6 mmol) in DMF (30 mL) dropwise. The

182 mixture was stirred at about -78 °C for about 2 h and diluted with aqueous HCl solution (1 M,

10mL). The mixture was diluted with saturated aqueous NaHCO₃ and extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were dried over MgSO₄, filtered and concentrated to afford 2,6-dichloropyrimidin-4-yl)methanol (8 g, 95%), which was used in Préparation 230. ¹H NMR (CDCI₃, 400MHz): δ 7.51 (s, 1H), 4.78 (s, 2H).

Préparation 232: 2,6-dichloropyrimidine-4-carbonyl chloride

A solution of 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (50 g, 0.32 mol) and PCk (220 g, 1.06 mol) in POCh (250 mL) was heated to reflux (120 °C) for about 16 h. The resulting mixture was concentrated and distilled under reduced pressure (120 °C, 10 mm Hg) to afford 2,6-dichloropyrimidine-4-carbonyl chloride (21 g, 31%), which was used in Prepartion 231.

Préparation 233: 4-methoxy-3-propoxybenzimidamide

Ethyl 4-methoxy-3-propoxybenzimidate (Préparation 234, 37.6 g, 158.45 mmol) was dissolved in EtOH (226 mL). Ammonia in methanol (226 mL) was added to the reaction mixture. The reaction mixture was stirred at about 28 °C for about 24 h. After concentration, MTBE (150 mL) was poured into the residue, stirred for 1h, and filtered and concentrated to afford 4methoxy-3-propoxybenzimidamide (33.8 g, 100%). ¹H NMR (CD₃OD, 400 MHz): δ 7.46 (dd, J = 2.2, 8.6 Hz, 1H), 7.36 (d, J= 2.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 4.04 (t, J = 6.5 Hz, 2H), 3.93 (s, 3H), 1.81-1.90 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H). LCMS m/z = 209 [MH]⁺.

Préparation 234: ethyl 4-methoxy-3-propoxybenzimidate

183

Acetvl chloride (69.0 g, 879 mmol) was added dropwise to a solution of 4-methoxy-3propoxybenzonitrile (Préparation 235, 21.0 g, 110 mmol) in dry EtOH (60.7 g, 1320 mmol), which was stirred at about 30 °C for about 12 h. The mixture was concentrated and to the residue was added MTBE (150 mL). The mixture was stirred for about 1 h and filtered to afford ethyl 4-methoxy-3-propoxybenzimidate (26.1 g, 100%). ¹H NMR (CDCh, 400 MHz): δ 12.28 (br s, 1 H), 11.56 (br s, 1 H), 8.01 (d, J = 2.2 Hz, 1 H), 7.98 (dd, J = 2.2, 8.6 Hz, 1 H), 7.0 (d, J = 8.6 Hz, 1 H), 4.91 (q, J = 7.0 Hz, 2H), 4.21 (t, J = 6.6 Hz, 2H), 3.96 (s, 3H), 1.85-1.96 (m, 2H), 1.61 (t, J = 7.0 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). LCMS m/z = 238 [MH]⁺.

Préparation 235: 4-methoxy-3-propoxybenzonitrile

4-methoxy-3-propoxybenzonitrile (32.10 g, 100%) was prepared in an analogous manner to Préparation 172 using 3-hydroxy-4-methoxybenzonitrile (25 g, 170 mmol) and 1iodopropane (57 g, 335 mmol). Ή NMR (CDCh, 400 MHz): δ 7.25-7.29 (m, 1 H), 7.08 (d, J = 2.0 Hz, 1H), 6.90 (d, J= 8.3 Hz, 1H), 3.99 (t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 1.84-1.93 (m, 2H), 1.031.09 (m, 3H). LCMS m/z = 191 [MH]⁺.

Préparation 236: 3-((tert-butyldimethylsilyl)oxy)propan-1-ol ^HO^^O,_s,/ ¹ P

Propane-1,3-diol (20 g, 260 mmol), tert-butylchlorodimethylsilane (47.5 g, 315 mmol), Et₃N (76.0 mL, 526 mmol) and DMAP (1.610 g, 13.1 mmol) were suspended in DCM (300 mL). The mixture was stirred at about 18 °C overnight. The reaction mixture was partitioned between DCM (3 x 300 mL) and water (300 mL). The combined DCM extracts were concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 97:3) to afford 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (50 g, 100%), which was used in Préparation 158.

184

Préparation 237: 1-(6-bromopyrïdin-2-yl)-2-hydroxyethan-1-one

Step 1: A solution of 1-(6-bromopyridin-2-yl)ethanone (CAS 49669-13-8, 5.0 g, 25.0 mmol) in AcOH (12 mL) was heated to about 70 °C. Bromine (1.4 mL, 27.5 mmol) was added dropwise over 30 min. The solution was stirred at about 70 °C for about 19 h. The solution was cooled EtOAc (50 mL) and hexanes (50 mL) were added. The precipitate was filtered and washed with heptane (2 x 50 mL). The combined filtrâtes were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated to give a 2-bromo-1-(6-bromopyridin-2-yl)ethan-1-one (6.85 g), which was used directly in the next step.

Step 2: To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (6.74 g) in DMF (30 mL) was added sodium nitrite (2.00 g). The solution was stirred at about 20 °C for about 22 h. The reaction was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layers extracted with EtOAc. The combined EtOAc extracts were washed with brine (20 mL), dried with MgSO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (90:10 to 70:30) to afford 1-(6bromopyridin-2-yl)-2-hydroxyethan-1-one (977 mg), which was used in Préparation 88. ¹H NMR (CDCh, 400 MHz): δ 7.99-8.11 (m, 1H), 7.68-7.83 (m, 2H), 5.08 (d, J = 5.1 Hz, 2H).

Example 1: 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 32, 500 mg, 1.67 mmol) was further purified by préparative SFC (Prep SFC Method A) to afford 4-(5-(3,4dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (233 mg, 46%). ¹H NMR (DMSO-cfe, 400MHz): δ 8.72 (d, J = 2.8 Hz, 2H), 8.43 (d, J = 2.0 Hz, 1 H), 7.95 (t, J = 2.0 Hz, 1 H), 7.25-7.29 (m, 1 H), 7.06 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 4.28 Hz, 1 H), 3.84-3.88 (m, 4H), 3.80 (s, 3H), 3.46-3.54 (m, 1H), 1.28-1.34 (m, 1H), 1.12-1.18 (m, 1H). LCMS m/z = 300 [MH]⁺; RT [Analytical SFC Method A] = 5.20 min.

185

Example 2: (S)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 33, 2.3 g, 7.3 mmol) was further purified by préparative SFC (Prep SFC Method B). The solids were recrystallized from EtOAc (442 mg in 2 mL) to afford 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1 (253 mg, 11%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 1.6 Hz, 1 H), 7.92-7.94 (m, 1 H), 7.23-7.29 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 4.28 (t, J = 8.2 Hz, 1H), 4.13 (q, J= 6.8 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.45-3.55 (m, 1H), 1.28-1.39 (m, 4H), 1.10-1.20 (m, 1H). LCMS m/z = 314 [MH]⁺; RT [Analytical SFC Method B] = 6.59 min. [α]²% +19.5 (c = 0.3, EtOH).

Example 3: (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

Further elution ofthe préparative SFC column (Prep SFC Method B) described in Example 2 provided enantiomer 2 that was recrystallization from EtOAc to afford (R) 4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (610 mg, 27%) as a crystalline solid. Ή NMR (DMSO-c/₆, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 1.6 Hz, 1 H), 7.92-7.94 (m, 1H), 7.23-7.29 (m, 2H), 7.06 (d, J= 8.2 Hz, 1H), 4.28 (t, J= 8.2 Hz, 1H), 4.13 (q, J = 6.8 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.45-3.55 (m, 1H), 1.28-1.39 (m, 4H), 1.ΙΟΙ .20 (m, 1H). LCMS m/z = 314 [MH]⁺; RT [Analytical SFC Method B] = 7.07 min. [a]²% -22.5 (c = 0.2, EtOH).

Example 4: (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

Method A:

To a mixture of (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronic acid (Préparation 6, 55 g, 120 mmol) in IPA (247 mL) was added 5 M hydrogen chloride in IPA (37 mL, 185 mmol) at about 20 °C. The mixture was

186

I stirred for about 3 h and concentrated. The residue was diluted with EtOAc (500 mL) and 1N

HCl (500 mL) was added. The layers were separated and the EtOAc layer was extracted with

0.5 N HCl (2 x 200 mL). The aqueous extracts were combined with the separated acidic aqueous layer and washed with EtOAc (3 x 250 mL). The combined acidic aqueous layers were treated with K₃PO₄ to pH 5-6. The mixture was extracted with EtOAc (1 x 500 mL, 2 x 200 mL). The combined EtOAc extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (34.5 g, 88%). This was further purified by préparative SFC (Prep SFC Method C) to afford 29 g as a crude product. The crude product was dissolved in methanol (250 mL) and water (50 mL) 10 and stirred at 20 °C for about 30 min before concentrating. The concentrated solution was partitioned between brine and EtOAc. The aqueous layer was separated and extracted with EtOAc. The EtOAc extracts were combined with the separate EtOAc layer and were washed with brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in degassed EtOAc (200 mL) and degassed heptane (100 mL) was added slowly. Heptane was added until a precipitate was observed and and the resulting mixture was stirred overnight under N₂. The solid was filtered to afford 8.08 g of product. The filtrate was concentrated and the residue dissolved in EtOAc (50 mL). Heptane (25 mL) was slowly added and the mixture stirred overnight open to air. The solid was filtered to afford a second batch (6.16 g). This was repeated a second time to afford 3.0 g. The filtrate was stirred overnight to afford additional batches (2.09 g and 3.1 g) respectively. The solid batches were combined to afford (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (22.3 g, 57%) as a crystalline solid. Ή NMR (DMSO-ds, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23-7.26 (m, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 4.28 (t, J = 8.2 Hz, 1H), 4.03 (t, J= 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.54 (m, 1H), 1.7125 1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J= 10.5, 16.4 Hz, 1H), 1.00 (t, J= ΊΑ Hz, 3H). LCMS m/z = 328 [MH]⁺; RT [Analytical SFC Method B] = 7.30 min. [a]²⁰ _D -23.7 (c = 0.9, EtOH). Elemental analysis calculated (%) for Ci8H₂₂BNO₄: C 66.08, H 6.78, N 4.28. Found: C 65.86, H 6.59, N 4.18.

Method B:

Step 1: To THF (18.0 mL) was added 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5(4-methoxy-3-propoxyphenyl)pyridine (Préparation 50, 3.0 g, 7.25 mmol), [lr(COD)CI]₂ (CAS 12112-67-3, 36.9 mg, 0.054 mmol) and (S)[(S_p)-2-(diphenylphosphino)ferrocenyl]-4isopropyloxazoline (CAS 163169-29-7, 52.4 mg, 0.109 mmol). Additional THF (6.0 mL) was added to the mixture which was warmed to about 50 °C for about 5 min. Catecholborane (10.9 mL, 1,0M in THF) was added to the mixture and stirred at about 50 °C for about 1 h. The mixture was cooled to about 20 °C and treated with HCl (12.2 M, 1.51 mL) over 1 min. The mixture was held at about 20 °C for about 1 h, afterwhich a precipitate had formed. The mixture

187 was cooled to about 10 °C and filtered. The filtered solid was washed with THF (6.0 mL) and dried overnight at 35°C under vacuum to afford (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyndine3-yl)-1,2-oxaborolan-2-ol hydrochloride monohydrate (3.98 g, 91%) as a crystalline solid. ¹H NMR (CD₃OD, 400MHz): δ 8.98 (d, J = 1.5 Hz, 1 H), 8.75 (s, 1 H), 8.67 (d, J = 1.3 Hz, 1 H), 7.377.43 (m, 2H), 7.15 (d, J= 8.3 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 3.89-3.92 (m, 1H), 3.86-3.95 (m, 5H), 3.46 (brs, 1H), 1.85 (m, 2H), 1.31-1.42 (m, 2H), 1.08 (t, J =7.4 Hz, 3H). LCMS m/z = 328 [MH]⁺.

Step 2: To a solution of (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3-yl)-1,2oxaborolan-2-ol hydrochloride monohydrate (2.0 g, 5.24 mmol) in water (60 mL) was added EtOAc (20 mL). To the stirred mixture was added NaOH (1N) dropwise to adjust the pH ofthe aqeous layer to 7-8. The mixture was stirred at about 20 °C for about 5 min. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined EtOAc extracts were concentrated. The residue was dissolved in THF/MTBE (1:3, 22 mL) and stirred at about 20 °C overnight. The precipitate was filtered and dried under vacuum to afford (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridine-3-yl)-1,2-oxaborolan-2-ol (1.17 g, 68%) as a crystalline solid. Ή NMR (DMSO-d₆, 400MHz): δ 8.70 (d, J= 2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.93 (s, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J= 8.2 Hz, 1H), 4.28 (t, J = 8.2 Hz, 1 H), 4.03 (t, J = 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1 H), 3.81 (s, 3H), 3.46-3.54 (m, 1 H), 1.71 1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J = 10.5, 16.4 Hz, 1H), 1.00 (t, J= 7.4 Hz, 3H). LCMS m/z = 328 [MH]⁺.

Method C:

To a solution of (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)boronic acid (Préparation 6, 29.0 g, 63.1 mmol) in THF (66 mL) was added aqueous HCl (84.2 mL, 252 mmol, 3.0 M) and stirred at 20 °C for about 1.5 h. The mixture was concentrated. The mixture was diluted with 1 M HCl and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with 1 M HCl (3 x 50 mL). The combined aqueous extracts were neutralized with K₃PO₄ to pH 7-8 and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were dried over Na₂SO₄, filtered and concentrated to afford (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (19.0 g, 92%). This was further purified by préparative SFC (Prep SFC Method C) to afford 18 g ofthe crude product. The crude product was dissolved in MeOH (100 mL) and water (50 mL). The mixture was partitioned between brine and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na₂SO₄ and concentrated to afford 15 g of product. The residue was dissolved in EtOAc (60 mL) and heptane (30 mL) was slowly added over about 3 h. The mixture was stirred at about 20 °C overnight. The precipitate was filtered and dried to afford (8.08 g). This process was repeated 2 more times to afford additional batches (2.01 g and 1.03 g), respectively. The three

188 batches were combined in heptane (100 mL), chilled to about -78 °C for about 10 min, filtered and dried to afford (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (10.4 g, 51 %) as a crystalline solid. ¹H NMR (DMSO-de, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23-7.26 (m, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 4.28 (t, J = 8.2 Hz, 1 H), 4.03 (t, J = 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1 H), 3.81 (s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J = 10.5, 16.4 Hz, 1H), 1.00 (t, J = 7 A Hz, 3H). LCMS m/z = 328 [MH]⁺.

Example 5: (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine (Préparation 50, 30 g, 73 mmol), [lr(COD)CI]₂ (CAS 12112-67-3, 1.22 g, 1.81 mmol), (R,R)-[2-(4'-i-propyloxazolin-2-yl)ferrocenyl]diphenylphosphine (CAS 541540-70-9, 1.75 g, 3.63 mmol) and THF (240 mL) was cooled in an ice bath for about 30 min. A solution of catecholborane (109 mL, 109 mmol, 1.0 M in THF) was added slowly over about 20 min, afterwhich the mixture was stirred at about 20 °C for about 3 h. The reaction was quenched with MeOH (30 mL). The mixture was concentrated and dried overnight. The residue was treated with 3 M aqueous HCI/THF (1:1, v/v) for about 2 h and washed with EtOAc. The aqueous layer was separated and neutralized to pH 7-8 and extracted with EtOAc. The EtOAc extract was dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF/MTBE (1:1, 180 mL) and stirred with Biotage MP-TMT resin (28 g, Biotage P/N 801470) at about 20 °C, under N2, overnight. The mixture was filtered and the resin was washed with THF (2 x 50 mL). The combined THF/MTBE filtrâtes were concentrated to afford (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (23.5 g, 71%). This was further purified via SFC purification (Prep SFC Method C) to afford 12 g of a crude product. The crude product was dissolved in MeOH (35 mL) and water (15 mL). The mixture was partitioned between brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAC. The combined EtOAc extracts were dried over Na₂SO4, filtered and concentrated. The residue was dissolved in EtOAc (30 mL) and heptane was added until just cloudy. The mixture was stirred overnight. The precipitate was filtered and dried to afford (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (5.39 g, 45%) as a crystalline solid. ¹H NMR (DMSO-de, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.93 (s, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J= 8.2 Hz, 1H), 4.28 (t, J= 8.2 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J= 10.5, 16.4 Hz, 1H), 1.00 (t, J= 7 A Hz, 3H). LCMS m/z

189 = 328 [ΜΗΓ; RT [Analytical SFC Method B] = 6.35 min. [a]²⁰ _D +27.3 (c = 0.6, EtOH). Elemental analysis calculated (%) for C18H22BNO4: C 66.08, H 6.78, N 4.28. Found: C 66.01, H 6.52, N 4.15.

Example 6: 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 35, 90 mg, 0.28 mmol) was further purified by préparative SFC (Prep SFC Method D) followed by preprative HPLC (Method A) to afford 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1 (17 mg, 19%). ¹H NMR (DMSO-d₆, 400MHz): δ 8.72 (s, 1H), 8.69 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.29 - 7.24 (m, 2H), 7.07 (d, J = 8.0 Hz, 1 H), 4.68-4.74 (m, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1 H), 3.79 (s, 3H), 3.47-3.55 (m, 1H), 1.26-1.35 (m, 7H), 1.10-1.18 (m, 1H). LCMS m/z = 328 [MH]⁺. RT [Analytical SFC Method C] = 5.425 min.

Example 7: 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 36, 5.0 g, 4.54 mmol) was further purified by préparative SFC (Prep SFC Method E) to afford 4-(5(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (205 mg, 41 %). ¹H NMR (DMSO-ds, 400MHz): δ 8.69-8.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.28 (dd, J = 2.4, 8.3 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.25-4.31 (m, 1 H), 3.97-4.01 (m, 1 H), 3.86 (t, J = 8.8 Hz, 1 H), 3.78 (s, 3H), 3.46-3.57 (m, 1 H), 1.32 (dd, J= 8.1, 16.4 Hz, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1H), 0.76-0.83 (m, 2H), 0.67-0.72 (m, 2H). LCMS m/z = 326 [MH]⁺. RT [Analytical SFC Method D] = 5.736 min.

190

Example 8: (-) 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 37, 1.5 g, 4.56 mmol) was further purified by préparative SFC (Prep SFC Method F) to afford 4(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (261 mg, 27%). Ή NMR (DMSO-c/_s, 400MHz): δ 8.70-8.72 (m, 2H), 8.42 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.30 (d, J= 2.0 Hz, 1H), 7.26 (dd, J = 2.1,8.4 Hz, 1H), 7.07 (d, J= 8.6 Hz, 1H), 4.88 (t, J = 5.4 Hz, 1 H), 4.25-4.30 (m, 1 H), 4.09 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1 H), 3.81 (s, 3H), 3.75 (q, J= 5.2 Hz, 2H), 3.46-3.53 (m, 1H), 1.28-1.34 (m, 1H), 1.15 (dd, J=10.5, 16.1 Hz, 1H). LCMS m/z = 348 [MH+H₂O]⁺; RT [Analytical SFC Method D] = 3.357 min. [α]²%-25.9 (c = 0.1, EtOH).

Example 9: (-) 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 38, 1.2 g, 7.28 mmol) was further purified by préparative SFC (Prep SFC Method G) to afford 4(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (639 mg, 35%). Ή NMR (DMSO-c/₆, 400MHz): δ 8.68-8.72 (m, 2H), 8.43 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.0 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 4.55 (t, J = 5.1 Hz, 1H), 4.27 (t, J= 8.3 Hz, 1H), 4.14 (t, J= 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.58 (q, J= 6.0 Hz, 2H), 3.44-3.55 (m, 1H), 1.86-1.92 (m, 2H), 1.27-1.35 (m, 1H), 1.11-1.19 (m, 1H). LCMS m/z = 344 [MH]⁺; RT [Analytical SFC Method F] = 1.060 min. [α]²% -19.5 (c = 0.02, EtOH).

Example 10: (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1

191

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 41, 800 mg, 2.20 mmol) was further purified by préparative SFC (Prep SFC Method H) to afford 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, 5 enantiomer 1 (308 mg, 39%). The material was recrystallized from EtOAc/ heptane (1:1, v/v) to afford a crystalline solid. Ή NMR (DMSO-d_s, 400MHz): δ 8.69 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.34 (d, J= 1.5 Hz, 1H), 7.61 (s, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.80-7.14 (m, 2H), 4.27 (t, J= 8.3 Hz, 1H), 4.08 (q, J= 6.8 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J= 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.251.38 (m, 4H), 1.00-1.12 (m, 1H). LCMS m/z = 364 [MH]⁺; RT [Analytical SFC Method E] = 3.640 10 min. [a]²³ _D-27.5 (c = 0.2, EtOH).

Example 11: (+) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

Further elution ofthe préparative SFC column (Prep SFC Method H) described in

Example 10 provided 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2 (259 mg, 32%). ¹H NMR (DMSO-de, 400MHz): δ 8.69 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 8.34 (d, J = 1.5 Hz, 1H), 7.61 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.807.14 (m, 2H), 4.27 (t, J= 8.3 Hz, 1H), 4.08 (q, J = 6.8 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J= 8.8 Hz,

1H), 3.45-3.54 (m, 1H), 1.25-1.38 (m, 4H), 1.00-1.12 (m, 1H). LCMS m/z = 364 [MH]⁺; RT

[Analytical SFC Method E] = 4.050 min. [o]²³d+18.3 (c= 0.2, EtOH).

Example 12: 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-Ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 44, 60 mg, 0.18 mmol) was further purified by préparative SFC (Prep SFC Method I) to afford 4-(5(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (18 mg,

192

30%). Ή NMR (DMSO-de, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1 H), 8.71 (s, 1 H), 8.47 (d, 4 = 1.47

Hz, 1 H), 8.00 (s, 1 H), 7.27 (dd, J = 2.0, 11.7 Hz, 1 H), 7.20 (s, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 4.21 (q, J = 6.9 Hz, 2H), 3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 350 [MH+H₂O]⁺; RT [Analytical SFC Method D] = 4.282 min.

Example 13: 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol enantiomer 1

4-(5-(3-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 45, 150 mg, 0.43 mmol) was further purified by préparative SFC (Prep SFC Method J) to afford 4(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (411.3 mg, 37%). ¹H NMR (DMSO-ds, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1 H), 8.70 (s, 1 H), 8.48 (d, J = 2.0 Hz, 1H), 8.02 (t, 4 = 2.2 Hz, 1H), 7.42 (d, 4 = 2.0 Hz, 1H), 7.34 (d, 4 = 2.0 Hz, 1H), 4.18-4.30 (m, 3H), 3.83-3.91 (m, 1 H), 3.81 (s, 3H), 3.44-3.57 (m, 1 H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.22 (m, 1H). LCMS m/z = 348 [MH]⁺; RT [Analytical SFC Method D] = 4.932 min.

Example 14: 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 46, 385 mg, 1.16 mmol) was further purified by préparative SFC (Prep SFC Method K) to afford 4(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (122 mg, 32%). ¹H NMR (DMSO-de, 400MHz): δ 8.72 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.09 (d, 4= 7.7 Hz, 1H), 7.03 (d, 4= 12.4 Hz, 1H), 4.28 (t, 4= 8.2 Hz, 1H), 4.07 (q, 4 = 7.0 Hz, 2H), 3.82-3.86 (m, 4H), 3.46-3.55 (m, 1H), 1.29-1.34 (m, 4H), 1.07-1.14 (m, 1H). LCMS m/z = 332 [MH]⁺; RT [Analytical SFC Method D] = 4.111 min.

Example 15: (-) 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 47, 1.6 g, 4.60 mmol) was further purified by préparative SFC (Prep SFC Method L) to afford 4-(5(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (550 mg,

34%). ¹H NMR (DMSO-d₆, 400MHz): δ 8.71 (s, 1 H), 8.48 (t, J = 2.0 Hz, 2H), 7.76 (t, J = 2.2 Hz,

1H), 7.15 (s, 1H), 7.01 (s, 1H), 4.26-4.30 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.81-3.85 (m, 4H), 3.47-3.55 (m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H). LCMS m/z = 348 [MH]⁺; RT [Analytical SFC Method G] = 4.089 min. [a]²%-18.0 (c = 0.1, EtOH).

Example 16: (-) 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol (Example 48, 770 mg, 2.22 mmol) was further purified by préparative SFC (Prep SFC Method M) to afford 415 (3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (298 mg, 39%). Ή NMR (DMSO-de, 400MHz): δ 8.89 (s, 1 H), 8.73 (s, 1 H), 8.49 (d, J = 2.0 Hz, 1 H), 8.09 (s, 1H), 7.49 (d, J = 12.0 Hz, 1H), 4.28-4.33 (m, 3H), 3.87 (s, 3H), 3.82 (t, J = 8.7 Hz, 1H), 3.493.57 (m, 1H), 1.73-1.81 (m, 2H), 1.31-1.37 (m, 1H), 1.03-1.09 (m, 1H), 0.98 (t, J= 7.5 Hz, 3H). LCMS m/z = 347 [MH]⁺; RT [Analytical SFC Method D] = 4.347 min. [α]²%-12.1 (c = 0.1, EtOH).

Example 17: (-) 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example

50, 506 mg, 1.39 mmol) was further purified by préparative SFC (Prep SFC Method N) to afford

4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (165 mg, 33%). Ή NMR (DMSO-d₆, 400MHz): δ 8.74 (d, J = 2.1Hz, 1H), 8.72 (s, 1H), 8.49 (d, J = 2.0Hz, 1 H), 8.00 (t, J = 2.0Hz, 1 H), 7.45 (d, J = 1,6Hz, 1 H), 7.28-7.31 (m, 2H), 7.09 (t, J =

194

J 74.5Hz, 1H), 4.28 (t, J= 8.3Hz, 1H), 4.12 (t, J = 6.4Hz, 2H), 3.87 (t, J = 9.1Hz, 1H), 3.47-3.56 (m, 1H), 1.73-1.82 (m, 2H), 1.29-1.35 (m, 1H), 1.12-1.19 (m, 1H), 1.01 (t, J = 7.5Hz, 3H). LCMS m/z = 381 [MH+H₂O]⁺; RT [Analytical SFC Method E] = 3.402 min. [α]²%-21.2 (c = 0.1, EtOH).

Example 18: (-) 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol, enantiomer 1

OH /°_V% _rB

II */ b

4-(6'-Methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol (Example 51, 1.1 g, 3.4 mmol) was further purified by préparative SFC (Prep SFC Method O) to afford 4-(6'10 methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (411 mg, 37%). ¹H NMR (DMSO-ds, 400MHz): δ 8.76 (d, J = 2.2 Hz, 1 H), 8.72 (s, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.06 (d, J= 2.0 Hz, 1H), 8.01 (t, J= 2.2 Hz, 1H), 7.61 (d, J= 2.2 Hz, 1H), 4.26-4.31 (m, 1H), 4.08 (t, J = 6.6 Hz, 2H), 3.92 (s, 3H), 3.87 (t, J = 9.1 Hz, 1H), 3.48-3.56 (m, 1H), 1.73-1.82 (m, 2H), 1.28-1.35 (m, 1H), 1.13-1.21 (m, 1H), 1.00 (t, J= 7.5 Hz, 3H). LCMS m/z = 347

[MH+H₂O]⁺; RT [Analytical SFC Method G] = 4.231 min. [α]²%-27.2 (c = 0.1, EtOH).

Example 19: (R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

OH r-B IA JC /°

4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 52,

171.7 mg, 0.53 mmol) was further purified by préparative SFC (Prep SFC Method P) to afford 4(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1, (66 mg, 36%). The material was recrystallized from EtOAc/heptane to afford a crystalline solid. ¹H NMR (DMSO-d₆, 400MHz): δ 8.67 (s, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1H), 6.94 (d, J= 2.0 Hz, 1H), 6.88 (dd, J= 2.0, 7.8 Hz, 1H), 4.24 (t, J = 8.1 Hz, 1H),

4.04 (q, J= 6.9 Hz, 2H), 3.76-3.83 (m, 4H), 3.39-3.50 (m, 1H), 2.40 (s, 3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺; RT [Analytical SFC Method H] = 1.768 min. [α]²%20.0 (c = 0.4, EtOH).

Example 20: (S)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

195

OH /

B O

Further elution ofthe préparative SFC column (Prep SFC Method P) described in Example 19 provided 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2ol, enantiomer 2, (69 mg, 40%). ¹H NMR (DMSO-d₆, 400MHz): δ 8.67 (s, 1H), 8.33 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 6.88 (dd, J = 2.0, 7.8 Hz, 1H), 4.24 (t, J= 8.1 Hz, 1H), 4.04 (q, J= 6.9 Hz, 2H), 3.76-3.83 (m, 4H), 3.39-3.50 (m, 1H), 2.40 (s, 3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺; RT [Analytical SFC Method H] = 2.168 min.

Example 21: 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 53, 45 mg, 0.14 mmol) was further purified by préparative SFC (Prep SFC Method I) to afford 4-(5(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (12.5 mg, 28%). Ή NMR (DMSO-c/₆, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.90 (d, J= 2.3 Hz, 1H), 6.82-6.85 (m, 1H), 4.24-4.28 (m, 1H), 4.03 (q, J= 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s, 3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H), 1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺; RT [Analytical SFC Method I] = 5.208 min.

Example 22: (-) 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol (Example 54, 2.5 g, 7.28 mmol) was further purified by préparative SFC (Prep SFC Method Q) to afford 4(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (68 mg, 22%). ¹H NMR (CD₃OD, 400MHz): δ 8.03 (dd, J = 2.0, 8.6 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.07 (s, 1H), 7.05 (d, J= 8.3 Hz, 1H), 4.17 (br s, 1H), 4.07 (t, J= 6.5 Hz, 2H), 4.00 (br s, 1H),

196

3.91 (s, 2H), 3.41 (brs, 1H), 2.52 (s, 2H), 1.84-1.89 (m, 2H), 1.29-1.38 (m, 1H), 1.21-1.29 (m,

H), 1.09 (t, J = 7.3 Hz, 3H). LCMS m/z = 343 [MH]⁺; RT [Analytical SFC Method J] = 3.148 min. [α]²%-23.2 (c= 0.1, EtOH).

Example 23: (-) 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (Example 55, 572 mg, 1.45 mmol) was further purified by préparative SFC (Prep SFC Method M) to afford 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan2-ol, enantiomer 2 (100 mg, 18%). ¹H NMR (DMSO-d6, 400MHz): δ 8.72 (s, 1H), 8.03 (dd, J = 2.0, 8.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d, J= 8.6 Hz, 1H), 4.32 (dd, J = 7 A, 9.0 Hz, 1H), 3.98-4.09 (m, 3H), 3.86 (s, 3H), 3.73-3.82 (m, 1H), 1.73-1.84 (m, 1H), 1.311.41 (m, 1H), 1.18-1.26 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). LCMS m/z = 397 [MH]⁺; RT [Analytical SFC Method E] = 4.765 min. [a]²⁰D-12.6 (c = 0.4, EtOH).

Example 24: 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(6-(3-Ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol (Example 56, 20 mg, 0.06 mmol) was further purified by préparative SFC (Prep SFC Method R) to afford 4-(6-(3ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (6.4 mg, 34%). LCMS m/z = 315 [MH]⁺. RT [Analytical SFC Method K] = 3.23 min.

Example 25: 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol

A mixture of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 8, 1.30 g, 2.41 mmol)

197 in AcOH (10 mL) and water (5 mL) was stirred at about 50 °C for about 1 h. The mixture was concentrated and EtOH (10 mL) was added. The mixture was stirred at about 0 °C for about 15 min and filtered. The solid was washed with water (15 mL) and dried to afford 4-(5-(4-methoxy3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol (560 mg, 68%). ¹H NMR (DMSO-de, 400MHz): δ 8.86 (d, J= 2.0 Hz, 1H), 8.77 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.14 (t, J =2.0 Hz, 1H), 7.31-7.34 (m, 2H), 7.08 (d, J= 8.0 Hz, 1H), 6.46 (s, 1H), 5.02 (s, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 1.72-1.81 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H). LCMS m/z = 326 [MH]⁺.

Example 26: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol

2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2yl)-6-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 31, 140 mg, 0.25 mmol) was dissolved in AcOH (4.3 mL) and water (0.2 mL) and stirred at about 20 °C for about 16 h. The mixture was concentrated and the residue was purified by preparative HPLC (Prep HPLC Method B) to afford 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol (60 mg, 70%). ¹H NMR (DMSO-d₆, 400MHz): δ 7.71-7.76 (m, 4H), 7.64-7.66 (m, 1H), 7.15-7.17 (m, 1H), 7.03 (d, J = 8.6Hz, 1H), 4.02 (t, J = 6.6Hz, 2H), 3.64-3.98 (m, 2H), 3.81 (m, 3H), 3.13-3.20 (m, 1H), 1.922.00 (m, 1H), 1.72-1.82 (m, 3H), 1.09 (d, J = 7.0Hz, 2H), 1.00 (t, J = 7.4Hz, 3H). LCMS m/z = 342 [MH]⁺.

Example 27: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol

A mixture of 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)ol (Example 28, 50 mg, 0.15 mmol) and Adam’s catalyst (10.0 mg, 0.044 mmol) in EtOAc (1.5 mL) was hydrogenated at 20 psig at about 40 °C for about 2 h. The reaction was filtered through a Celite® pad and the filtrate was concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (80:20 to 0:100) followed by DCM/MeOH (90:10) to afford 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2oxaborolan-2-ol (40 mg, 80%). ¹H NMR (CDCh, 400 MHz): δ 7.73 (br s, 1H), 7.51-7.66 (m, 4H), 6.92-7.00 (m, 2H), 4.36 (d, J= 3.1 Hz, 2H), 4.12 (t, J= 6.8 Hz, 2H), 3.92 (s, 3H), 3.56 (br s, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 1 H), 1.08 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H). LCMS m/z = 342 [MH]⁺.

198

199

Example 28: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol

4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol (105 mg, 46%) was prepared in an analogous manner to Example 25 using 3-(1 -((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5-(4methoxy-3-propoxyphenyl)pyridine (Préparation 32, 370 mg, 0.668 mmol). ¹H NMR (DMSO-de, 400MHz): δ 8.71 (s, 1 H), 7.86-7.91 (m, 2H), 7.75 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 2.0, 8.6 Hz, 1 H), 7.36-7.44 (m, 1 H), 7.07 (d, J = 8.6 Hz, 1 H), 4.95 (d, J = 2.0 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 2.15 (s, 3H), 1.71-1.85 (m, 2H), 1.01 (t, J= 7 A Hz, 3H). LCMS m/z = 340 [MH]⁺.

Example 29: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol

To a solution of ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (Préparation 33, 134 mg, 0.277 mmol) in THF (3.0 mL) at about 20 °C was added LiBH₄ (6.0 mg, 0.28 mmol), followed by water (0.10 mL). The reaction mixture was stirred at about 20 °C for about 3 h. Another portion of LiBH₄ (25 mg, 1.15 mmol) and water (0.2 mL) was added. The mixture was stirred at about 20 °C for about 5 min. Another portion of LiBH₄ (25 mg, 1.15 mmol) and water (0.3 mL) was added and stirred at about 20 °C for about 10 min. The mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine and dried over Na₂SO4. The mixture was filtered, concentrated and dissolved in THF (3 mL) and water (1 mL).The solution was treated with excess L1BH4 at about 20 °C for about 3 h. The mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by préparative HPLC (Prep HPLC Method C) to afford 4(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol (46.1 mg, 49%). ¹H NMR (CD₃OD, 500MHz): δ 7.80 (br s, 1H), 7.74 (d, J= 1.5 Hz, 1H), 7.67 (d, J= 8.1 Hz, 1H), 7.62 (m, 1H), 7.32 (d, J= 7.1 Hz, 1H), 7.07 (d, J= 8.3 Hz, 1H), 5.51 (s, 1H), 4.29 (d, J = 8.8 Hz, 1H), 4.07-4.16 (m, 3H), 3.92 (s, 3H), 3.47 (m, 1H), 3.19 (m, 1H), 1.88 (m, 2H), 1.55 (d, J= 16.1 Hz, 1H), 1.51 (s, 3H), 1.20 (d, J = 15.7 Hz, 1H), 1.10 (t, J = 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺.

200

Example 30: 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol

A mixture of 5-(3-((tert-butyldimethylsilyl)oxy)-1 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)butan-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine (Préparation 34, 160 mg, 0.29 mmol) in AcOH (6 mL) and water (1 mL) was stirred at about 70 °C for about 21 h. The mixture was concentrated, dissolved in MeCN (15 mL) and concentrated again. The mixture was purified by préparative HPLC (Prep HPLC Method D) to afford 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin4-yl)-5-methyl-1,2-oxaborolan-2-ol (10.6 mg, 11%). Ή NMR (DMSO-d₆, 400MHz): δ 9.12 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1 H), 7.68-7.81 (m, 3H), 7.07-7.16 (m, 2H), 4.64 (t, J = 6.5 Hz, 1H), 4.25-4.35 (m, 1H), 4.04 (t, J = 6.5 Hz, 3H), 3.84 (s, 5H), 3.64 (d, J= 9.0 Hz, 1H), 2.92-3.01 (m, 1H), 1.74-1.83 (m, 3H), 1.48 (dd, J= 10.0, 16.1 Hz, 1H), 1.24-1.39 (m, 2H), 1.17 (d, 4 = 6.0 Hz, 3H), 1.01 (t, 4 = 7.0 Hz, 6H), 0.77 (d, 4 = 7.0 Hz, 1H). LCMS m/z = 343 [MH]⁺.

Example 31: 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan2-ol

Turbo Grignard (0.5 mL, 1.3 M in THF) was stirred with anhydrous 1,4-dioxane (0.05 mL) at about 20 °C under N₂ for about 30 min to afford a mixture which was used directly in the following procedure (Reagent A). To a solution of 3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 77, 120 mg, 0.25 mmol) in THF (0.50 mL) under N₂ was added Reagent A. The mixture was stirred at about 20 °C for about 1 h. Trimethyl borate (0.33 mL, 2.98 mmol) was added and stirred at about 20 °C under N₂ for about 1 h. The cooled mixture was treated with HCl in IPA (5.5 M, 0.45 mL, 2.48 mmol) for about 1 h. The mixture was diluted with 1 M HCl and washed with EtOAc. The EtOAc layer was extracted with 1 M HCl (2x5 mL). The combined aqueous extracts were neutralized to pH 6-7 with K3PO4. The aqueous extract was extracted with EtOAc (3x10 mL). The combined EtOAc extracts were dried over Na₂SO₄, filtered and concentrated. The residue was purified by préparative SFC (Prep SFC Method S) to afford 4-(hydroxymethyl)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (38 mg, 43%). ¹H NMR (DMSO-de, 400MHz): δ 8.69 (d, 4= 2.0 Hz, 1H), 8.63 (s, 1H), 8.37 (d, 4 = 2.0 Hz, 1H), 7.75 (m, 1H), 7.19 - 7.28 (m, 2H),

201

7.08 (d, J= 8.6 Hz, 1H), 4.99 (m, 1H), 4.39 (d, J = 9.0 Hz, 1H), 4.00 - 4.13 (m, 4H), 3.82 (s, 3H),

3.47 (brs, 2H), 1.77 (m, 2H), 1.28- 1.38 (m, 1H), 1.14-1.22 (m, 1 H), 0.96 - 1.08 (m, 3H). LCMS m/z = 358 [MH]⁺.

Example 32: 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (Préparation 1, 1.0 g, 1.95 mmol) in AcOH (15 mL), THF (5 mL) and water (5 mL) was stirred at about 55 °C for about 6 h. The mixture was concentrated and the residue was purified by préparative HPLC (Prep HPLC Method E) to afford 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (98 mg, 17%). ¹H NMR (DMSO-d₆, 400MHz): δ 8.72 (d, J = 2.8 Hz, 2H), 8.43 (d, J = 2.0 Hz, 1 H), 7.95 (t, J = 2.0 Hz, 1 H), 7.25-7.29 (m, 1 H), 7.06 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 4.28 Hz, 1 H), 3.84-3.88 (m, 4H), 3.80 (s, 3H), 3.46-3.54 (m, 1H), 1.28-1.34 (m, 1H), 1.12-1.18 (m, 1H). LCMS m/z = 300 [MH]⁺

Example 33: 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (Préparation 3, 3.80 g, 7.20 mmol) in AcOH (60 mL) and water (10 mL) was stirred at about 50 °C for about 1 h. The mixture was concentrated and the residue was purified by préparative HPLC (Prep HPLC Method F) to afford 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (810 mg, 34%). ¹H NMR (DMSO-de, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 1.6 Hz, 1 H), 7.92-7.94 (m, 1H), 7.23-7.29 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 4.28 (t, J = 8.2 Hz, 1H), 4.13 (q, J = 6.8 Hz, 2H), 3.86 (t, J= 9.0 Hz, 1H), 3.80 (s, 3H), 3.45-3.55 (m, 1H), 1.28-1.39 (m, 4H), 1.1 ΟΙ.20 (m, 1H). LCMS m/z = 314 [MH]⁺.

Example 34: 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

202

A mixture of 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Préparation 5, 3.44 g, 6.35 mmol) in AcOH (60 mL) and water (10 mL) was stirred at about 50 °C for about 1 h. The mixture was concentrated and the residue was purified by préparative HPLC (Prep HPLC Method G) to afford 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.04 g, 49%). ¹H NMR (DMSO-c/_s, 400MHz): δ 8.70 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23-7.26 (m, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 4.28 (t, J = 8.2 Hz, 1H), 4.03 (t, J= 6.4 Hz, 2H), 3.86 (t, J= 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.54 (m, 1H), 1.7110 1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J= 10.5, 16.4 Hz, 1H), 1.00 (t, J = 7.4 Hz, 3H). LCMS m/z = 328 [MH]⁺.

Example 35: 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (103 mg, 43%) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-isopropoxy-4methoxyphenyl)pyridine (Préparation 9, 400 mg, 0.74 mmol) and purified by préparative HPLC (Prep HPLC Method H). Ή NMR (DMSO-d₆, 400MHz): δ 8.72 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H),

8.42 (d, J = 2.0 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.29 - 7.24 (m, 2H), 7.07 (d, J = 8.0 Hz, 1 H),

4.68-4.74 (m, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1 H), 3.79 (s, 3H), 3.47-3.55 (m, 1H), 1.26-1.35 (m, 7H), 1.10-1.18 (m, 1 H). LCMS m/z = 328 [MH]⁺.

Example 36: 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yI)-1,2-oxaborolan-2-ol

4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (45 mg, 10 %) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-cyclopropoxy-425

203 methoxyphenyl)pyridine (Préparation 10, 750 mg, 1.39 mmol) and purified by préparative HPLC (Prep HPLC Method I). Ή NMR (DMSO-d₆, 400MHz): δ 8.69-8.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.28 (dd, J = 2.4, 8.3 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.25-4.31 (m, 1 H), 3.97-4.01 (m, 1 H), 3.86 (t, J = 8.8 Hz, 1 H), 3.78 (s, 3H), 3.463.57 (m, 1H), 1.32 (dd, J = 8.1, 16.4 Hz, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1 H), 0.76-0.83 (m, 2H), 0.67-0.72 (m, 2H). LCMS m/z = 326 [MH]⁺.

Example 37: 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.5 g, 75%) was prepared in an analogous manner to Example 33 using 3-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine (Préparation 11, 4.0 g, 6.1 mmol) and purified by préparative HPLC (Prep HPLC Method J). ¹H NMR (DMSO-de, 400MHz): δ 8.70-8.72 (m, 2H), 8.42 (d, J = 2.0 Hz, 1 H), 7.94 (t, J = 2.2 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 7.26 (dd, J = 2.1, 8.4 Hz, 1 H), 7.07 (d, J = 8.6 Hz, 1 H), 4.88 (t, J = 5.4 Hz, 1 H), 4.25-4.30 (m, 1 H), 4.09 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1 H), 3.81 (s, 3H), 3.75 (q, J = 5.2 Hz, 2H), 3.46-3.53 (m, 1 H), 1.28-1.34 (m, 1H), 1.15 (dd, 4=10.5, 16.1 Hz, 1H). LCMS m/z = 330 [MH]⁺.

Example 38: 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (2.5 g, 41%) was prepared in an analogous manner to Example 33 using 3-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(3-((tertbutyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Préparation 12, 12 g, 18.0 mmol) and purified by préparative HPLC (Prep HPLC Method K). ¹H NMR (DMSO-de, 400MHz): δ 8.68-8.72 (m, 2H), 8.43 (d, J = 2.0 Hz, 1 H), 7.94 (t, J = 2.0 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.23-7.27 (m, 1H), 7.06 (d, J= 8.5 Hz, 1H), 4.55 (t, J= 5.1 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.86 (t, J = 9.0 Hz, 1 H), 3.80 (s, 3H), 3.58 (q, J = 6.0 Hz, 2H), 3.44-3.55 (m, 1H), 1.86-1.92 (m, 2H), 1.27-1.35 (m, 1H), 1.11-1.19 (m, 1H). LCMS m/z = 344 [MH]⁺.

204

Example 39: 4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (122 mg, 29%) was prepared in an analogous manner to Example 33 using 3-(1-((tert5 butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2fluoroethoxy)-4-methoxyphenyl)pyridine (Préparation 13, 700 mg, 1.28 mmol) and purified by préparative HPLC (Prep HPLC Method L). ¹H NMR (DMSO-d₆, 400MHz): δ 8.71-8.78 (m, 2H), 8.44 (d, J= 1.5 Hz, 1H), 7.96 (t, J = 2.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.10 (d, 4= 8.0 Hz, 1H), 4.81-4.87 (m, 1 H), 4.70-4.75 (m, 1 H), 4.38-4.43 (m, 1 H), 4.30-4.34 (m, 1 H), 4.27 (d, J = 8.5 Hz, 10 1H), 3.87 (t, J= 9.0 Hz, 1H), 3.83 (s, 3H), 3.47-3.57 (m, 1H), 1.32 (dd, J= 8.3, 16.3 Hz, 1H),

1.10 -1.21 (m, 1H). LCMS m/z = 332 [MH]⁺.

Example 40: 4-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol was prepared in an analogous manner Example 33 using tert-butyl(2-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilane (Préparation 14). Ή NMR (DMSO-c/₆, 400MHz): δ 7.50 (brs, 1H), 7.46 (d, J= 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H) 7.18-7.25 (m, 3H), 7.04 (d, J = 8.2 Hz, 1H), 4.69 (t, 4= 5.9 Hz, 1H), 4.57 (t, J = 5.9 Hz, 1H), 4.26 (t, 4= 7.8 Hz, 1H), 4.02-4.18 (m, 3H), 3.80 (s, 3H), 3.42-3.51 (m, 1H), 2.07-

2.19 (m, 2H), 1.22-1.32 (m, 1H), 1.05-1.12 (m, 1H). LCMS m/z = 345 [MH]⁺.

Example 41: 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2ol

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol was prepared (80 mg, 42%) in an analogous manner to Example 33 using 3-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Préparation 15, 300 mg, 0.519 mmol) and

205 purified by préparative HPLC (Prep HPLC Method M). ¹H NMR (DMSO-d₆, 400MHz): δ 8.69 (s,

H), 8.48 (d, J = 2.0 Hz, 1 H), 8.34 (d, J = 1.5 Hz, 1 H), 7.61 (s, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 6.80-7.14 (m, 2H), 4.27 (t, J = 8.3 Hz, 1 H), 4.08 (q, J = 6.8 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.25-1.38 (m, 4H), 1.00-1.12 (m, 1H). LCMS m/z = 364 [MH]⁺.

Example 42: 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2carbonitrile

To a solution of 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,Tbiphenyl]-2-carbonitrile (Example 43, 500 mg, 1.43 mmol) in EtOAc (15 mL) was added PtO₂(16 mg, 72 umol) under N₂. The mixture was stirred under H₂ (15 psi) at about 0 °C for about 2 h. The mixture was filtered and concentrated. The residue was purified by préparative HPLC (Prep HPLC Method N) to afford 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'biphenyl]-2-carbonitrile (284 mg, 55%). ¹H NMR (DMSO-de, 400MHz): δ 7.45 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1 H), 7.34 (t, J = 7.2 Hz, 2H), 7.26 (d, J = 8.8 Hz, 1 H), 4.26 (t, J = 8.0 Hz, 1H), 4.12 (t, J= 6.0 Hz, 2H), 3.89 (s, 3H), 3.81 (t, J= 8.8 Hz, 1H), 3.43-3.52 (m, 1H), 1.691.78 (m, 2H), 1.29 (q, J= 8.0 Hz, 1H). 1.07-1.11 (m, 1H), 1.01 (t, J= 7.6 Hz, 3H). LCMS m/z = 352 [MH]⁺.

Example 43: 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]2-carbonitrile

To a mixture of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (Préparation 30, 13.6 g, 28.5 mmol) in THF (150 mL) and MeOH (5 mL) was added NaBH₄ (754 mg, 19.9 mmol) slowly at about 0 °C. The mixture was stirred at about 20 °C for about 1 h. Water (150 mL) was added and the mixture was extracted with EtOAc (2 x 150 mL). The combined EtOAc extracts were washed with brine (150 mL), dried with Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1), then re-crystallized from EtOH (30 mL) at about 0 °C to afford 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3propoxy-[1,1'-biphenyl]-2-carbonitrile (2.60 g, 26%). ¹H NMR (DMSO-de, 400MHz): δ 8.71 (s,

206

H), 7.70 (s, 1 H), 7.64-7.65 (m, 1 H), 7.53 (d, J = 4.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 4.95 (s, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.91 (s, 3H), 1.69-1.77 (m, 2H), 1.02 (t, J= 7.2 Hz, 3H). LCMS m/z = 350 [MH]⁺.

207

Example 44: 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (90 mg, 25%) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridine (Préparation 16, 600 mg, 1.1 mmol) and purified by préparative HPLC (Prep HPLC Method O). ¹H NMR (DMSO-d₆, 400MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J = 1.47 Hz, 1 H), 8.00 (s, 1 H), 7.27 (dd, J = 2.0, 11.7 Hz, 1 H), 7.20 (s, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 4.21 (q, J = 6.9 Hz, 2H), 3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 332 [MH]⁺.

Example 45: 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (150 mg, 30%) was prepared in an analogous manner to Example 33 using 3-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-chloro-5ethoxy-4-methoxyphenyl)pyridine (Préparation 17, 800 mg, 1.42 mmol) and purified by préparative HPLC (Prep HPLC Method P). Ή NMR (DMSO-c/₆, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1 H), 8.70 (s, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.02 (t, J = 2.2 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.34 (d, J= 2.0 Hz, 1H), 4.18-4.30 (m, 3H), 3.83-3.91 (m, 1H), 3.81 (s, 3H), 3.44-3.57 (m, 1H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.22 (m, 1H). LCMS m/z = 347 [MH]⁺.

Example 46: 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (385 mg,

32%) was prepared in an analogous manner to Example 33 using 3-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(5-ethoxy-2fluoro-4-methoxyphenyl)pyridine (Préparation 18, 2.0 g, 3.67 mmol) and purified by préparative

208

HPLC (Prep HPLC Method Q). Ή NMR (DMSO-d₆, 400MHz): δ 8.72 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.03 (d, J= 12.4 Hz, 1H), 4.28 (t, J= 8.2 Hz, 1H),

4.07 (q, J= 7.0 Hz, 2H), 3.82-3.86 (m, 4H), 3.46-3.55 (m, 1H), 1.29-1.34 (m, 4H), 1.07-1.14 (m, 1 H). LCMS m/z = 332 [MH]⁺.

Example 47: 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.6 g, 65%) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-chloro-5-ethoxy-4methoxyphenyl)pyridine (Préparation 19, 4.1 g, 7.30 mmol) and purified by préparative HPLC (Prep HPLC Method R). Ή NMR (DMSO-d₆, 400MHz): δ 8.71 (s, 1H), 8.48 (t, J= 2.0 Hz, 2H), 7.76 (t, J= 2.2 Hz, 1H), 7.15 (s, 1H), 7.01 (s, 1H), 4.26-4.30 (m, 1H), 4.06 (q, J= 7.0 Hz, 2H), 3.81-3.85 (m, 4H), 3.47-3.55 (m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H). LCMS m/z = 348 [MH]⁺.

Example 48: 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol

4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol (780 mg, 49%) was prepared in an analogous manner to Example 33 using 5'-(1 -((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)propan-2-yl)-3-fluoro-5methoxy-6-propoxy-2,3'-bipyridine (Préparation 22, 4.02 g, 7.14 mmol) and purified by préparative HPLC (Prep HPLC Method S). Ή NMR (DMSO-d_e, 400MHz): δ 8.89 (s, 1H), 8.73 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J = 12.0 Hz, 1H), 4.28-4.33 (m, 3H), 3.87 (s, 3H), 3.82 (t, J = 8.7 Hz, 1 H), 3.49-3.57 (m, 1 H), 1.73-1.81 (m, 2H), 1.31-1.37 (m, 1 H), 1.031.09 (m, 1 H), 0.98 (t, J = 7.5 Hz, 3H). LCMS m/z = 347 [MH]⁺.

Example 49: 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

209

4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.2 g, 49%) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-fluoro-4-methoxy-55 propoxyphenyl)pyridine (Préparation 20, 4.0 g, 7.1 mmol) and purified by préparative HPLC (Prep HPLC Method T). ¹H NMR (DMSO-d₆, 400MHz): δ 8.89 (s, 1H), 8.74 (s, 1H), 8.49 (d, J = 2.0 Hz, 1 H), 8.09 (s, 1 H), 7.47-7.53 (m, 1 H), 4.27-4.36 (m, 3H), 3.87 (s, 3H), 3.82 (t, J = 8.7 Hz, 1H), 3.50-3.56 (m, 1H), 1.75-1.80 (m, 2H), 1.34 (dd, J= 8.2, 16.3 Hz, 1H), 1.01-1.12 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 347 [MH]⁺.

Example 50: 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (0.51 g, 31%) was prepared in an analogous manner to Example 33 using 3-(1 -((tert15 butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4(difluoromethoxy)-3-propoxyphenyl)pyridine (Préparation 21,2.6 g, 4.50 mmol) and purified by préparative HPLC (Prep HPLC Method U). Ή NMR (DMSO-d₆, 400MHz): δ 8.74 (d, J = 2.1Hz, 1 H), 8.72 (s, 1 H), 8.49 (d, J = 2.0Hz, 1 H), 8.00 (t, J = 2.0Hz, 1 H), 7.45 (d, J = 1,6Hz, 1 H), 7.287.31 (m, 2H), 7.09 (t, J = 74.5Hz, 1 H), 4.28 (t, J = 8.3Hz, 1 H), 4.12 (t, J = 6.4Hz, 2H), 3.87 (t, J =

9.1Hz, 1H), 3.47-3.56 (m, 1H), 1.73-1.82 (m, 2H), 1.29-1.35 (m, 1H), 1.12-1.19 (m, 1H), 1.01 (t,

J = 7.5Hz, 3H). LCMS m/z = 382 [MH+H₂O]⁺.

Example 51: 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol

OH

4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol was prepared (720 mg, 25%) in an analogous manner to Example 33 using 5'-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine (Préparation 23, 1.034 g, 1.9 mmol) and purified by préparative HPLC (Prep HPLC Method V).

210

Ή NMR (DMSO-d₆, 400ΜΗζ): δ 8.76 (d, J = 2.2 Hz, 1 H), 8.72 (s, 1 H), 8.48 (d, J = 2.0 Hz, 1 H),

8.06 (d, J = 2.0 Hz, 1 H), 8.01 (t, J = 2.2 Hz, 1 H), 7.61 (d, J = 2.2 Hz, 1 H), 4.26-4.31 (m, 1 H), 4.08 (t, J= 6.6 Hz, 2H), 3.92 (s, 3H), 3.87 (t, J= 9.1 Hz, 1H), 3.48-3.56 (m, 1H), 1.73-1.82 (m, 2H), 1.28-1.35 (m, 1H), 1.13-1.21 (m, 1H), 1.00 (t, J= 7.5 Hz, 3H). LCMS m/z = 329 [MH]⁺.

Example 52: 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (182 mg, 43%) was prepared in an analogous manner to Example 33 using 5-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yI)-3-(3-ethoxy-4methoxyphenyl)-2-methylpyridine (Préparation 24, 700 mg, 1.29 mmol) and purified by préparative HPLC (Prep HPLC Method W). Ή NMR (DMSO-c/₆, 400MHz): δ 8.67 (s, 1H), 8.33 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 6.88 (dd, 4= 2.0, 7.8 Hz, 1H), 4.24 (t, 4= 8.1 Hz, 1H), 4.04 (q, 4 = 6.9 Hz, 2H), 3.76-3.83 (m, 4H), 3.39-3.50 (m, 1H), 2.40 (s, 3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺.

Example 53: 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (0.06 g, 33%) was prepared in an analogous manner to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4methylpyridine (Préparation 35, 0.28 g, 0.51 mmol) and purified by préparative HPLC (Prep HPLC Method X). ¹H NMR (DMSO-c/_e, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 2.3 Hz, 1 H), 6.82-6.85 (m, 1 H), 4.24-4.28 (m, 1 H), 4.03 (q, J = 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s, 3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H), 1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺.

Example 54: 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol

211

4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpynmidin-4-yl)-1,2-oxaborolan-2-ol (314 mg, 95%) was prepared in an analogous manner to Example 33 using ethyl 2-(6-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy3-propoxyphenyl)pyrimidin-4-yl)acetate (Préparation 28, 500 mg, 0.96 mmol) and purified by préparative HPLC (Prep HPLC Method Y). Ή NMR (CD₃OD, 400MHz): δ 8.03 (dd, J = 2.0, 8.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.07 (s, 1H), 7.05 (d, J= 8.3 Hz, 1H), 4.17 (br s, 1H), 4.07 (t, J = 6.5 Hz, 2H), 4.00 (br s, 1 H), 3.91 (s, 2H), 3.41 (br s, 1 H), 2.52 (s, 2H), 1.84-1.89 (m, 2H), 1.29-1.38 (m, 1 H), 1.21-1.29 (m, 1 H), 1.09 (t, J = 7.3 Hz, 3H). LCMS m/z = 343 [MH]⁺.

Example 55: 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (582 mg, 36%) was prepared in an analogous manner to Example 33 using 4-( 1 -((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (Préparation 25, 2.5 g, 4.09 mmol) and purified by préparative HPLC (Prep HPLC Method Z). Ή NMR (DMSO-de, 400MHz): δ 8.72 (s, 1H), 8.03 (dd, J= 2.0, 8.6 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d, J= 8.6 Hz, 1H), 4.32 (dd, J = 7.4, 9.0 Hz, 1 H), 3.98-4.09 (m, 3H), 3.86 (s, 3H), 3.73-3.82 (m, 1 H), 1.73-1.84 (m, 1H), 1.31-1.41 (m, 1H), 1.18-1.26 (m, 2H), 1.01 (t, J =7.4 Hz, 3H). LCMS m/z = 397 [MH]⁺.

Example 56: 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol

4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol (30 mg, 7%) was prepared in an analogous manner to Example 33 using 2-(1-((tert-butyldimethylsilyl)oxy)-320225

212 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine (Préparation 26, 720 mg, 1.36 mmol) and purified by préparative HPLC (Prep HPLC Method AA). ¹H NMR (DMSO-c/β, 400MHz): δ 9.06 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.37-8.50 (m, 1H), 7.65-7.79 (m, 2H), 7.08 (d, J= 8.8 Hz, 1H), 4.30 (t, J= 8.2 Hz, 1H), 4.12 (q, J= 6.9 Hz, 2H), 3.98 (dd, J= 6.5, 8.9 Hz, 1H), 3.83 (s, 3H), 3.66-3.70 (m, 1H), 1.37 (t, J= 7.0 Hz, 3H), 1.27-1.34 (m, 1H), 1.14-1.22 (m, 1H). LCMS m/z = 315 [MH]⁺.

Example 57: 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (0.2 g, 38.4%) was prepared in an analogous manner to Example 33 using 4-(1-((tertbutyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(((tertbutyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (Préparation 29, 1.0 g, 1.5 mmol) and purified by préparative HPLC (Prep HPLC Method BA). ¹H NMR (DMSO-c/e, 400MHz): δ 8.71 (s, 1 H), 8.00 (dd, J = 2.0, 8.0 Hz, 1 H), 7.96 (d, J = 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.27-7.31 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 5.60-5.66 (m, 1 H), 4.59 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 7.0, 9.0 Hz, 1 H), 3.96-4.04 (m, 2H), 3.83 (s, 3H), 3.57-3.65 (m, 1 H), 1.75-1.82 (m, 2H), 1.25-1.35 (m, 1H), 1.12-1.21 (m, 1H), 0.96-1.07 (m, 3H). LCMS m/z = 359 [MH]⁺.

Example 58: 4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol

4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol (0.31 g, 37%) was prepared in an analogous manner to Example 33 using 4-(1-((tert-butyldimethylsilyl)oxy)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole (Préparation 36, 1.42 g, 2.66 mmol) and purified by préparative HPLC (Prep HPLC Method CA). Ή NMR (DMSO-c/β, 400MHz): δ 8.66 (br s, 1 H), 7.42-7.46 (m, 2H), 7.30 (s, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 4.24-4.28 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2H), 3.90-3.95 (m, 1 H), 3.82 (s, 3H), 3.55-3.63 (m, 1H), 1.36 (t, J= 7.0 Hz, 3H), 1.25-1.31 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z = 320 [MH]⁺.

213

Example 59: (2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2dioxaborinan-2-yl)propan-1-ol

To hexylene glycol (1.0 g, 8.46 mmol) was added (R)-4-(5-(4-methoxy-35 propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4, 0.051 g, 0.16 mmol) at about 20 °C. The mixture was stirred until homogeneous to afford (2R)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol (5 wt% solution in hexylene glycol) as a mixture of diastereomers (1:1 ratio). ¹H NMR (DMSO-de, 400MHz): δ 8.64 (d, J = 2.2 Hz, 1 H), 8.32 (d, J = 1.9 Hz, 1 H), 7.77 (t, J = 2.2 Hz, 1 H), 7.23 (s,

1H), 7.17-7.25 (m, 1H), 7.06 (d, J= 8.1 Hz, 1H), 4.61 (m, 1H), 4.02 (t, J= 6.6 Hz, 2H), 3.97-4.07 (m, 1H), 3.80 (s, 3H), 3.46-3.58 (m, 2H), 2.84-2.98 (m, 1H), 1.69-1.83 (m, 3H), 1.14 (m, 1H), 1.02-1.09 (m, 10H), 1.00 (t, J = 7.4 Hz, 3H), 0.83 (dd, J = 9.0, 15.0 Hz, 1 H). LCMS m/z = 428 [MH]⁺.

The following compounds, Example 60-, were prepared similarly using methods described above. Examples containing an asterisk (*), désignâtes a single enantiomer obtained through chiral purification methods. For those examples characterized by HPLC rétention time (RT), the analytical HPLC methods are described.

Example No.	Structure and Name	Analytical Data
60	OH T X Γ .b N ' 4-(5-methoxy-6-propoxy-[2,3'-bipyridin]5'-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-dg, 400 MHz): δ 9.04 (d, J = 2.0 Hz, 1 H), 8.71 (s, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 8.22 (t, J = 2.2 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1 H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m, 1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1 H), 1.75-1.84 (m, 2H), 1.33 (dd, J = 8.3, 16.1 Hz, 1H), 1.06- 1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 329 [MH]⁺.

214

Example 61	OH Γ II b 4-(5-methoxy-6-propoxy-[2,3'-bipyridin]- 5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-d₆,400 MHz): δ 9.04 (d, J = 2.0 Hz, 1 H), 8.71 (s, 1 H), 8.45 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m, 1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1 H), 1.75-1.84 (m, 2H), 1.33 (dd, J = 8.3, 16.1 Hz, 1H), 1.06- 1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 329 [MH]⁺. RT [Analytical SFC Method I] = 4.57 min.
62	OH r-B T 1 * Γ > 4-(5-methoxy-6-propoxy-[2,3'-bipyridin]5'-yl)-1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-d₆,400 MHz): δ 9.04 (d, J = 2.0 Hz, 1 H), 8.71 (s, 1 H), 8.45 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m, 1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1 H), 1.75-1.84 (m, 2H), 1.33 (dd, J = 8.3, 16.1 Hz, 1H), 1.06- 1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 329 [MH]⁺. RT [Analytical SFC Method I] = 4.98 min.
63	OH r-B f JC X X z° 4-(3'-(2-fluoroethoxy)-4'-methoxy-[1,1 'biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 7.51 (br s, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1H), 7.18-7.23 (m, 3H), 7.06 (d, J= 8.2 Hz, 1H), 4.81-4.83 (m, 1H), 4.694.71 (m, 1H), 4.36-4.38 (m, 1H), 4.244.30 (m, 2H), 3.79-3.83 (m, 4H), 3.423.51 (m, 1H), 1.26-1.32 (m, 1H), 1.051.12 (m, 1H). LCMS m/z = 331 [MH]⁺.

215

64	OH ....... ΌΗ 4-(4-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-c/β, 400MHz): δ 8.59 (br s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.577.66 (m, 2H), 7.11 (s, 1H), 7.00-7.06 (m, 1H), 5.41 (brs, 1H), 4.56 (s, 2H), 4.28 (dd, J = 7.3, 8.78 Hz, 1H), 3.94-4.03 (m, 3H), 3.80 (s, 3H), 3.52-3.62 (m, 1H), 1.70-1.82 (m, 2H), 1.13-1.30 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 376 [MH+H₂O]⁺.
65	I OH V^;i X (j 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.59 (s, 1H), 7.70-7.75 (m, 3H), 7.62 (dd, J = 2.0, 8.3 Hz, 1H), 7.10-7.20 (m, 1H), 7.03 (d, J = 8.6 Hz, 1 H), 4.90 (t, J = 5.9 Hz, 1 H), 4.29 (t, J = 8.2 Hz, 1H), 3.99 (dd, J = 7.0, 8.9 Hz, 1H), 3.79 (s, 3H), 3.56-3.63 (m, 1H), 1.87-2.04 (m, 2H), 1.68-1.81 (m, 4H), 1.59 (brs, 2H), 1.16-1.30 (m, 2H). LCMS m/z = 372 [MH+H₂O]⁺.
66	I OH rx °^ί r^B' \A„ÀXNr/^b O ψ 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1	LCMS m/z = 354 [MH]⁺. RT [Analytical SFC Method V] = 3.60 min.
67	I OH /x vk zLL»X/“ (j 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 2	LCMS m/z = 354 [M+H]⁺. RT [Analytical SFC Method V] = 3.93 min.

216

68	I OH A ΛΑ Α> ⁰ Tj^z ΙΨ 4-(5-(4-methoxy-3-(thietan-3yloxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.72 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.31 (dd, J = 2.3, 8.3 Hz, 1 H), 7.22 (d, J = 2.5 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 5.445.53 (m, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.47 (dd, J = 3.8, 7.8 Hz, 5H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.11 1.19 (m, 1H). LCMS m/z = 358 [MH]⁺.
69	OH T X F b 4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	¹H NMR (MeOD-dg, 400 MHz): δ 8.40 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.69 (t, J = 2.0 Hz, 1 H), 6.92 (s, 1 H), 6.80 (s, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.83-3.90 (m, 4H), 3.33-3.40 (m, 1H), 2.21 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.16-1.33 (m, 2H) LCMS m/z = 328 [MH]⁺.
70	OH T X *Γ b 4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.69 (br s, 1 H), 8.31-8.49 (m, 2H), 7.66 (br s, 1 H), 6.91 (brs, 1H), 6.81 (brs, 1H), 4.27 (br s, 1H), 4.01 (d, J = 5.9 Hz, 2H), 3.733.90 (m, 4H), 3.49 (br s, 1H), 2.18 (br s, 3H), 1.30 (brs, 3H), 0.99-1.16 (m, 2H). LCMS m/z = 346 [MH+H₂O]⁺. RT [Analytical SFC Method L] = 2.67 min.
71	OH X^ X T b TF 4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.69 (br s, 1H), 8.31-8.49 (m, 2H), 7.66 (brs, 1H), 6.91 (brs, 1H), 6.81 (brs, 1H), 4.27 (br s, 1H), 4.01 (d, J = 5.9 Hz, 2H), 3.733.90 (m, 4H), 3.49 (br s, 1H), 2.18 (brs, 3H), 1.30 (brs, 3H), 0.99-1.16 (m, 2H). LCMS m/z = 327 [MH]⁺. RT [Analytical SFC Method L] = 2.91 min.

217

72	\ Π ,ΟΗ Λ~Β ' //Χ/Ο S-_N 4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4- thiadiazol-3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 7.58 (dd, J = 1.8, 8.4 Hz, 1H), 7.46 (d, J = 1.71 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.27-4.37 (m, 1H), 4.07-4.16 (m, 3H), 3.85 (s, 3H), 3.76-3.83 (m, 1H), 1.231.43 (m, 5H). LCMS m/z = 321.1 [MH]⁺.
73	OH -Vz A JL JJ / o ^° iCi N 4-(5-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 2.0 Hz, 1 H), 7.81 (d, J = 1.5 Hz, 1 H), 7.26 (t, J = 8.8 Hz, 1H), 7.01 (dd, J= 1.0, 8.8 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.06 (q, J = 7.3 Hz, 2H), 3.80-3.90 (m, 4H), 3.44-3.58 (m, 1H), 1.24-1.39 (m, 4H), 0.99-1.16 (m, 1H). LCMS m/z = 332 [MH]⁺.
74	OH N 4-(5-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 2.0 Hz, 1 H), 7.81 (d, J = 1.5 Hz, 1 H), 7.26 (t, J = 8.8 Hz, 1H), 7.01 (dd, J = 1.0, 8.8 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.06 (q, J = 7.3 Hz, 2H), 3.80-3.90 (m, 4H), 3.44-3.58 (m, 1H), 1.24-1.39 (m, 4H), 0.99-1.16 (m, 1H). LCMS m/z = 332 [MH]⁺. RT [Analytical SFC Method GA] = 6.58 min.
75	OH r-B jT JJ Γ b 4-(3'-isopropoxy-4’-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-de, 400MHz): δ 7.48 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.14-7.24 (m, 3H), 7.00-7.06 (m, 1H), 4.61-4.71 (m, 1H), 4.22-4.29 (m, 1H), 3.77-3.85 (m, 3H), 3.37-3.53 (m, 1H), 1.22-1.31 (m, 7H), 0.99-1.12 (m, 3H). LCMS m/z = 327 [MH]⁺.

218

76	OH ΌΗ (-) 4-(6-(hydroxymethyl)-2-(4-methoxy- 3-propoxyphenyl)pyrimidin-4-yl)-1,2- oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-de, 400MHz): δ 8.71 (s, 1H), 8.00 (dd, J = 2.0, 8.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.277.31 (m, 1H), 7.06 (d, J= 8.5 Hz, 1H), 5.60-5.66 (m, 1 H), 4.59 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 7.0, 9.0 Hz, 1 H), 3.964.04 (m, 2H), 3.83 (s, 3H), 3.57-3.65 (m, 1H), 1.75-1.82 (m, 2H), 1.25-1.35 (m, 1H), 1.12-1.21 (m, 1H), 0.96-1.07 (m, 3H). LCMS m/z = 359 [MH]⁺. [α]²% -10.0 (c = 0.1, EtOH).
77	OH T jl Γ b 4-(3'-ethoxy-4'-methoxy-[1,1 '-bip heny I]3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-c/β, 400MHz): δ 8.65 (s, 1H), 7.50 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.16 (d, J = 1.71 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.26 (t, J = 8.3 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.77-3.84 (m, 4H), 3.42-3.49 (m, 1H), 1.35 (t, J = 7.0 Hz, 3H), 1.28 (dd, J = 8.2, 16.3 Hz, 1H), 1.08 (dd, J = 10.0, 16.4 Hz, 1H). LCMS m/z = 313 [MH]⁺.
78	I OH 4-(5-(4-methoxy-3- ((tetrahydrothiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (brs, 1H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55 (m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, 3H), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J = 10.3, 16.3 Hz, 1H). LCMS m/z = 372 [MH]⁺.

219

4-(5-(4-methoxy-3((tetrahydrothiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, diastereomer 1

4-(5-(4-methoxy-3((tetrahydrothiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, diastereomer 2

4-(5-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol ¹H NMR (DMSO-c/e, 400MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.0 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (br s, 1H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55 (m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, 3H), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J = 10.3, 16.3 Hz, 1H). LCMS m/z = 372.3 [MH]⁺. RT [Analytical SFC Method EA] = 3.30 min.

Ή NMR (DMSO-d₆, 400MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H),5.30 (br s, 1H), 4.27 (t, J = 8.3 Hz, 1H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55 (m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1 H), 2.85-3.00 (m, 3H), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J = 10.3, 16.3 Hz, 1H). LCMS m/z = 372.1 [MH]⁺. RT [Analytical SFC Method EA] = 4.18 min.

Ή NMR (DMSO-ds, 400MHz): δ 8.71 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1 H), 7.82 (d, J = 1.5 Hz, 1 H), 7.26 (t, J = 8.7 Hz, 1 H), 7.01 (dd, J = 1.5, 8.8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H), 3.80-3.86 (m, 1H), 3.44-3.57 (m, 1H), 1.63-1.72 (m, 2H), 1.31 (dd, J = 8.2, 16.3 Hz, 1H), 1.10 (dd, J = 10.3, 16.1 Hz, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺.

220

4-(5-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(6-(1 -hydroxyethyl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, diastereomer 1

4-(5-(4-methoxy-3-propoxyphenyl)-4methylpyridin-3-yl)-1,2-oxaborolan-2-ol

Ή NMR (DMSO-de, 400MHz): δ 8.71 (s, 1 H), 8.54 (t, J = 2.0 Hz, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 7.82 (d, J = 1.5 Hz, 1 H), 7.26 (t, J = 8.7 Hz, 1 H), 7.01 (dd, J = 1.5, 8.8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H), 3.80-3.86 (m, 1H), 3.44-3.57 (m, 1H), 1.63-1.72 (m, 2H), 1.31 (dd, J = 8.2, 16.3 Hz, 1H), 1.10 (dd, J = 10.3, 16.1 Hz, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 372 [MH]⁺. RT [Analytical SFC Method E] = 4.76 min. Ή NMR (DMSO-c/6, 400MHz): δ 8.68 (s, 1H), 8.00 (dd, J = 2.0, 8.3 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1 H), 7.32 (s, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 5.57 (d, J = 4.9 Hz, 1 H), 4.65-4.75 (m, 1H), 4.30 (dd, J = 7.3, 9.3 Hz, 1H), 3.96-4.03 (m, 3H), 3.83 (s, 3H), 3.61 (s, 1H), 1.71-1.83 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.27 (dd, J = 1.5, 8.3 Hz, 1H), 1.11-1.20 (m, 1H), 1.01 (t, J = 7.6 Hz, 3H). LCMS m/z = 391 [MH+H₂O]⁺. RT [Analytical SFC Method E] = 4.07 min.

¹H NMR (DMSO-c/₆, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 6.84 (dd, J = 2.0, 8.3 Hz, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 3.89-3.97 (m, 3H), 3.80 (s, 3H), 3.67 (t, J = 8.1 Hz, 1H), 2.21 (s, 3H), 1.68-1.77 (m, 2H), 1.33 (dd, J = 8.3, 16.1 Hz, 1 H), 1.08 (dd, J = 8.6, 16.4 Hz, 1H), 0.97 (t, J = 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺.

221

85	OH °ΤΊ i r^B' ^ο ΐιΊ ^NT (+) 4-(5-(4-methoxy-3-propoxyphenyl)4-methylpyridin-3-yl)-1,2-oxaborolan-2ol, enantiomer 1	Ή NMR (DMSO-de, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 6.84 (dd, J = 2.0, 8.3 Hz, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 3.89-3.97 (m, 3H), 3.80 (s, 3H), 3.67 (t, J = 8.1 Hz, 1H), 2.21 (s, 3H), 1.68-1.77 (m, 2H), 1.33 (dd, J = 8.3, 16.1 Hz, 1H), 1.08 (dd, J = 8.6, 16.4 Hz, 1 H), 0.97 (t, J = 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺. [α]²% +14.7 (c = 0.1, EtOH).
86	I r 6-(6-(2-hydro yl)pyridin-2-y propoxybenz	OH . / X r^B I 1J i XX i xy-1,2-oxaborolan-4)-3-methoxy-2- onitrile	Ή NMR (DMSO-de, 400MHz): δ 8.58 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1 H), 7.56 - 7.52 (m, 1 H), 7.447.49 (m, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 4.24-4.31 (m, 1H), 4.06-4.14 (m, 3H), 3.91 (s, 3H), 3.60-3.68 (m, 1H), 1.701.79 (m, 2H), 1.20-1.37 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). LCMS m/z = 353 [MH]⁺.
87	I r 6-(6-(2-hydro yl)pyridin-2-y propoxybenz	OH . / X r^B Π I XX J xy-1,2-oxaborolan-4- )-3-methoxy-2- onitrile, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.58 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1 H), 7.56 - 7.52 (m, 1 H), 7.447.49 (m, 1H), 7.32 (d, J = 7.6 Hz, 1H), 4.24-4.31 (m, 1H), 4.06-4.14 (m, 3H), 3.91 (s, 3H), 3.60-3.68 (m, 1H), 1./ΟΙ.79 (m, 2H), 1.20-1.37 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). LCMS m/z = 353.3 [MH]⁺. RT [Analytical SFC Method M] = 5.79 min.
88	OH °ΥΊ r^B' l X X z° 4-(4'-methoxy-3’-propoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	1H NMR (DMSO-ds, 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1 H), 4.26 (t, J = 8.0 Hz, 1 H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H), 1.73-1.79 (m, 2H), 1.25-1.29 (m,

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		1H), 1.07-1.11 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺.
89	OH II J o 4-(4'-methoxy-3'-propoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1	1H NMR (DMSO-de, 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1 H), 4.26 (t, J = 8.0 Hz, 1 H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H), 1.73-1.79 (m, 2H), 1.25-1.29 (m, 1H), 1.07-1.11 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺. RT [Analytical SFC Method N] = 3.76 min.
90	OH ^z°n ύ Il .1 * I o 4-(4'-methoxy-3'-propoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2	1H NMR (DMSO-ds, 400 MHz): δ 8.66 (s, 1 H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1 H), 4.26 (t, J = 8.0 Hz, 1 H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H), 1.73-1.79 (m, 2H), 1.25-1.29 (m, 1H), 1.07-1.11 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺. RT [Analytical SFC Method N] = 3.97 min.
91	OH / ^F f b /H N ο—Z νχ/ Il / /=/ ^Xs J Æ° 4-(2-(5-ethoxy-2-fluoro-4- methoxyphenyl)thiazol-4-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.66 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.41 (s, 1H), 7.05-7.10 (m, 1H), 4.26 (dd, J = 7.5, 8.5 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.93 (dd, J = 7.5, 9.0 Hz, 1H), 3.83 (s, 3H), 3.57-3.66 (m, 1 H), 1.34 (t, J = 7.0 Hz, 3H), 1.25-1.32 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 338 [MH]⁺.

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92	^F *[ B-OH o—\ w T / j>=/ ^x Æ° (-) 4-(2-(5-ethoxy-2-fluoro-4- methoxyphenyl)thiazol-4-yl)-1,2- oxaborolan-2-ol enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.66 (s, 1 H), 7.62 (d, J = 7.0 Hz, 1 H), 7.41 (s, 1H), 7.05-7.10 (m, 1H), 4.26 (dd, J = 7.5, 8.5 Hz, 1 H), 4.05 (q, J = 6.9 Hz, 2H), 3.93 (dd, J = 7.5, 9.0 Hz, 1H), 3.83 (s, 3H), 3.57-3.66 (m, 1 H), 1.34 (t, J = 7.0 Hz, 3H), 1.25-1.32 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 338 [MH]⁺. RT [Analytical SFC Method O] = 4.13 min. [α]²% -37.9 (c= 0.1, EtOH).
93	I OH Z \ L if I o N 4-(3-(4-(cyclopentyloxy)-5methoxypyrimidin-2-yl)phenyl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.67 (br s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 8.108.15 (m, 1H), 7.39-7.45 (m, 1H), 7.347.38 (m, 1H), 5.56-5.63 (m, 1H), 4.264.32 (m, 1H), 3.89 (s, 3H), 3.80 (t, J = 8.6 Hz, 1H), 3.48-3.55 (m, 1H), 2.04-2.15 (m, 2H), 1.60-1.85 (m, 6H), 1.33 (dd, J = 8.3, 16.1 Hz, 1H), 0.99-1.08 (m, 1H). LCMS m/z = 355 [MH]⁺.
94	OH A L II I o '° iCl F^F N 4-(5-(3-ethoxy-4-methoxy-2(trifluoromethyl)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 8.70 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.26-8.32 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.37-7.43 (m, 1H), 7.05 (d, J = 9.0 Hz, 1 H), 4.19-4.34 (m, 1 H), 4.09 (td, J = 3.1, 9.9 Hz, 2H), 3.87-3.95 (m, 3H), 3.723.83 (m, 1H), 3.46-3.55 (m, 1H), 1.261.37 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 382 [MH]⁺.

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95	OH .L II * 1 o F^F 4-(5-(3-ethoxy-4-methoxy-2- (trifluoromethyl)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-d₆, 400MHz): δ 8.70 (d, J = 2.5 Hz, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.26-8.32 (m, 1H), 7.58 (d, J = 2.0 Hz, 1 H), 7.37-7.43 (m, 1 H), 7.05 (d, J = 9.0 Hz, 1H), 4.19-4.34 (m, 1H), 4.09 (td, J = 3.1, 9.9 Hz, 2H), 3.87-3.95 (m, 3H), 3.723.83 (m, 1H), 3.46-3.55 (m, 1H), 1.261.37 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 382 [MH]⁺. RT [Analytical SFC Method E] = 3.14 min.
96	OH ^°XX J 4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 8.688.75 (m, 2H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23 (dd, J = 1.8, 8.3 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1H), 3.453.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMS m/z = 328 [MH]⁺.
97	OH L II .J b ^KF 4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)- 1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-c/₆, 400MHz): δ 8.688.75 (m, 2H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23 (dd, J = 1.8, 8.3 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1H), 3.453.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMS m/z = 345 [MH+H₂O]⁺. RT [Analytical SFC Method D] = 5.73 min.

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98	OH >G N 4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)- 1,2-oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-de, 400MHz): δ 8.688.75 (m, 2H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23 (dd, J = 1.8, 8.3 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1 H), 3.453.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMS m/z = 328 [MH]⁺. RT [Analytical SFC Method D] = 5.37 min.
99	I OH ΛΊ ³ΥΊ X \ A /L· A A o “ C 4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s, 1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.197.24 (m, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m, 1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H). LCMS m/z = 370 [MH]⁺.
100	I OH r-B ΑΊ A a * y ° 4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol enantiomer 1	¹H NMR (DMSO-c/6, 400MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s, 1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.197.24 (m, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m, 1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H). LCMS m/z = 388 [MH+H₂O]⁺. RT [Analytical SFC Method P] = 3.83 min.

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101	I OH γΑ \ JL * θ 4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s, 1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.197.24 (m, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m, 1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H). LCMS m/z = 388 [MH+H2O]⁺. RT [Analytical SFC Method P] = 4.17 min.
102	OH /°y^ _rB '°'ï Ό I 4-(2-(4-methoxy-3-propoxyphenyl)-6(methoxymethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-ds, 400MHz): δ 8.69 (br s, 1H), 7.99 (dd, J = 1.9, 8.4 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1 H), 7.22 (s, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.54 (s, 2H), 4.30 (dd, J = 7.5, 8.8 Hz, 1H), 3.96-4.03 (m, 3H), 3.83 (s, 3H), 3.58-3.65 (m, 1H), 3.43 (s, 3H), 1.73-1.81 (m, 2H), 1.241.34 (m, 1H), 1.12-1.21 (m, 1H), 0.961.06 (m, 3H). LCMS m/z = 391 [MH+H₂O]⁺.
103	OH /°yx Γ-θ AJCnvA/O N 05® Ό I (-) 4-(2-(4-methoxy-3-propoxyphenyl)- 6-(methoxymethyl)pyrimidin-4-yl)-1,2- oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.69 (br s, 1 H), 7.99 (dd, J = 1.9, 8.4 Hz, 1 H), 7.95 (d, J = 1.8 Hz, 1 H), 7.22 (s, 1 H), 7.07 (d, J = 8.8 Hz, 1H), 4.54 (s, 2H), 4.30 (dd, J = 7.5, 8.8 Hz, 1 H), 3.96-4.03 (m, 3H), 3.83 (s, 3H), 3.58-3.65 (m, 1H), 3.43 (s, 3H), 1.73-1.81 (m, 2H), 1.241.34 (m, 1H), 1.12-1.21 (m, 1H), 0.961.06 (m, 3H). LCMS m/z = 391 [MH+H₂O]⁺. RT [Analytical SFC Method Q] = 3.25 min. [α]²% -38.3 (c = 0.1, EtOH).

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104	OH ^°X1 IT 4-(5-(4-ethoxy-3- propoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol	¹H NMR (DMSO-c/β, 400MHz): δ 8.71 (s, 1 H), 8.70 (d, J = 1.5 Hz, 1 H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1 H), 7.03-7.07 (m, 1 H), 4.27 (t, J = 8.3 Hz, 1H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, 3H), 1.27-1.37 (m, 3H), 1.ΙΟΙ.19 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺.
105	OH GG -G '^'^ο'^ιΠι TT 4-(5-(4-ethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.71 (s, 1 H), 8.70 (d, J = 1.5 Hz, 1 H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1 H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, 3H), 1.27-1.37 (m, 3H), 1.ΙΟΙ.19 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺. RT [Analytical SFC Method R] = 3.48 min.
106	OH /ο-' / 4-(5-(4-ethoxy-3- propoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-c/6, 400MHz): δ 8.71 (s, 1 H), 8.70 (d, J = 1.5 Hz, 1 H), 8.42 (d, J = 1.5 Hz, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1 H), 7.03-7.07 (m, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, 3H), 1.27-1.37 (m, 3H), 1.ΙΟΙ.19 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺. RT [Analytical SFC Method R] = 2.25 min.

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107	OH i jx /χ o ^χ°Ύυ N 4-(5-(2-fluoro-3,4- dimethoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.72 (s, 1H), 8.56 (dd, J = 2.0, 8.8 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1 H), 7.82 (s, 1 H), 7.257.29 (m, 1H), 7.02 (d, J= 8.8 Hz, 1H), 4.28 (t, J= 8.4 Hz, 1H), 3.81-3.87 (m, 7H), 3.41-3.55 (m, 1H), 1.29-1.35 (m, 1H), 1.06-1.13 (m, 1H). LCMS m/z = 318 [MH]⁺.
108	OH jf Ί *Γ b ^X°TU N 4-(5-(2-fluoro-3,4- dimethoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1	LCMS m/z = 332 [MH+H₂O]⁺. RT [Analytical SFC Method S] = 5.28 min.
109	OH r-B JT Ί b θΎΥ/ N 4-(5-(2-fluoro-3,4- dimethoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	LCMS m/z = 318 [MH]⁺. RT [Analytical SFC Method S] = 5.35 min.
110	OH /°^ _rB II / b 4-(4'-methoxy-3'-(pentyloxy)-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	LCMS m/z = 355 [MH]⁺.

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111	OH F K X X b (-) 4-(5-(2-fluoro-4-methoxy-5propoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-de, 400MHz): δ 8.89 (s, 1 H), 8.74 (s, 1 H), 8.49 (d, J = 2.0 Hz, 1H), 8.09 (s, IH), 7.47-7.53 (m, 1H), 4.27-4.36 (m, 3H), 3.87 (s, 3H), 3.82 (t, J = 8.7 Hz, 1H), 3.50-3.56 (m, 1H), 1.751.80 (m, 2H), 1.34 (dd, J= 8.2, 16.3 Hz, 1H), 1.01-1.12 (m, 1H), 0.98 (t, J= 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. [α]²%-17.7 (c = 0.15, EtOH).
112	OH Y X Co °fj'^z 4-(5-(4-(methylthio)-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-de, 400MHz): δ 8.74 (d, J = 2.5 Hz, 1 H), 8.73 (s, 1 H), 8.46 (d, J = 2.0 Hz, 1 H), 7.98 (t, J = 2.0 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.26 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1 H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1 H), 3.46-3.57 (m, 1 H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.271.36 (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 344 [MH]⁺.
113	OH z^sy\ rK II b 4-(5-(4-(methylthio)-3- propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.74 (d, J = 2.5 Hz, 1 H), 8.73 (s, 1 H), 8.46 (d, J = 2.0 Hz, 1 H), 7.98 (t, J = 2.0 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.26 (d, J = 1.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 4.28 (t, J = 8.3 Hz, 1 H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1 H), 3.46-3.57 (m, 1 H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.271.36 (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. RT = 5.23 min.

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114	OH •'θΎΑ H L II * I o ^ο ΓΧ'^ 4-(5-(4-(methylthio)-3- propoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-d₆, 400MHz): δ 8.74 (d, J = 2.5 Hz, 1H), 8.73 (s, 1H), 8.46 (d, J = 2.0 Hz, 1 H), 7.98 (t, J = 2.0 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.26 (d, J = 1.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 4.28 (t, J = 8.3 Hz, 1H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.46-3.57 (m, 1H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.271.36 (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. RT = 5.63 min.
115	OH r® ΧΧ,νΥΑ ₀^y 4-(6-(4-methoxy-3- propoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 9.06 (s, 1 H), 8.67 (s, 1 H), 8.44 (s, 1 H), 7.73 (br s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 4.30 (t, J = 8.2 Hz, 1H), 3.94-4.06 (m, 3H), 3.83 (s, 3H), 3.61-3.74 (m, 1H), 1.71-1.83 (m, 2H), 1.26-1.36 (m, 1H), 1.14-1.22 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 329 [MH]⁺.
116	OH XX x$ 4-(2'-fluoro-4'-methoxy-3'-propoxy-[1,1 'biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-d₆,400 MHz): δ 8.65 (s, 1H), 7.36-7.40 (m, 2H), 7.26-7.32 (m, 2H), 7.16 (t, J= 8.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.25 (t, J= 8.0 Hz, 1H), 3.96 (t, J = 4.2 Hz, 2H), 3.86 (s, 3H), 3.79 (t, J = 8.8 Hz, 1H), 3.34-3.49 (m, 1H), 1.651.71 (m, 2H), 1.26-1.28 (m, 1H), 1.021.08 (m, 1 H), 0.98 (t, J = 8.0 Hz, 3H). LCMS m/z = 343 [MH]’.

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117	N II OH °Ί u L II 1 o 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5dimethoxy-[1,1 '-biphenyl]-3-carbonitrile	Ή NMR (DMSO-de, 400MHz): δ 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1 H), 1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J = 10.0, 16.2 Hz, 1H). LCMS m/z = 324 [MH]⁺.
118	h I ^o^ 3-ethoxy-5 oxaborolar methoxybe	J । OH / -(5-(2-hydroxy-1,2i-4-yl)pyridin-3-yl)-2jnzonitrile	¹H NMR (DMSO-c/₆, 400MHz): δ 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H), 1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J= 10.0, 16.2 Hz, 1H). LCMS m/z = 339 [MH]⁺.
119	r 3-ethoxy-5 oxaborolar methoxybe	t ¹ OH / -(5-(2-hydroxy-1,2- i-4-yl)pyridin-3-yl)-2- ïnzonitrile, enantiomer 1	Ή NMR (DMSO-d₆, 400MHz): δ 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1 H), 1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J = 10.0, 16.2 Hz, 1 H). LCMS m/z = 339.1 [MH]⁺. RT [Analytical SFC Method T] = 4.71 min.
120	OH T 1 JT b 4-(3-(6-ethoxy-5-methoxypyridin-2yl)phenyl)-1,2-oxaborol-2(5H)-ol	¹H NMR (DMSO-de, 400MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 6.27 (s, 1 H), 4.97 (s, 2H), 4.47 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H). LCMS m/z = 312 [MH]⁺.

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121	OH r^B X jl C b ^Ο^Ν^γ^^ 4-(3-(6-ethoxy-5-methoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol	Ή NMR (DMS0-d₆, 400MHz): δ 8.65 (s, 1 H), 7.88 (s, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.32-7.36 (m, 2H), 7.24 (d, J = 7.2 Hz, 1 H), 4.44 (q, J = 7.2 Hz, 2H), 4.27 (t, J = 8.0 Hz, 1 H), 3.82 (m, 4H), 3.43-3.51 (m, 1H) 1.38 (t, J = 6.8 Hz, 3H), 1.30 (q, J= 8.0 Hz, 1H), 1.03-1.10 (m, 1H). LCMS m/z = 314 [MH]⁺.
122	OH .O. d JL if / o ^ Ν^γγ^⁷ 4-(3-(4,5-dimethoxypyrimidin-2yl)phenyl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.67 (br s, 1H), 8.33 (s, 1H), 8.12-8.27 (m, 2H), 7.31-7.50 (m, 2H), 4.24-4.34 (m, 1H), 4.06 (s, 3H), 3.90 (s, 3H), 1.32 (br dd, J = 8.4, 16.2 Hz, 1H), 1.04 (brdd, J = 9.6, 16.1 Hz, 1H). LCMS m/z = 317 [MH]⁺.
123	OH L JJ 4 ,o ^ο^Ν^γγγ^^⁷ 4-(3-(4,5-dimethoxypyrimidin-2yl)phenyl)-1,2-oxaborolan-2-ol, enantiomer 1	RT [Analytical SFC Method U] = 1.64 min.
124	OH z°Y% T_F F T (+) 4-(2-(4-methoxy-3-propoxyphenyl)- 6-(trifluoromethyl)pyrimidin-4-yl)-1,2- oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-de, 400MHz): δ 8.72 (s, 1 H), 8.03 (dd, J = 2.0, 8.6 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d, J = 8.6 Hz, 1 H), 4.32 (dd, J = 7.4, 9.0 Hz, 1H), 3.98-4.09 (m, 3H), 3.86 (s, 3H), 3.73-3.82 (m, 1H), 1.73-1.84 (m, 1H), 1.31-1.41 (m, 1H), 1.18-1.26 (m, 2H), 1.01 (t, J= 7A Hz, 3H). LCMS m/z = 397 [MH+H2O]⁺. [a]²⁰D + 19.4 (c = 0.1, EtOH).

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125	I OH ΛΊ °ΥΊ A 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.70-7.73 (m, 2H), 7.05-7.10 (m, 1H), 4.92 (t, J = 6.1 Hz, 1 H), 4.31 (dd, J = 7.3, 9.3 Hz, 1H), 3.99 (dd, J = 6.6, 9.0 Hz, 1H), 3.81 (s, 3H), 3.64-3.72 (m, 1 H), 1.94 (d, J = 6.4 Hz, 2H), 1.68-1.81 (m, 4H), 1.55-1.64 (m, 2H), 1.27-1.36 (m, 1H), 1.14-1.23 (m, 1H). LCMS m/z = 355 [MH]⁺.
126	I OH an °Ύ^ r^B' <Y YJY« YY 4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-oi, enantiomer 1	Ή NMR (DMSO-c/β, 400MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.70-7.73 (m, 2H), 7.05-7.10 (m, 1H), 4.92 (t, J = 6.1 Hz, 1H), 4.31 (dd, J = 7.3, 9.3 Hz, 1H), 3.99 (dd, J = 6.6, 9.0 Hz, 1H), 3.81 (s, 3H), 3.64-3.72 (m, 1H), 1.94 (d, J = 6.4 Hz, 2H), 1.68-1.81 (m, 4H), 1.55-1.64 (m, 2H), 1.27-1.36 (m, 1H), 1.14-1.23 (m, 1H). LCMS m/z = 355 [MH]⁺. RT [Analytical SFC Method C] = 7.2 min.
127	OH /°^ γ^β/ .. ΑΥ,^Υ Q 4-(6-(4-methoxy-3- propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-de, 400MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, 3H), 7.64 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 2.8, 5.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1 H), 4.29 (t, J = 8.1 Hz, 1H), 3.94-4.05 (m, 3H), 3.81 (s, 3H), 3.55-3.63 (m, 1H), 1.72-1.84 (m, 2H), 1.22-1.31 (m, 1H), 1.14-1.21 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z = 346 [MH]⁺.
128	OH γ^β/, Υλ Y-¹ (-) 4-(6-(4-methoxy-3- propoxyphenyl)pyridin-2-yl)-1,2- oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-c/β, 400MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, 3H), 7.64 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 2.8, 5.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1 H), 4.29 (t, J = 8.1 Hz, 1H), 3.94-4.05 (m, 3H), 3.81 (s, 3H), 3.55-3.63 (m, 1 H), 1.72-1.84 (m, 2H), 1.22-1.31 (m, 1H), 1.14-1.21 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z = 328 [MH]⁺. [α]²%-39.5 (c = 3.8, EtOH).

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129	I OH r-^B X.X £ζθ °i/X' 4-(3'-(cyclopentyloxy)-4'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborol-2(5H)-ol	¹H NMR (DMSO-d₆, 400MHz): δ 7.71 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.51-7.53 (m, 1H), 7.44-7.48 (m, 1H), 7.21-7.24 (m, 2H), 7.04 (d, J = 8.0 Hz, 1 H), 6.27 (s, 1H), 4.94-4.98 (m, 3H), 3.79 (s, 3H), 1.87-1.94 (m, 2H), 1.74-1.78 (m, 4H), 1.54-1.62 (m, 2H). LCMS m/z = 351 [MH]⁺.
130	I OH /-Y r-B XX XL X £ z° 4-(3'-(cyclopentyloxy)-4'-methoxy-[1,1 'biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 7.48 (s, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.15-7.17 (m, 2H), 7.02 (d, J= 8.8 Hz, 1H), 4.91-4.94 (m, 1H), 4.26 (t, J= 8.0 Hz, 1H), 3.81 (t, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.42-3.51 (m, 1H), 1.88-1.92 (m, 2H), 1.73-1.76 (m, 4H), 1.58 (m, 2H), 1.29 (q, J= 8.0 Hz, 1H), 1.05-1.11 (m, 1H). LCMS m/z = 353 [MH]⁺.
131	I OH VL AJVnVV⁵Tl 4-(6-(3-(cyclopentyloxy)-4- methoxyphenyl)-5-fluoropyridin-2-yl)- 1,2-oxaborolan-2-ol	Ή NMR (DMSO-c/e, 400MHz): δ 8.61 (s, 1 H), 7.68 (dd, J = 8.3, 11.8 Hz, 1 H), 7.58 (s, 1H), 7.50-7.55 (m, 1H), 7.27 (dd, J = 3.3, 8.3 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.81-4.86 (m, 1H), 4.28 (dd, J = 7.5, 9.0 Hz, 1 H), 3.97 (dd, J = 7.3, 8.8 Hz, 1 H), 3.81 (s, 3H), 3.58-3.66 (m, 1H), 1.92 (d, J = 6.5 Hz, 2H), 1.68-1.80 (m, 4H), 1.59 (brs, 2H), 1.23-1.31 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 344 [MH]⁺.

235

132	I OH /-! °V> r® VL zULnJs/» cy 4-(2-(3-(cyclopentyloxy)-4- methoxyphenyl)-6-methoxypyrimidin-4yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 8.66 (br s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.96 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 4.83-4.90 (m, 1H), 4.26 (dd, J = 7.5, 9.0 Hz, 1H), 3.92-4.01 (m, 4H), 3.81 (s, 3H), 3.50 (td, J = 7.3, 14.9 Hz, 1 H), 1.94 (d, J = 6.5 Hz, 2H), 1.68-1.82 (m, 4H), 1.59 (br s, 2H), 1.20-1.29 (m, 1 H), 1.091.18 (m, 1H). LCMS m/z = 385 [MH]⁺.
133	OH v^B , AJx.+ V O ethyl 2-(6-(2-hydroxy-1,2-oxaborolan-4yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)acetate	¹H NMR (DMSO-c/β, 400MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.3 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1 H), 7.23 (s, 1 H), 7.07 (d, J = 8.6 Hz, 1H), 4.30 (dd, J = 7.5, 8.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.95-4.02 (m, 3H), 3.88 (s, 2H), 3.83 (s, 3H), 3.543.62 (m, 1H), 1.73-1.81 (m, 2H), 1.251.33 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.12-1.19 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 433 [MH+H₂O]⁺.
134	OH _rB XzX J / ,· /¹' .-⁰γ^ OH 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2(4-methoxy-3-propoxyphenyl)pyrimidin4-yl)acetic acid	Ή NMR (CD₃OD, 400MHz): δ 8.05 (s, 2H), 7.18 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.16-4.22 (m, 1H), 4.07 (t, J = 6.5 Hz, 2H), 3.96-4.02 (m, 1H), 3.90 (s, 3H), 3.70 (s, 2H), 3.40-3.46 (m, 1H), 1.811.90 (m, 2H), 1.15-1.31 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). LCMS m/z = 387 [MH]⁺.

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135	OH r-B sAAnJj> ^JL jl 4-(5-fluoro-6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.61 (s, 1 H), 7.68 (dd, J = 8.8, 11.7 Hz, 1 H), 7.58 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 3.4, 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1 H), 4.27 (dd, J = 7.3, 8.8 Hz, 1 H), 3.92-4.01 (m, 3H), 3.82 (s, 3H), 3.583.65 (m, 1H), 1.71-1.80 (m, 2H), 1.231.31 (m, 1H), 1.11-1.19 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺.
136	OH T A X ° ^o^yV^ M 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1	LCMS m/z = 342.3 [MH]⁺. RT [Analytical SFC Method V] = 6.90 min.
137	OH r-B T A *X ζθ 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2	LCMS m/z = 342.3 [MH+H₂O]⁺. RT [Analytical SFC Method V] = 7.90 min.
138	OH ^F^^F A JL A JX/° ^Z''°^±Y N 4-(4-(difluoromethyl)-5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	LCMS m/z = 364.4 [MH]⁺. RT [Prep HPLC Method C] = 2.30 min.

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139	OH χ Ί X JL/° 4-(4-(difluoromethyl)-5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	Ή NMR (CDCh, 400MHz): δ 8.72-8.92 (m, 1 H), 8.50 (br s, 1 H), 6.95-7.01 (m, 1H), 6.86 (dd, J = 2.3, 8.2 Hz, 1H), 6.516.83 (m, 2H), 4.48 (t, J = 8.2 Hz, 1H), 4.02-4.27 (m, 4H), 3.94 (s, 3H), 3.74 (s, 1H), 1.63 (dt, J = 8.6, 16.6 Hz, 2H), 1.49 (t, J = 7.0 Hz, 2H), 1.23-1.38 (m, 1 H). LCMS m/z = 364 [MH]⁺. RT [Analytical SFC Method W] = 3.95 min.
140	OH /O^^ F^F _B' J χ X JL? 4-(4-(difluoromethyl)-5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2	Ή NMR (CDCh, 400MHz): δ 8.72-8.92 (m, 1H), 8.50 (br s, 1H), 6.95-7.01 (m, 1H), 6.86 (dd, J = 2.3, 8.2 Hz, 1H), 6.516.83 (m, 2H), 4.48 (t, J = 8.2 Hz, 1H), 4.02-4.27 (m, 4H), 3.94 (s, 3H), 3.74 (s, 1H), 1.63 (dt, J = 8.6, 16.6 Hz, 2H), 1.49 (t, J = 7.0 Hz, 2H), 1.23-1.38 (m, 1 H). LCMS m/z = 364 [MH]⁺. RT [Analytical SFC Method W] = 3.95 min.
141	OH T X X J /0 4-(5-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4-methylpyridin-3-yl)- 1,2-oxaborolan-2-ol	¹H NMR (CD₃OD, 400MHz): δ 8.40 (s, 1H), 8.16 (s, 1H), 6.91 (d, J = 11.0 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 4.04 (q, J = 6.9 Hz, 3H), 3.89 (s, 4H), 3.64 (br s, 1H), 2.25 (d, J = 1.0 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 1.16-1.34 (m, 2H). LCMS m/z = 346 [MH]⁺.
142	OH Y X χ JL L° yj (-) 4-(5-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4-methylpyridin-3-yl)- 1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.02 (d, J = 11.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.26 (t, J = 8.3 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.93 (br s, 1H), 3.82 (s, 3H), 3.64-3.72 (m, 1H), 2.14 (s, 3H), 1.271.38 (m, 4H), 0.98-1.12 (m, 1H). LCMS m/z = 346 [MH]⁺. [α]²% -8.83 (c = 0.1, EtOH).

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143	OH /O_XZ\/F R ΧΎ i *ΧΧθ °^ΥΎ^ 4-(5-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4-methylpyridin-3-yl)1,2-oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.02 (d, J = 11.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.26 (t, J = 8.3 Hz, 1 H), 4.00 (q, J = 7.0 Hz, 2H), 3.93 (br s, 1H), 3.82 (s, 3H), 3.64-3.72 (m, 1H), 2.14 (s, 3H), 1.271.38 (m, 4H), 0.98-1.12 (m, 1H). LCMS m/z = 346.2 [MH]⁺. RT [Analytical SFC Method X] = 3.52 min.
144	OH ^SY® H Il J / o ^hL 4-(5-(3-ethoxy-4- (methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.66 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.26 (br s, 1H), 7.18-7.25 (m, 2H), 7.18 (s, 1H), 4.26 (t, J = 8.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 8.9 Hz, 1H), 3.43-3.52 (m, 1 H), 2.40 (s, 3H), 1.36 (t, J = 7.0 Hz, 2H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J= 10.1, 16.3 Hz, 1H). LCMS m/z = 329 [MH]⁺.
145	OH ! X J Γ b 4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.678.79 (m, 2H), 8.48 (d, J = 2.0 Hz, 1 H), 7.99 (s, 1H), 7.37-7.46 (m, 1H), 7.247.33 (m, 2H), 6.98 (d, J = 6.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.453.60 (m, 1H), 1.69-1.86 (m, 2H), 1.251.38 (m, 1H), 1.16 (dd, J = 10.5, 16.1 Hz, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z = 298 [MH]⁺.

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146	OH JX jl * Γ b ' ° Α'Ύ (-) 4-(5-(3-propoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-cfe, 400MHz): δ 8.678.79 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.37-7.46 (m, 1H), 7.247.33 (m, 2H), 6.98 (d, J = 6.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.453.60 (m, 1H), 1.69-1.86 (m, 2H), 1.251.38 (m, 1H), 1.16 (dd, J= 10.5, 16.1 Hz, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z = 298 [MH]⁺. [o]²⁰d -25.7 (c = 0.1, EtOH).
147	Il I ,oh ' // V-O S~N 4-(5-(4-methoxy-3-propoxyphenyl)- 1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2ol	¹H NMR (DMSO-de, 400MHz): δ 8.70 (br s, 1 H), 7.56-7.64 (m, 1 H), 7.47 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.294.35 (m, 1H), 4.12 (dd, J = 6.7, 9.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.81 (t, J = 7.7 Hz, 1 H), 1.72-1.81 (m, 2H), 1.27-1.40 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 335 [MH]⁺.
148	Il i ^oAAx^^s ^S~N (-) 4-(5-(4-methoxy-3-propoxyphenyl)1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2ol, enantiomer 2	Ή NMR (DMSO-d₆, 400MHz): δ 8.70 (br s, 1 H), 7.56-7.64 (m, 1 H), 7.47 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.294.35 (m, 1H), 4.12 (dd, J = 6.7, 9.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.81 (t, J = 7.7 Hz, 1 H), 1.72-1.81 (m, 2H), 1.27-1.40 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 335 [MH]⁺. [α]²% -10.3 (c= 0.1, EtOH).
149	I OH /a °YN H < I II J / o 4-(5-(3-(cyclopentyloxy)-4- methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.658.74 (m, 2H), 8.43 (d, J = 1.7 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1H), 7.17-7.30 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1 H), 4.27 (t, J = 8.3 Hz, 1 H), 3.86 (t, J = 9.0 Hz, 1 H), 3.79 (s, 3H), 3.413.59 (m, 1H), 1.90 (d, J = 6.4 Hz, 2H), 1.66-1.80 (m, 4H), 1.58 (br s, 2H), 1.29 (d, J = 8.3 Hz, 1H), 1.14 (dd, J = 10.4, 16.3 Hz, 1H). LCMS m/z = 354 [MH]⁺.

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150	OH T X Y b 4-(2'-fluoro-4',5'-dimethoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-c/e, 400 MHz): δ 8.66 (s, 1H), 7.33-7.44 (m, 3H), 7.26 (d, J= 6.4 Hz, 1H), 6.94-7.05 (m, 2H), 4.23-4.28 (m, 1H), 3.74-3.85 (m, 6H), 3.45-3.50 (m, 1H), 1.29 (dd, J= 16.0, 8.0 Hz, 1H), 1.05 (dd, J= 16.0, 10.0 Hz, 1H), 1.02-1.09 (m, 1H). LCMS m/z = 317 [MH]⁺.
151	OH _rB N 2-ethoxy-6-(6-(2-hydroxy-1,2oxaborolan-4-yl)pyridin-2-yl)-3methoxybenzonitrile	Ή NMR (DMSO-de, 400MHz): δ 8.58 (s, 1 H), 7.85 (t, J = 7.7 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.50 (m, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 4.254.31 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.09 (t, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.60-3.68 (m, 1H), 1.21-1.38 (m, 5H). LCMS m/z = 339 [MH]⁺.
152	OH r-B X X Γ b 4-(3-(5,6-dimethoxypyridin-2-yl)phenyl)- 1,2-oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1 H), 7.91 (s, 1 H), 7.85 (d, J = 8.0 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.24 (d, J = 7.6 Hz, 1 H), 4.27 (t, J= 8.0 Hz, 1H), 3.97 (s, 3H), 3.80-3.82 (m, 4H), 3.43-3.52 (m, 1H), 1.27-1.33 (m, 1H), 1.04-1.10 (m, 1H). LCMS m/z = 300 [MH]⁺.
153	OH n & ^χ°ΎΥϊ 1 1 N 6-(5-(2-hydroxy-1,2-oxaborolan-4- yl)pyridin-3-yl)-2,3dimethoxybenzonitrile	¹H NMR (DMSO-dg, 400MHz): δ 8.72 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1 H), 7.93 (s, 1 H), 7.51 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.84 (t, J = 9.0 Hz, 1H), 3.49-3.57 (m, 1H), 1.32 (dd, J = 8.2, 16.3 Hz, 1H), 1.12 (dd, J = 10.4, 16.3 Hz, 1H). LCMS m/z = 325 [MH]⁺.

241

154	OH /OyyF _rE! XXX/NaXX y--/ ΌΗ (-) 4-(2-(2-fluoro-4-methoxy-5- propoxyphenyl)-6- (hydroxymethyl)pyrimidin-4-yl)-1,2- oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.66 (s, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.34 (s, 1H), 6.95 (d, J = 12.7 Hz, 1H), 5.62 (t, J = 5.6 Hz, 1 H), 4.57 (d, J = 5.9 Hz, 2H), 4.26-4.33 (m, 1 H), 4.00 (dd, J = 7.1, 9.0 Hz, 1H), 3.93 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.58-3.66 (m, 1H), 1.69-1.78 (m, 2H), 1.25-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 377 [MH]⁺. [o]²⁰d -11.9 (c = 0.1, EtOH).
155	OH X X F b ^^O^ N 4-(3-(5-methoxy-6-propoxypyridin-2yl)phenyl)-1,2-oxaborol-2(5H)-ol	Ή NMR (DMSO-de, 400MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J = 7.2 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1 H), 6.26 (s, 1 H), 4.97 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.80 (q, J = 6.8 Hz, 2H), 1.00 (t, J = 6.8 Hz, 3H). LCMS m/z = 326 [MH]⁺.
156	OH r-B X X F b n XX^^ 4-(3-(5-methoxy-6-propoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-ds, 400MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J= 7.2 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.26 (s, 1 H), 4.97 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.80 (q, J = 6.8 Hz, 2H), 1.00 (t, J = 6.8 Hz, 3H). LCMS m/z = 328 [MH]⁺.
157	OH r-B X^ X F b °\ 4-(3',4',5-trimethoxy-[1,1 '-bi phe ny l]-3yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-ds, 400MHz): δ 8.65 (s, 1H), 7.12-7.22 (m, 2H), 7.09 (s, 1H), 6.95-7.05 (m, 3H), 6.79 (s, 1H), 4.24 (t, J = 8.2 Hz, 1 H), 3.84 (s, 3H), 3.79 (d, J = 8.0 Hz, 7H), 3.40-3.50 (m, 1H), 1.19-1.33 (m, 1H), 1.08 (dd, J = 10.0, 16.1 Hz, 1H), 1.01-1.13 (m, 1H). LCMS m/z = 329 [MH]⁺.

242

158	OH 4-(6-(4-methoxy-3-propoxyphenyl)-4methylpyridin-2-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.58 (br s, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 4.26 (t, J = 8.1 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.96 (dd, J = 6.8, 8.8 Hz, 1 H), 3.80 (s, 3H), 3.49-3.57 (m, 1H), 2.34 (s, 3H), 1.721.80 (m, 2H), 1.20-1.28 (m, 1H), 1.131.20 (m, 1 H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺.
159	OH / _rB / s-^ —o 4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)- 1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.64 (s, 1H), 7.42-7.48 (m, 2H), 7.31 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.26 (dd, J = 7.7, 8.7 Hz, 1H), 3.93 (dd, J = 7.6, 8.8 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.56-3.62 (m, 1H), 1.24-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 306 [MH]⁺.
160	OH / ,, * I 0 /fWr —o 4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)- 1,2-oxaborolan-2-ol, enantiomer 2	LCMS m/z = 319.9 [MH]⁺. RT [Analytical SFC Method Y] = 5.76 min.
161	OH .O. /N. d 1 X Γ b 4-(3-(5,6-dimethoxypyridin-3-yl)phenyl)- 1,2-oxaborolan-2-ol	¹H NMR (DMSO-c/6, 400MHz): δ 7.98 (s, 1H), 7.55-7.57 (m, 1H), 7.50-7.52 (m, 2H), 7.39-7.41 (m, 1H), 7.28-7.37 (m, 1 H), 4.26 (t, J = 8.0 Hz, 1 H), 3.89 (s, 3H), 3.88 (s, 3H), 3.82 (t, J = 8.0 Hz, 1H), 3.32-3.79 (m, 1H), 1.28-1.32 (m, 1H), 1.03-1.14 (m, 1H). LCMS m/z = 300 [MH]⁺.

243

162	OH Τι r^B' “TiJ 4-(6-(2-fluoro-3,4- dimethoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-c/e, 400 MHz): δ 8.59 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 8.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.26-4.30 (m, 1H), 4.01-4.97 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.32-3.65 (m, 1H), 1.18-1.30 (m, 2H). LCMS m/z = 318 [MH]⁺.
163	OH T X Γ b N 4-(5-(3-ethoxy-2,6-difluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-c/e, 400MHz): δ 8.71 (s, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.46 (s, 1H), 7.78 (s, 1H), 7.06 (d, J = 12.2 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 350 [MH]⁺.
164	OH ^z°yY u II *1 o Tu N (-) 4-(5-(3-ethoxy-2,6-difluoro-4methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-ds, 400MHz): δ 8.71 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 7.78 (s, 1H), 7.06 (d, J = 12.2 Hz, 1 H), 4.28 (t, J = 8.3 Hz, 1 H), 4.02 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 318 [MH]⁺. [α]²% -20.6 (c = 0.22, EtOH).
165	OH jX X X b \T°^TCi 4-(3'-(cyclopropylmethoxy)-4'-methoxy[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol

244

166	OH _ό (Ci 4-(3'-ethoxy-2'-fluoro-4'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 7.367.39 (m, 2H), 7.31-7.32 (m, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.15-7.19 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.25 (t, J = 8.0 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.79 (t, J = 8.8 Hz, 1H), 3.41-3.50 (m, 1H), 1.26-1.32 (m, 4H), 1.02-1.08 (m, 1H). LCMS m/z = 331 [MH]⁺.
167	OH T X Xb /° M 4-(5-(2,4-dimethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.70 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1H), 4.25-4.32 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.79-3.87 (m, 4H), 3.65 (s, 3H), 3.45-3.54 (m, 1H), 1.65-1.76 (m, 2H), 1.32 (dd, J = 8.2, 16.3 Hz, 1H), 1.03-1.12 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H). LCMS m/z = 358 [MH]⁺.
168	OH Il Ί *1 b ^oVyv^ (-) 4-(5-(2,4-dimethoxy-3- propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-c/e, 400MHz): δ 8.70 (s, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1 H), 4.25-4.32 (m, 1 H), 3.90 (t, J = 6.5 Hz, 2H), 3.79-3.87 (m, 4H), 3.65 (s, 3H), 3.45-3.54 (m, 1H), 1.65-1.76 (m, 2H), 1.32 (dd, J = 8.2, 16.3 Hz, 1H), 1.03-1.12 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H). LCMS m/z = 358 [MH]⁺. [o]²⁰ _D -18.8 (c = 0.1, EtOH).

245

169	I OH fl 1X r> 4-(5-(4-methoxy-3-((tetrahydro-2Hthiopyran-4-yl)oxy)phenyl)pyridin-3-yl)1,2-oxaborolan-2-ol	Ή NMR (DMSO-de,400 MHz): δ 8.69 (br s, 1 H), 8.42 (br s, 1 H), 7.90 (br s, 1 H), 7.34 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1 H), 4.44-4.54 (m, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.74-3.89 (m, 4H), 3.45-3.56 (m, 1H), 2.75-2.85 (m, 2H), 2.56-2.66 (m, 2H), 2.13-2.18 (m, 2H), 1.76-1.88 (m, 2H), 1.27-1.37 (m, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1H). LCMS m/z = 386 [MH]⁺.
170	I OH _s/y θ' 11 IC ° Û 4-(5-(4-methoxy-3-((tetrahydro-2Hthiopyran-4-yl)oxy)phenyl)pyridin-3-yl)1,2-oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-de,400 MHz): δ 8.69 (br s, 1 H), 8.42 (br s, 1 H), 7.90 (br s, 1 H), 7.34 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1 H), 4.44-4.54 (m, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.74-3.89 (m, 4H), 3.45-3.56 (m, 1H), 2.75-2.85 (m, 2H), 2.56-2.66 (m, 2H), 2.13-2.18 (m, 2H), 1.76-1.88 (m, 2H), 1.27-1.37 (m, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1H). LCMS m/z = 386 [MH]⁺. RT [Analytical SFC Method Z] = 5.20 min.
171	OH T I Γ b 4-(5-(3-ethoxy-4-methoxyphenyl)-6- ethylpyridin-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-cy 400MHz): δ 8.65 (s, 1H), 8.39 (s, 1H), 7.43 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.3 Hz, 1 H), 4.24 (t, J = 8.3 Hz, 1 H), 4.03 (q, J = 6.8 Hz, 2H), 3.75-3.84 (m, 4H), 3.39-3.52 (m, 1H), 2.69 (q, J = 7.4 Hz, 2H), 1.21-1.37 (m, 4H), 1.00-1.17 (m, 4H). LCMS m/z = 342 [MH]⁺.

246

172	OH ^b' A A A ζθ 4-(3'-ethoxy-4'-(methylthio)-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-cfe, 400MHz): δ 8.66 (s, 1 H), 7.54 (s, 1 H), 7.49 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 9.8 Hz, 2H), 7.17-7.22 (m, 2H), 4.26 (t, J = 8.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 8.9 Hz, 1H), 3.43-3.52 (m, 1 H), 2.40 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J = 10.1, 16.3 Hz, 1H). LCMS m/z = 329 [MH]⁺.
173	Cl OH ^O^A A ΤΊ -Γ> tT 4-(5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-c/6, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1 H), 8.70 (s, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.02 (t, J = 2.2 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 2.0 Hz, 1H), 4.18-4.30 (m, 3H), 3.83-3.91 (m, 1H), 3.81 (s, 3H), 3.44-3.57 (m, 1H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 1 H), 1.12-1.22 (m, 1H). LCMS m/z = 348 [MH]⁺. RT [Analytical SFC Method E] = 5.33 min
174	OH l A A z° 4-(3-(4,5-dimethoxypyridin-2-yl)phenyl)- 1,2-oxaborolan-2-ol	Ή NMR (DMSO-d₆, 400MHz): δ 8.65 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.38 (t, J = 7.6 Hz, 1 H), 7.29 (d, J = 7.2 Hz, 1 H), 4.27 (t, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.82 (t, J= 8.4 Hz, 1H), 3.44-3.53 (m, 1H), 1.30 (q, J= 8.0 Hz, 1H), 1.08 (q, J= 10.0 Hz, 1H). LCMS m/z = 300 [MH]⁺.

247

175	I OH Γ\ °ΥΊ A °\ 4-(4-(3-(cyclopentyloxy)-4- methoxyphenyl)-6-methoxypyrimidin-2yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-de, 400MHz): δ 8.60 (s, 1H), 7.72-7.79 (m, 2H), 7.23 (s, 1H), 7.05 (d, J = 8.5 Hz, 1 H), 4.92 (br s, 1 H), 4.29 (t, J = 8.0 Hz, 1H), 4.10 (dd, J = 6.0, 8.5 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.553.63 (m, 14.2 Hz, 1H), 1.93 (d, J = 5.5 Hz, 2H), 1.72 (br s, 4H), 1.58 (br s, 2H), 1.22-1.36 (m, 2H). LCMS m/z = 385 [MH]⁺.
176	I OH /-i °YN _rB V+ ajYnyy °^YT °\ 4-(4-(3-(cyclopentyloxy)-4- methoxyphenyl)-6-methoxypyrimidin-2yl)-1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-c/θ, 400MHz): δ 8.60 (s, 1H), 7.72-7.79 (m, 2H), 7.23 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 4.92 (br s, 1H), 4.29 (t, J = 8.0 Hz, 1H), 4.10 (dd, J = 6.0, 8.5 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.553.63 (m, 14.2 Hz, 1 H), 1.93 (d, J = 5.5 Hz, 2H), 1.72 (br s, 4H), 1.58 (br s, 2H), 1.22-1.36 (m, 2H). LCMS m/z = 385 [MH]⁺. RT [Analytical SFC Method Z] = 2.79 min.
177	OH jT j] Γ b Il N 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4dimethoxy-[1,1 '-biphenyl]-2-carbonitrile	¹H NMR (DMSO-ds, 400MHz): δ 7.197.53 (m, 7H) 4.22-4.31 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.79-3.83 (t, J = 8.8 Hz, 1H), 3.42-3.53 (m, 1H), 1.26-1.32 (m, 1H), 1.04-1.11 (m, 1H). LCMS m/z = 322 [MH]⁺.
178	OH L Jf / o 4-(5-methoxy-4-propoxy-[2,3'-bipyridin]5'-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-c/θ, 400MHz): δ 8.89 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.87 (br s, 1 H), 3.39 (br s, 1 H), 1.85-1.94 (m, 2H), 1.29 (d, J = 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). LCMS m/z = 329 [MH]⁺.

248

179	OH γΒ L if *I o ''/©Ί' ⁷ N 4-(5-methoxy-4-propoxy-[2,3'-bipyridin]- 5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-ds, 400MHz): δ 8.89 (d, J = 2.0 Hz, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 8.24 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.87 (br s, 1 H), 3.39 (br s, 1 H), 1.85-1.94 (m, 2H), 1.29 (d, J = 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). LCMS m/z = 329 [MH]⁺. RT [Analytical SFC Method G] = 4.36 min.
180	OH /°A jJ j] * Γ b A ΌΗ 4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-cfe, 400MHz): δ 8.73 (s, 1H), 7.61-7.67 (m, 3H), 7.26 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.40 (t, J = 5.9 Hz, 1H), 4.58 (d, J = 5.4 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.85 (t, J = 8.8 Hz, 1 H), 3.81 (s, 3H), 3.463.54 (m, 1H), 1.72-1.81 (m, 2H), 1.32 (dd, J = 8.3, 16.1 Hz, 1H), 1.09 (dd, J = 9.5, 16.4 Hz, 1H), 0.98-1.03 (m, 3H). LCMS m/z = 358 [MH]⁺. RT [Analytical SFC Method L] = 3.58 min.
181	Alll _zoh L //A/O S-N (-) 4-(5-(3-cyclopropoxy-4- methoxyphenyl)-1,2,4-thiadiazol-3-yl)- 1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-de, 400MHz): δ 8.69 (s, 1 H), 7.78 (d, J = 2.2 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.32 (dd, J = 7.6, 9.0 Hz, 1 H), 4.12 (dd, J = 6.6, 9.0 Hz, 1 H), 3.97-3.99 (m, 1 H), 3.76-3.88 (m, 4H), 1.25-1.43 (m, 2H), 0.77-0.86 (m, 2H), 0.67-0.74 (m, 2H). LCMS m/z = 333 [MH]⁺. [a]²% -12.7 (c = 0.1, EtOH).
182	OH J. Il / b ''θ'^ιΟι 4-(4’-ethoxy-3'-methoxy-[1,1 ’-biphenyl]3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-de, 400MHz): δ 7.50 (br s, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.8Hz, 1H), 7.14-7.22 (m, 3H), 7.01 (d, J = 8.2 Hz, 1 H), 4.26 (t, J = 7.8 Hz, 1 H), 4.04 (q, J = 7.0 Hz, 2H), 3.79-3.84 (m, 4H), 3.42-3.51 (m, 1H), 1.26-1.36 (m, 4H), 1.05-1.12 (m, 1H). LCMS m/z = 313 [MH]⁺.

249

183	OH L II I o 4-(3'-isobutoxy-4'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-ds, 400MHz): δ 7.447.56 (m, 2H), 7.32-7.39 (m, 1H), 7.157.24 (m, 3H), 7.00-7.04 (m, 1H), 4.15 (t, J= 10.5 Hz, 1H), 4.02-4.06 (m, 1H), 3.79-3.84 (m, 5H), 3.43-3.51 (m, 1H), 1.99-2.09 (m, 1H), 1.22-1.32 (m, 1H), 1.05-1.11 (m, 1H), 0.98-1.01 (m, 6H). LCMS m/z = 359 [MH+H₂O]⁺.
184	I OH r-B jL J Y > 4-(3'-cyclobutoxy-4'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 7.46 (s, 1H), 7.40-7.44 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.16 (dd, J = 2.1,8.4 Hz, 1 H), 6.99-7.05 (m, 2H), 4.75-4.83 (m, 1 H), 4.26 (t, J = 8.2 Hz, 1H), 3.78-3.84 (m, 4H), 3.41-3.54 (m, 1H), 2.39-2.47 (m, 2H), 2.02-2.14 (m, 2H), 1.74-1.84 (m, 1H), 1.59-1.71 (m, 1H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.05-1.12 (m, 1H), 1.03 (d, J = 6.8 Hz, 1H). LCMS m/z = 339 [MH]⁺.
185	OH 4-(2-(3-ethoxy-4-methoxyphenyl)-6methoxypyrimidin-4-yl)-1,2-oxaborolan2-ol	¹H NMR (DMSO-d₆, 400MHz): δ 8.67 (s, 1H), 7.99 (dd, J = 2.0, 8.5 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 4.00 (s, 3H), 3.95 (dd, J = 6.0, 9.0 Hz, 1H), 3.83 (s, 3H), 3.48-3.54 (m, 1 H), 1.37 (t, J = 7.0 Hz, 3H), 1.21-1.27 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z = 345 [MH]⁺.
186	OH (-) 4-(2-(3-ethoxy-4-methoxyphenyl)-6methoxypyrimidin-4-yl)-1,2-oxaborolan2-ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.67 (s, 1 H), 7.99 (dd, J = 2.0, 8.5 Hz, 1 H), 7.96 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1 H), 4.10 (q, J = 6.9 Hz, 2H), 4.00 (s, 3H), 3.95 (dd, J = 6.0, 9.0 Hz, 1H), 3.83 (s, 3H), 3.48-3.54 (m, 1 H), 1.37 (t, J = 7.0 Hz, 3H), 1.21-1.27 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z = 345 [MH]⁺.

250

		[o]²⁰d -37.4 (c= 0.1, EtOH).
187	OH T 1 Γ b 4-(5-(4-ethoxy-3methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.73 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.21-7.25 (m, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H), 1.27-1.37 (m, 4H), 1.10-1.19 (m, 1H). LCMS m/z = 314 [MH]⁺.
188	OH Tl .. * Γ b 4-(5-(4-ethoxy-3- methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-ds, 400MHz): δ 8.73 (s, 1 H), 8.71 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.94 (t, J = 2.2 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1H), 7.21-7.25 (m, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H), 1.27-1.37 (m, 4H), 1.10-1.19 (m, 1H). LCMS m/z = 314 [MH]⁺. RT [Analytical SFC Method AA] = 3.61 min.
189	OH i r-B j? ïi i χ θ 4-(5-(3-ethoxy-4-methoxyphenyl)-4methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-de, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.82-6.85 (m, 1H), 4.24-4.28 (m, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s, 3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H), 1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H). LCMS m/z = 328 [MH]⁺. RT [Analytical SFC Method E] = 5.71 min.
190	OH T T . rt 4-(5-(3-isopropoxy-4- methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-de, 400MHz): δ 8.72 (s, 1 H), 8.69 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.29 - 7.24 (m, 2H), 7.07 (d, J = 8.0 Hz, 1 H), 4.68-4.74 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H), 3.86 (t, J= 9.0 Hz, 1H), 3.79 (s, 3H), 3.47-3.55 (m, 1H), 1.26-1.35 (m, 7H), 1.10-1.18 (m, 1H). LCMS m/z = 328

251

		[MH]⁺. RT [Analytical SFC Method BA] = 5.69 min.
191	/^o^ I r 3-ethoxy-3'-(2-l 4-yl)-4-methox\ carbonitrile	OH ! \ r-B I J iydroxy-1,2-oxaborolan- <-[1,1 '-biphenyl]-2-	¹H NMR (DMSO-de, 400MHz): δ 7.317.46 (m, 3H), 7.33-7.36 (m, 2H), 7.27 (d, J= 8.8 Hz, IH), 4.18-4.28 (m, 3H), 3.90 (s, 3H), 3.81 (t, J= 8.8 Hz, 1H), 3.453.52 (m, 1H), 1.26-1.34 (m, 4H), 1.081.11 (m, 1 H) . LCMS m/z = 338 [MH]⁺.
192	^O^ I t 3-ethoxy-3'-(2-l 4-yl)-4-methox} carbonitrile, en	OH ία» I si iydroxy-1,2-oxaborolan- /-[1,1'-biphenyl]-2- antiomer 2	RT [Analytical SFC Method CA] = 3.14 min.
193	OH z°W\ rt-B J? jl *Γ'ο 4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.698.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.28 (dd, J = 2.4, 8.3 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.25-4.31 (m, 1H), 3.97-4.01 (m, 1H), 3.86 (t, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.46-3.57 (m, 1H), 1.32 (dd, J = 8.1, 16.4 Hz, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1H), 0.76-0.83 (m, 2H), 0.67-0.72 (m, 2H). LCMS m/z = 326 [MH]⁺. RT [Analytical SFC Method D] = 5.38 min.
194	OH / J b o^ t / )>=/ ^X Æ° (-) 4-(2-(3-ethoxy-4- methoxyphenyl)thiazol-4-yl)-1,2- oxaborolan-2-ol, enantiomer 1	’H NMR (DMSO-de, 400MHz): δ 8.66 (br s, 1H), 7.42-7.46 (m, 2H), 7.30 (s, 1H), 7.05 (d, J= 8.3 Hz, 1H), 4.24-4.28 (m, 1H), 4.09 (q, J= 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.82 (s, 3H), 3.55-3.63 (m, 1H), 1.36 (t, J= 7.0 Hz, 3H), 1.25-1.31 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z = 320

252

[MH]⁺. RT [Analytical SFC Method DA] = 4.47 min. [a]²⁰ _D-17.4 (c= 0.1, EtOH).

253

195

4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

196

(-) 4-(6-(2-hydroxyethoxy)-2-(4methoxy-3-propoxyphenyl)pyrimidin-4yl)-1,2-oxaborolan-2-ol, enantiomer 1

197

4-(6-(3,4-dimethoxyphenyl)pyridin-2-yl)1,2-oxaborolan-2-ol ¹H NMR (DMSO-d₆, 400MHz): δ 8.65 (s, 1 H), 7.97 (dd, J = 2.0, 8.3 Hz, 1 H), 7.93 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.42-4.47 (m, 2H), 4.26 (dd, J = 7.3, 9.0 Hz, 1 H), 4.00 (t, J = 6.5 Hz, 2H), 3.95 (dd, J = 6.4, 9.0 Hz, 1H), 3.83 (s, 3H), 3.74-3.80 (m, 2H), 3.47-3.54 (m, 1H), 1.73-1.81 (m, 2H), 1.20-1.28 (m, 1H), 1.10-1.17 (m, 1H), 1.01 (t, J = 7.3 Hz, 3H). LCMS m/z = 406 [MH+H₂O]⁺.

¹H NMR (DMSO-c/6, 400MHz): δ 8.65 (s, 1H), 7.97 (dd, J = 2.0, 8.3 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1 H), 6.64 (s, 1 H), 4.89 (t, J = 5.4 Hz, 1 H), 4.42-4.47 (m, 2H), 4.26 (dd, J = 7.3, 9.0 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.95 (dd, J = 6.4, 9.0 Hz, 1H), 3.83 (s, 3H), 3.74-3.80 (m, 2H), 3.47-3.54 (m, 1H), 1.73-1.81 (m, 2H), 1.20-1.28 (m, 1H), 1.10-1.17 (m, 1H), 1.01 (t, J = 7.3 Hz, 3H). LCMS m/z = 406 [MH+H2O]⁺. [a]²⁰D -38.9 (c = 0.1, EtOH).

Ή NMR (DMSO-de, 400 MHz): δ 8.59 (s, 1H), 7.73-7.75 (m, 3H), 7.64 (d, J= 8.4 Hz, 1H), 7.15-7.17 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.27-4.31 (m, 1H), 3.95-3.99 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.573.60 (m, 1H), 1.15-1.29 (m, 2H) . LCMS m/z = 298 [MH]'.

254

198	OH ΌΗ 4-(4-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyrimidin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-ds,400 MHz): δ 8.71 (br s, 1H), 7.70-7.81 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.07-7.14 (m, 1H), 5.71 (br s, 1H), 4.55 (d, J = 5.5 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 3.95-4.11 (m, 2H), 3.81-3.88 (m, 4H), 1.71-1.83 (m, 2H), 1.27 (d, J = 8.0 Hz, 1H), 0.96-1.05 (m, 4H). LCMS m/z = 359 [MH]⁺.
199	OH Ï U 4-(6-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSC-d₆,400 MHz): δ 8.60 (br s, 1H), 7.75-7.82 (m, 1H), 7.67 (t, J = 8.8 Hz, 1 H), 7.55 (d, J = 6.4 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.25-4.32 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.96-4.02 (m, 1H), 3.87 (s, 3H), 3.61 (td, J = 8.0, 15.8 Hz, 1H), 1.13-1.32 (m, 5H). LCMS m/z = 332 [MH]⁺.
200	OH \ AA 1 d 4-(1-(4-methoxy-3-propoxyphenyl)-1 Hpyrazol-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-ds, 400 MHz): δ 8.61 (s, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 2.5, 8.5 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H), 6.37 (d, J = 2.5 Hz, 1H), 4.18-4.25 (m, 1H), 3.98 (t, J = 6.5 Hz, 2H), 3.89 (t, J = 8.5 Hz, 1H), 3.78 (s, 3H), 3.44-3.52 (m, 1H), 1.711.80 (m, 2H), 1.27 (dd, J = 8.5, 16.1 Hz, 1H), 1.03-1.13 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H). LCMS m/z = 317 [MH]⁺.
201	OH r-B IX. £ z° N 4-(5-(3-methoxy-4- (methylthio)phenyl)pyridin-3-yI)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-d₆,400 MHz): δ 8.60 (br s, 1 H), 7.75-7.82 (m, 1 H), 7.67 (t, J = 8.8 Hz, 1 H), 7.55 (d, J = 6.4 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.25-4.32 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.96-4.02 (m, 1H), 3.87 (s, 2H), 3.57-3.65 (m, 1H), 1.13-1.33 (m, 5H). LCMS m/z = 316 [MH]⁺.

255

202	OH Tff u L II 1 o ΌΗ 4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2- oxaborolan-2-ol	¹H NMR (DMSO-c/e,400 MHz): δ 8.74 (s, 1H), 7.61-7.69 (m, 3H), 7.26 (s, 1H), 7.03 (d, J = 8.3 Hz, 1 H), 5.40 (t, J = 5.6 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1 H), 4.00 (t, J = 6.4 Hz, 2H), 3.82-3.89 (m, 1H), 3.81 (s, 3H), 3.473.56 (m, 1H), 1.72-1.81 (m, 2H), 1.32 (dd, J = 8.3, 16.1 Hz, 1H), 1.09 (dd, J = 9.8, 16.6 Hz, 1H), 1.01 (t, J = 7.6 Hz, 3H). LCMS m/z = 358 [MH]⁺.
203	OH Λα H ij 4-(6-(3-ethoxy-4(methylthio)phenyl)pyridin-2-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-c/e, 400MHz): δ 8.61 (br s, 1H), 7.44-7.83 (m, 2H), 7.67-7.73 (m, 2H), 7.18-7.24 (m, 2H), 4.26-4.32 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.97 (dd, J = 6.6, 8.8 Hz, 1H), 3.57-3.64 (m, 1H), 2.42 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H), 1.22-1.31 (m, 1H), 1.14-1.22 (m, 1H). LCMS m/z = 330 [MH]⁺.
204	OH _rB 4-(6-(3-ethoxy-4- (methylthio)phenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1	RT [Analytical SFC Method Y] = 7.70 min.
205	OH i r^B' Il d I J o (+) 4-(5-(3-ethoxy-4-methoxyphenyl)- 4,6-dimethylpyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1	¹H NMR (DMSO-de,400 MHz): δ 8.70 (d, J = 2.0 Hz, 1 H), 8.31 (s, 1 H), 7.03 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 2.0, 3.9 Hz, 1H), 6.65 (ddd, J = 2.0, 4.2, 8.1 Hz, 1H), 4.22 (dd, J = 7.3, 8.8 Hz, 1H), 3.96-4.01 (m, 2H), 3.84-3.92 (m, 1H), 3.80 (s, 3H), 3.54-3.62 (m, 1H), 2.13 (s, 3H), 1.97 (s, 3H), 1.25-1.34 (m, 4H), 0.99-1.09 (m, 1H). LCMS m/z = 342 [MH]⁺. [α]²% +9.6 (c = 0.1, EtOH).

256

206	OH II 1 o “ Qf' 4-(3'-methoxy-4'-(methylthio)-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-d₆,400 MHz): δ 8.65 (s, 1 H), 7.56 (s, 1 H), 7.51 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 4.26 (t, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.82 (t, J = 8.9 Hz, 1H), 3.44-3.52 (m, 1H), 2.41 (s, 3H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J= 10.3, 16.1 Hz, 1H). LCMS m/z = 315 [MH]⁺.
207	OH X X A /° 4-(3',4'-dimethoxy-5-methyl-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol	¹H NMR (DMSO-ds, 400MHz): δ 8.64 (s, 1H), 7.27-7.30 (m, 2H), 7.14-7.18 (m, 2H), 6.99-7.02 (m, 2H), 4.22-4.26 (m, 1H), 3.78-3.84 (m, 7H), 3.37-3.46 (m, 1H), 2.34 (s, 3H), 1.24-1.30 (m, 1H), 1.04-1.11 (m, 1H). LCMS m/z 313 [MH]⁺.
208	OH /O^_F _B' X X XJ° (+) 4-(3-fluoro-5-methoxy-6-propoxy- [2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2- ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.89 (s, 1 H), 8.73 (s, 1 H), 8.49 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J=12.0 Hz, 1H), 4.28-4.33 (m, 3H), 3.87 (s, 3H), 3.82 (t, J= 8.7 Hz, 1H), 3.49-3.57 (m, 1H), 1.73-1.81 (m, 2H), 1.31-1.37 (m, 1H), 1.03-1.09 (m, 1 H), 0.98 (t, J = 7.5 Hz, 3H). LCMS m/z = 347 [MH]⁺. [α]²% +20.4 (c = 0.1, EtOH).
209	OH /°y\ rA L Il / b Au 4-(2'-fluoro-3',4'-dimethoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol	Ή NMR (DMSO-d₆,400 MHz): δ 8.66 (br s, 1H), 7.35-7.40 (m, 2H), 7.26-7.34 (m, 2H), 7.18 (t, J= 8.4 Hz, 1H), 6.95-7.00 (m, 1H), 4.22-4.28 (m, 1H), 3.86 (s, 3H), 3.77-3.84 (m, 4H), 3.41-3.52 (m, 1H), 1.29 (q, J= 8.0 Hz, 1H), 1.04 (q, 8.0 Hz, 1H). LCMS m/z = 317 [MH]⁺.

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210	I OH XX X^ X x > 4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-4-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-cfe, 400MHz): δ 8.72 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.2, 8.6 Hz, 1H), 7.18 (dd, J = 1.2, 5.1 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 4.874.94 (m, 1H), 4.24-4.31 (m, 1H), 3.84 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.42-3.55 (m, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 4H), 1.56-1.63 (m, 2H), 1.30 (dd, J = 8.3, 16.1 Hz, 1H), 1.10 (dd, J = 10.0, 16.4 Hz, 1H). LCMS m/z = 354 [MH]⁺.
211	I OH XX X. X *X ° 4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-cfe, 400MHz): δ 8.72 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 7.77 (s, 1 H), 7.66 (d, J = 2.0 Hz, 1 H), 7.62 (dd, J = 2.2, 8.6 Hz, 1H), 7.18 (dd, J = 1.2, 5.1 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 4.874.94 (m, 1H), 4.24-4.31 (m, 1H), 3.84 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.42-3.55 (m, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 4H), 1.56-1.63 (m, 2H), 1.30 (dd, J = 8.3, 16.1 Hz, 1H), 1.10 (dd, J = 10.0, 16.4 Hz, 1H). LCMS m/z = 354 [MH]⁺. RT [Analytical SFC Method EA] = 4.27 min.
212	OH _rB ' Ό 4-(2-(4-methoxy-3- propoxyphenyl)pyrimidin-4-yl)-1,2- oxaborolan-2-ol	Ή NMR (DMSO-dg.400 MHz): δ 8.71 (d, J = 5.1 Hz, 1H), 8.69 (s, 1H), 8.00 (dd, J = 1.8, 8.4 Hz, 1 H), 7.96 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 4.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.30 (dd, J = 7.5, 8.9 Hz, 1H), 3.97-4.02 (m, 3H), 3.83 (s, 3H), 3.55-3.63 (m, 1H), 1.73-1.82 (m, 2H), 1.25-1.33 (m, 1H), 1.13-1.20 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z = 329 [MH]⁺.

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213	OH ο y ^f 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-de,400 MHz): δ 8.61 (s, 1H), 7.75-7.80 (m, 1H), 7.66 (t, J = 8.8 Hz, 1 H), 7.55 (dd, J = 1.8, 7.7 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1H), 6.99-7.04 (m, 1 H), 4.27 (dd, J = 7.8, 8.6 Hz, 1 H), 3.924.02 (m, 3H), 3.86 (s, 3H), 3.57-3.65 (m, 1H), 1.63-1.72 (m, 2H), 1.14-1.31 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺.
214	F OH d x° 4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-d₆, 400MHz): δ 8.75 (d, J = 2.0 Hz, 1 H), 8.71 (s, 1 H), 8.47 (d, J = 1.47 Hz, 1 H), 8.00 (s, 1 H), 7.27 (dd, J = 2.0, 11.7 Hz, 1 H), 7.20 (s, 1 H), 4.27 (t, J = 8.3 Hz, 1H), 4.21 (q, J= 6.9 Hz, 2H), 3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J= 6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 349 [MH+H₂O]⁺. RT [Analytical SFC Method D] = 4.59 min.
215	OH XX. ΧΧν®//° ⁰ jCj N 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2- oxaborolan-2-ol	¹H NMR (DMSC-d₆,400 MHz): δ 8.81 (d, J = 2.4 Hz, 1 H), 8.69 (s, 1 H), 8.53 (s, 1 H), 7.67 (t, J = 8.8 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1H), 4.31 (t, J = 8.3 Hz, 1H), 3.94-4.06 (m, 3H), 3.89 (s, 3H), 3.673.75 (m, 1H), 1.64-1.73 (m, 2H), 1.271.36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 347 [MH]⁺.
216	OH z°yy d ⁰ iïr N 4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-c/s.400 MHz): δ 8.81 (d, J = 2.4 Hz, 1 H), 8.69 (s, 1 H), 8.53 (s, 1H), 7.67 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1 H), 4.31 (t, J = 8.3 Hz, 1 H), 3.94-4.06 (m, 3H), 3.89 (s, 3H), 3.673.75 (m, 1H), 1.64-1.73 (m, 2H), 1.271.36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 347 [MH]⁺. RT [Analytical SFC Method C] = 4.40 min.

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217	OH ^°X1 X^B° AU N 4-(5-(4-ethoxy-2-fluoro-3methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-dg,400 MHz): δ 8.72 (s, 1 H), 8.54 (t, J = 2.0 Hz, 1 H), 8.48 (d, J = 2.5 Hz, 1 H), 7.82 (d, J = 1.5 Hz, 1 H), 7.24 (t, J = 8.8 Hz, 1H), 6.98-7.02 (m, 1H), 4.25-4.31 (m, 1H), 4.14 (q, J = 6.9 Hz, 2H), 3.81-3.87 (m, 4H), 3.46-3.56 (m, 1 H), 1.38 (t, J = 6.8 Hz, 3H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10 (dd, J = 10.0, 16.1 Hz, 1H). LCMS m/z = 332 [MH]⁺.
218	OH /<V A Y X Γ b ’° X/ N 4-(6'-methoxy-2-methyl-5'-propoxy- [3,3'-bipyridin]-5-yl)-1,2-oxaboroIan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 8.69 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.69 (m, 1H), 7.54-7.56 (m, 1H), 7.27-7.33 (m, 1H), 4.23-4.27 (m, 1H), 3.98-4.01 (m, 2H), 3.91 (s, 3H), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H), 2.41 (s, 3H), 1.721.77 (m, 2H), 1.26-1.30 (m, 1H), 1.071.11 (m, 1H), 0.96-1.00 (m, 3H). LCMS m/z = 343 [MH]⁺.
219	OH II J b (-) 4-(6'-methoxy-2-methyl-5'-propoxy[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.69 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.69 (m, 1H), 7.54-7.56 (m, 1H), 7.27-7.33 (m, 1H), 4.23-4.27 (m, 1H), 3.98-4.01 (m, 2H), 3.91 (s, 3H), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H), 2.41 (s, 3H), 1.721.77 (m, 2H), 1.26-1.30 (m, 1H), 1.071.11 (m, 1H), 0.96-1.00 (m, 3H). LCMS m/z = 343 [MH]⁺. RT [Analytical SFC Method Z] = 2.28 min. [α]²% -16.2 (c = 0.1, EtOH).
220	OH Q ^F F ^F4-(6-(3-ethoxy-4-methoxyphenyl)-4(trifluoromethyl)pyridin-2-yl)-1,2oxaborolan-2-ol	Ή NMR (MeOD-ds, 400MHz): δ 7.85 (s, 1 H), 7.76 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 2.0, 8.3 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 3H), 4.02 (br s, 1 H), 3.89 (s, 3H), 3.57 (br s, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.33-1.41 (m, 1H), 1.24-1.32 (m, 1H). LCMS m/z 382 [MH]⁺.

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221	OH N II d * / o ° Tj 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)- 1,2-oxaborolan-2-ol, enantiomer 2	Ή NMR (DMSO-d₆, 400MHz): δ 8.72 (d, J = 2.8 Hz, 2H), 8.43 (d, J = 2.0 Hz, 1 H), 7.95 (t, J = 2.0 Hz, 1H), 7.25-7.29 (m, 1 H), 7.06 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 4.28 Hz, 1H), 3.84-3.88 (m, 4H), 3.80 (s, 3H), 3.46-3.54 (m, 1H), 1.28-1.34 (m, 1 H), 1.12-1.18 (m, 1H). LCMS m/z = 300 [MH]⁺. RT [Analytical SFC Method FA] = 6.04 min.
222	OH J AL· JJ⁵ °d 4-(6-ethoxy-2-(3-ethoxy-4methoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol	¹H NMR (DMSO-ds, 400MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 4.47 (q, J = 6.9 Hz, 2H), 4.25 (t, J = 8.0 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48 (br s, 1 H), 1.36 (t, J = 7.0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m, 1H). LCMS m/z [Analytical SFC Method FA] = 359 [MH]⁺.
223	OH °d 4-(6-ethoxy-2-(3-ethoxy-4methoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-d₆, 400MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, J = 8.5 Hz, 1 H), 6.59 (s, 1 H), 4.47 (q, J = 6.9 Hz, 2H), 4.25 (t, J = 8.0 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48 (br s, 1 H), 1.36 (t, J = 7.0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m, 1H). LCMS m/z = 359 [MH]⁺. RT [Analytical SFC Method D] = 2.97 min.
224	OH AA^nAL·³o y at 4-(6-methoxy-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol	Ή NMR (DMSO-cfe, 400MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.5 Hz, 1H), 7.947.97 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 4.26 (dd, J = 7.5, 9.0 Hz, 1H), 3.97-4.03 (m, 5H), 3.94 (dd, J = 6.0, 9.0 Hz, 1H), 3.82 (s, 3H), 3.50 (d, J = 8.0 Hz, 1H), 1.72-1.81 (m, 2H), 1.20-1.27 (m, 1H), 1.10-1.17 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 359 [MH]⁺.

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225	OH /° (-) 4-(6-methoxy-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2	¹H NMR (DMSO-c/6, 400MHz): δ 8.69 (s, 1 H), 7.98 (dd, J = 2.0, 8.5 Hz, 1 H), 7.947.97 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.63 (s, 1H), 4.26 (dd, J = 7.5, 9.0 Hz, 1H), 3.97-4.03 (m, 5H), 3.94 (dd, J = 6.0, 9.0 Hz, 1H), 3.82 (s, 3H), 3.50 (d, J = 8.0 Hz, 1H), 1.72-1.81 (m, 2H), 1.20-1.27 (m, 1H), 1.10-1.17 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z = 359 [MH]⁺. [α]²%-16.9 (c= 0.1, EtOH).
226	I OH /Y C* Yk YYnYY YYî ZJ Il + N 2-(cyclopentyloxy)-6-(6-(2-hydroxy-1,2oxaborolan-4-yl)pyridin-2-yl)-3methoxybenzonitrile	¹H NMR (DMSO-c/6, 400MHz): δ 8.57 (s, 1H), 7.81-7.88 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49-7.55 (m, 1H), 7.42-7.48 (m, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 5.11 (t, J = 5.1 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.08 (t, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.593.68 (m, 1H), 1.79-1.93 (m, 4H), 1.681.76 (m, 2H), 1.54-1.63 (m, 2H), 1.281.36 (m, 1H), 1.21-1.28 (m, 1H). LCMS m/z = 379 [MH]⁺.
227	OH rt-B JL jl JT b N^z 4-(2-(3,4-dimethoxyphenyl)pyridin-4-yl)- 1,2-oxaborol-2(5H)-ol	¹H NMR (DMSO-c/₆, 400 MHz): δ = 8.85 (s, 1H), 8.65 (d, J= 5.2 Hz, 1H), 7.97 (s, 1H), 7.73-7.74 (m, 2H), 7.43 (d, J= 4.8 Hz, 1 H), 7.06 (d, J = 4.8 Hz, 1 H), 6.58 (s, 1 H), 5.00 (d, J = 1.6 Hz, 1 H), 3.86 (m, 3H), 3.82 (s, 3H). LCMS m/z = 298 [MH]⁺.
228	OH HO JL J. * 1 ζθ (+) 4-(5-(3-(2-hydroxyethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2	1H NMR (CD₃OD, 400MHz): δ 8.60 (br s, 1 H), 8.37 (br s, 1 H), 7.93 (s, 1 H), 7.227.30 (m, 2H), 7.10 (d, J = 8.3 Hz, 1H), 4.16 (t, J = 4.6 Hz, 2H), 4.08 (br s, 1H), 3.83-3.95 (m, 6H), 3.34-3.42 (m, 1H), 1.25-1.39 (m, 2H). LCMS m/z = 330 [MH]⁺. [α]²% +31.9 (c = 0.1, EtOH).

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229	OH z°xA cA x 1 jx o 4-(5-(3-ethoxy-4- methoxyphenyl)pyridin-3-yl)-1,2oxaborol-2(5H)-ol	Ή NMR (DMSO-c/6, 400MHz): δ 8.85 (d, J = 2.0 Hz, 1 H), 8.77 (s, 1 H), 8.73 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.31-7.33 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 5.01 (s, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 1.36 (q, J = 6.8 Hz, 3H). LCMS m/z = 312 [MH]⁺.
230	OH AJCnYJ⁵ί J 4-(3-fluoro-6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1	Ή NMR (DMSO-de, 400MHz): δ 8.64 (br s, 1 H), 7.84 (dd, J = 3.4, 8.8 Hz, 1 H), 7.67 (t, J = 4.6 Hz, 2H), 7.60 (dd, J = 1.5, 8.3 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 4.27 (t, J = 7.8 Hz, 1 H), 3.98-4.07 (m, 3H), 3.85 (d, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.72-1.80 (m, 2H), 1.22-1.27 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. RT [Analytical SFC Method G] = 3.25 min.
231	OH X X X b o (-) 4-(5-methoxy-2'-methyl-6-propoxy[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2ol, enantiomer 1	¹H NMR (DMSO-d₆, 400MHz): δ 8.67 (s, 1H), 8.34 (s, 1H), 7.65 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.21-4.28 (m, 3H), 3.76-3.85 (m, 4H), 3.41-3.50 (m, 1H), 2.52 (s, 3H), 1.701.78 (m, 2H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.06 (dd, J = 10.0, 16.1 Hz, 1H), 0.95 (t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. [a]²% -20.1 (c = 0.1, EtOH).
232	OH T X Γ b 4-(3',4'-dimethoxy-[1,1 '-biphenyl]-3-yl)1,2-oxaborolan-2-ol	Ή NMR (DMSO-de, 400MHz): δ 7.51 (s, 1 H), 7.45 (br d, J = 7.6 Hz, 1 H), 7.347.35 (m, 1H), 7.16-7.23 (m, 3H), 7.02 (d, J = 8.0 Hz, 1 H), 4.22-4.28 (m, 1 H), 3.84 (s, 3H), 3.81 (s, 1H), 3.79 (s, 3H), 3.423.51 (m, 1H), 1.25-1.31 (m, 1H), 1.051.12 (m, 1 H). LCMS m/z = 299 [MH]⁺.

263

Example 233

OH Λλ r^B' 4-(6-(3-ethoxy-4- methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

¹H NMR (DMSO-c/6,400 MHz): δ 8.57 (s, 1 H), 7.61-7.70 (m, 3H), 7.59 (d, J = 2.0 Hz, 1H), 7.11-7.13 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.23-4.28 (m, 1H), 4.07-4.09 (m, 2H), 3.92-3.96 (m, 1H), 3.78 (s, 3H), 3.56-3.58 (m, 1H), 1.33 (t, J= 7.0 Hz, 3H), 1.16-1.24 (m, 2H). LCMS m/z = 314 [MH]⁺.

Single Crystal X-Ray Analysis of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol (Example 3)

The crystal structure of Example 3 was determined by single crystal X-ray diffraction analysis. The single crystal X-ray diffraction data collection was performed on a Bruker D8 Quest diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Monoclinic class space group P2i. The structure was subsequently refined by the full-matrix least squares method. AH non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms. Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010).

The Hooft parameter is reported as 0.02 with an Esd of 0.003 and the Parson’s parameter is reported as 0.02 with an Esd of 0.003. The final R-index was 4.5%. A final différence Fourier revealed no missing or misplaced électron density.

Figure 1 is the obtained X-ray structure (ORTEP drawing) of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3). The crystal structure data is summarized in Table 3.

Table 3

Crystal data and structure refinement for Example 3

Empirical formula Formula weight	C17 H20 B N O4 313.15
25	Température Wavelength Crystal system Space group	296(2) K 1.54178 A Monoclinic P2i
	Unit cell dimensions	a = 11.0798(5) A	a= 90°.
30	Volume Z	b = 13.1083(6) A c= 11.2398(6) A 1610.77(13) A³4	β= 99.346(2)° γ = 90°.

264

•	Density (calculated)	1.291 Mg/m³
5	Absorption coefficient F(000) Crystal size Thêta range for data collection	0.738 mm'¹ 664 0.360x0.220x0.140 mm³ 3.986 to 70.310°
10	Index ranges Reflections collected Independent reflections Completeness to thêta = 67.679° Absorption correction	-13<=h<=13, -16<=k<=15, -13<=l<=12 29459 6084 [R(int) = 0.0304] 99.9 % Empirical
15	Refinement method Data / restraints / parameters Goodness-of-fit on F² Final R indices [l>2sigma(l)] R indices (ail data)	Full-matrix least-squares on F²6084 /3/426 1.132 R1 = 0.0446, wR2 = 0.1005 R1 = 0.0452, wR2 = 0.1013
	Absolute structure parameter Extinction coefficient Largest diff. peak and hole	0.02(3) 0.125(4) 0.307 and -0.371 e.Â'³

Single Crystal X-Ray Analysis of crystalline (R) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol (Example 4)

The crystal structure of Example 4 was determined by single crystal X-ray diffraction analysis. The single crystal X-ray diffraction data collection was performed on a Bruker D8 Venture diffractometer at -150 °C température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Monoclinic class space group P2i. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms. Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). The Hooft parameter is reported as 0.08 with an Esd of 0.003 and the Parson’s parameter is reported as 0.15 with an Esd of 0.002. The final R-index was 4.6%. A final différence Fourier revealed no missing or misplaced électron density.

Figure 2 is the obtained X-ray structure (ORTEP drawing) of crystalline (R) 4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4). The crystal structure data is summarized in Table 4.

265

Table 4

Crystal data and structure refinement for Example 4.

Empirical formula Formula weight Température Wavelength Crystal system Space group Unit cell dimensions

Volume

Z

Density (calculated)

Absorption coefficient

F(000)

Crystal size

Thêta range for data collection

Index ranges

Reflections collected Independent reflections Completeness to thêta = 67.679° Absorption correction Refinement method

Data / restraints / parameters

Goodness-of-fit on F³

Final R indices [l>2sigma(l)J R indices (ail data)

Absolute structure parameter Extinction coefficient

Largest diff. peak and hole

Cis H22 B N O4 327.17 123(2) K 1.54178 A Monoclinic

P2i a = 10.7077(14) A	a= 90°.
b = 13.4140(17) A	β= 110.396(5)°
c= 13.0151(16) A 1752.2(4) A³	γ = 90°.
4

1.240 Mg/m³

0.699 mrrH

696

0.240x0.160x0.120 mm³

3.623 to 72.240°

-12<=h<=13, -16<=k<=16, -16<=l<=16

63647

6737 [R(int) = 0.0312]

98.8 %

Empirical

Full-matrix least-squares on F³

6737 /3/443

1.044

R1 = 0.0457, wR2 = 0.1282

R1 = 0.0477, wR2 = 0.1311

0.08(3) n/a

0.279 and -0.203 e.Â'³

Single Crystal X-Ray Analysis of crystalline (S) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol (Example 5)

The crystal structure of Example 5 was also determined by single crystal X-ray diffraction analysis. The single crystal X-ray diffraction data collection was performed on a Bruker D8 Quest diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Monoclinic space group P2i. The structure was subsequently refined by the full-matrix least squares method. AH non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms. Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). The Hooft parameter is reported as 0.01 with an Esd of 0.007and the Parson’s

266 parameter is reported as 0.01 with an Esd of 0.006. The final R-index was 4.8%. A final différence Fourier revealed no missing or misplaced électron density.

Figure 3 is the obtained X-ray structure (ORTEP drawing) of crystalline (S) 4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5). The crystal structure data is summarized in Table 5.

Table 5.

Crystal data and structure refinement for Example 5

Volume

Z

Density (calculated)

Absorption coefficient

F(000)

Crystal size

Thêta range for data collection Index ranges

Data / restraints / parameters

Goodness-of-fit on F²

Final R indices [l>2sigma(l)] R indices (ail data)

Absolute structure parameter Extinction coefficient

Largest diff. peak and hole

Cis H22 B N O4
327.17 296(2) K 1.54178 A Monoclinic P2i a = 10.6918(4) A	a= 90°.
b = 13.4115(4) A	β= 110.311(2)°
c = 13.0161(4) A	γ = 90°.
1750.37(10) A³ 4

1.242 Mg/m³

0.700 mm'¹

696

0.260x0.220x0.140 mm³

3.621 to 70.234°

-12<=h<=13, -16<=k<=16, -15<=l<=15

16854

6536 [R(int) = 0.0328]

99.3 %

Empirical

Full-matrix least-squares on F²

6536 /3/446

1.065

R1 = 0.0478, wR2 = 0.1176

R1 = 0.0512, wR2 = 0.1220

0.01(7)

0.0385(19)

0.236 and -0.273 e.Â'³

267

I Single Crystal X-Ray Analysis of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19)

The crystal structure of Example 19 was also determined by single crystal X-ray diffraction analysis. The single crystal X-ray diffraction data collection was performed on a

Bruker D8 Quest diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Monoclinic class space group P2!. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms. Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). The Hooft parameter is reported as 0.06 with an Esd of 0.004 and the Parson’s parameter is reported as 0.06 with an Esd of 0.003. The final R-index was 4.0%. A final différence Fourier revealed no missing or misplaced électron density.

Figure 4 is the obtained X-ray structure (ORTEP drawing) of crystalline (R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19). The crystal structure data is summarized in Table 6.

Table 6.

Crystal data and structure refinement for Example 19

Empirical formula Formula weight	C₃6 H44 B₂ N2 Os 654.35
25 Température	296(2) K
Wavelength	1.54178 A
Crystal System	Monoclinic
Space group	P2i
Unit cell dimensions	a = 11.2655(18) A a= 90°.
30	b = 12.903(2) A β= 111.269(5)° C= 12.959(2) A γ = 90°.
Volume	1755.4(5) A³
Z	2
Density (calculated)	1.238 Mg/m³
35 Absorption coefficient	0.698 mrrH
F(000)	696
Crystal size	0.420x0.360x0.120 mm³
Thêta range for data collection	3.660 to 72.747°
Index ranges	-13<=h<=13, -15<=k<=15, -15<=l<=16
40 Reflections collected	53020
Independent reflections	6907 [R(int) = 0.0361]
Completeness to thêta = 67.679°	100.0 %
Absorption correction	Empirical
Refinement method	Full-matrix least-squares on F²

268 φ Data ! restraints / parameters Goodness-of-fit on F³Final R indices [l>2sigma(l)] R indices (ail data)

Absolute structure parameter Extinction coefficient

Largest diff. peak and hole

6907 /3/446

1.055

R1 = 0.0396, wR2 = 0.1023

R1 = 0.0414, wR2 = 0.1043

0.06(4)

0.0261(13)

0.230 and -0.298 e.Â’³

X-Ray Powder Diffraction 10 The crystal structures of Examples 3, 4, 5, 10 and 19 were analyzed using X-ray powder ' diffraction (“PXRD”).

For Example 4, powder X-ray diffraction analysis was conducted using a Bruker AXS D8 ADVANCE diffractometer equipped with a Cu radiation source (K-α average). The system is equipped with a 2.5 axial Soller slits on the primary side. The secondary side utilizes 2.5 axial 15 Soller slits and motorized slits. Diffracted radiation was detected by a Lynx Eye XE detector.

The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.037 degrees and a step time of 10 seconds per step. Samples were prepared by placing them in a low background holder (Bruker part number: C79298A3244B261) 20 and rotated during collection. Data were collected using Bruker DIFFRAC Plus software.

Analysis performed by EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 and a width of 0.3 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was 25 visually checked and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3% were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to +/- 0.2° 2-Theta (USP-941).

For Examples 3, 5, 10, and 19, powder X-ray diffraction analysis was conducted using a 30 Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source (K-α average).

The System is equipped with a 2.5 axial Soller slits on the primary side. The secondary side utilizes 2.5 axial Soller slits and motorized slits. Diffracted radiation was detected by a Lynx Eye XE detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-2Theta goniometer at the Cu wavelength from 3.0 to 43.0 35 degrees 2-Theta using a step size of 0.020 degrees and a step time of 3 seconds per step.

Samples were prepared by placing them in a low background holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software. Analysis performed by EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 and a width of 0.3 were used to make preliminary peak assignments. To

269

F ensure validity, adjustments were manually made; the output of automated assignments was visually checked and peak positions were adjusted to the peak maximum. Peaks with relative intensity of £ 3% were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to +/- 0.2° 2-Theta (USP-941).

As will be appreciated by the skilled crystallographer, the relative intensities ofthe various peaks reported in the Tables and Figures below may vary due to a number of factors such as orientation effects of crystals in the X-ray beam or the purity of the material being analyzed or the degree of crystallinity of the sample. The peak positions will remain substantially 10 as defined. The skilled crystallographer also will appreciate that measurements using a different wavelength will resuit in different shifts according to the Bragg équation -nÀ=2d sin Θ. Such further PXRD patterns ofthe crystalline materials ofthe présent invention and as such are within the scope ofthe présent information.

Figure 5 is the obtained powder X-ray diffraction pattern for crystalline (R)-4-(5-(315 ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3) and Table 7 lists the PXRD peaks.

Table 7

270

30.2	10.2
32.1	3.2
33.5	5.3
33.8	3.0
34.5	4.4
37.7	4.7
40.5	6.4
41.3	3.5

Figure 6 is the obtained powder X-ray diffraction pattern for crystalline (R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4) and Table 8 lists the PXRD peaks.

Table 8

Example 4 PXRD Data

Angle (2-Theta) Degrees	Rel. Intensity %
11.0	94.9
11.4	64.8
13.2	43.1
14.5	27.3
15.1	39.3
15.6	23.1
15.9	9.4
17.7	10.0
18.8	81.8
19.4	13.0
19.7	49.3
20.5	12.4
21.3	45.1
22.0	8.5
22.9	100.0
23.8	5.7
24.5	6.0
25.1	71.8
25.6	4.6
25.9	20.5
26.4	36.0
27.5	17.1
28.4	8.9
28.8	4.9
30.4	3.6

Figure 7 is the obtained powder X-ray diffraction pattern for crystalline (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5) and Table 9 lists the

PXRD peaks.

271

Table 9

Example 5 PXRD Data

Angle (2-Theta) Degrees	Rel. Intensity %
11.0	60.0
11.4	44.8
13.2	28.3
14.5	18.6
15.1	27.2
15.6	16.5
15.9	6.9
17.7	7.2
18.7	67.4
19.4	10.4
19.7	42.6
20.5	10.8
21.2	40.4
21.9	8.1
22.1	4.3
22.8	100.0
23.8	5.7
24.4	6.3
25.0	67.0
25.5	5.0
25.9	19.98
26.4	33.9
27.4	18.8
28.3	10.5
28.8	5.7
30.0	3.5
30.4	4.1
32.1	3.5
35.5	3.4
36.1	4.1
38.0	3.7
38.5	3.3
39.0	3.1
39.6	3.3
41.4	3.9

Figure 8 is the obtained powder X-ray diffraction pattern for crystalline (-) 4-(5-(25 (difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 10) and Table 10 lists the PXRD peaks.

272

Table 10

Example 10 PXRD Data

Angle 2-Theta (Degrees)	Rel. Intensity %
8.9	12.7
12.0	18.0
12.3	14.5
12.8	100.0
13.7	5.6
13.9	20.6
14.2	13.2
14.5	3.7
15.9	5.8
17.6	14.4
17.8	31.5
19.2	21.6
19.4	16.5
19.6	17.2
20.4	59.3
21.4	13.9
22.0	16.3
22.3	17.4
22.5	15.1
22.9	32.3
23.1	31.4
24.2	14.5
25.7	44.2
27.3	3.7
27.5	6.3
28.5	11.7
28.8	7.0
29.6	5.2
30.7	12.9
33.7	3.9
35.6	9.9
40.3	3.7
40.9	5.4

Figure 9 is the obtained powder X-ray diffraction pattern for crystalline (R)-4-(5-(35 ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19) and Table 11 lists the PXRD peaks.

273

Table 11

Example 19 PXRD Data

	Angle 2-Theta (Degrees)	ReL Intensity %
10.1	4.9
10.9	65.9
11.3	23.2
13.1	4.3
13.7	3.9
14.7	7.5
17.0	14.7
17.3	33.4
19.0	32.4
19.3	59.2
19.7	17.8
19.7	23.6
20.2	4.5
20.6	7.4
21.1	59.0
21.9	5.8
22.7	85.5
23.6	14.1
23.8	100.0
23.9	61.7
24.1	10.6
24.5	6.6
24.8	18.8
25.4	47.8
25.4	38.6
26.2	6.4
26.5	13.9
26.8	3.6
27.1	15.4
27.1	11.8
27.5	10.1
28.5	3.8
28.5	5.8
29.5	3.1
30.4	28.8
30.5	16.9
32.2	4.9

274

34.2	4.0
35.9	3.5
39.1	5.4
39.5	3.8
39.9	5.0
40.9	4.2
42.2	7.1

Formulation Examples

An embodiment of the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, 5 or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 5% (w/w) to about 15% (w/w) solvent, and (c) an ointment base. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 5% (w/w) to about 15% (yj/w) solvent, and (c) petrolatum. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 5% (w/w) to about 15% (w/w) solvent, (c) ointment, (d) an antioxidant, (e) a stabilizer, (f) an emulsifying agent, and (g) a stiffening agent. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 5% (w/w) to about 15% (w/w) solvent, (c) ointment, (d) an antioxidant, (e) an emulsifying agent, and (f) a stiffening agent. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent 20 ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 5% (w/w) to about 15% (w/w) solvent, (c) petrolatum, (d) an antioxidant, (e) an emulsifying agent, and (f) a stiffening agent. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 8% (w/w) to about 10% (w/w) propylene or hexylene glycol, (c) from about 75%(w/w) to about 80% (w/w) white petrolatum, (d) from about 8% (w/w) to about 10% of a glyceride blend, (e) from about 4% to about 6% paraffin, and (f) from about 0.05% to 0.5% butylated hydroxytoluene. In an embodiment, the present invention provides a topical pharmaceutical formulation comprising:

(a) an active agent ofthe invention which treats an inflammatory related condition, or a pharmaceutically acceptable sait, or a hydrate or a solvaté thereof, (b) from about 8% (w/w) to about 10% (w/w) hexylene glycol, (c) from about 75%(w/w) to about 80% (w/w) white

275 petrolatum, (d) from about 8% (w/w) to about 10% of a glyceride blend, (e) from about 4% to about 6% paraffin, and (f) from about 0.05% to 0.5% butylated hydroxytoluene.

In an embodiment, the présent invention provides a topical pharmaceutical formulation comprising an active agent wherein “active agent” is a compound ofthe présent invention or a pharmaceutically acceptable sait, hydrate or a solvaté thereof. In another embodiment, the active agent is (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable sait, hydrate, or solvaté thereof. In another embodiment, the active agent is (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable sait, hydrate, or solvaté thereof. In another embodiment, the active agent is (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable sait, hydrate, or solvaté thereof. In another embodiment, the active agent is (R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable sait, hydrate, or solvaté thereof. In another embodiment, the active agent is (-)-4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, or a pharmaceutically acceptable sait, hydrate, or solvaté thereof.

In another embodiment, the présent invention provides a topical pharmaceutical formulation comprising an active agent présent in a concentration of about 0.0001% to about 3.0% (w/w). In another embodiment, the active agent is présent in a concentration of about 0.001% to about 2.0% (w/w). In another embodiment, the active agent is présent in a concentration of about 0.01% to about 1.0% (w/w). In another embodiment, the active agent is présent in a concentration of about 0.05% to about 0.5% (w/w).

In another embodiment, the présent invention provides an active agent, or a sait, hydrate or solvaté thereof. In another embodiment, the présent invention provides a combination of an active agent and a second active agent wherein the second active agent is useful for the treatment of inflammatory disorders such as atopie dermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, and inflammation resulting from surgical complications. The combination may be comprised of an admixture or co-formulation of the two active ingrédients. Altematively, the combination may be packaged in a dispenser wherein one active agent is in one chamber and another active ingrédient is in a second chamber, but upon dispensing, the two active agents are simultaneously delivered together such that administration ofthe combination may occur in one application. Altematively, the active agents may individually be administered with the other active agent, wherein the second active agent may be administered either orally or topically.

In another embodiment, the présent invention provides an active agent described herein, or a sait, hydrate or solvaté thereof, in a topical formulation which comprises a solvent. In another embodiment, the solvent is an alkyl glycol or alkyl alcohol. In another embodiment, the solvent is an alkyl glycol. In another embodiment, the solvent is propylene glycol. In another embodiment, the solvent is hexylene glycol. In another embodiment, the solvent is butylène

276 glycol. In another embodiment, the solvent is présent in a concentration of about 5.0% (w/w) to about 15.0% (w/w). In another embodiment, the solvent is présent in a concentration of about 6.0% (w/w) to about 12.0% (w/w). In another embodiment, the solvent is présent in a concentration of about 7.0% (w/w) to about 11.0% (w/w). In another embodiment, the solvent is présent in a concentration of about 8.0% (w/w) to about 10.0% (w/w).

In another embodiment, the présent invention provides an active agent described herein, or a sait, hydrate or soivate thereof, in a topical formulation which comprises an ointment base. In another embodiment, the ointment base is white petrolatum. In another embodiment, the ointment base is minerai jelly, petroleum jelly, yellow petrolatum, yellow soft paraffin, yellow Petroleum jelly, white petrolatum jelly, or white soft paraffin. In another embodiment, the base is minerai oil, light minerai oil, paraffin, or lanolin alcohol. The amount of ointment base in the topical pharmaceutical formulation will be dépendent on the amounts ofthe other components. In another embodiment, the ointment base is présent in a quantum satis concentration. In another embodiment, the ointment base is présent in a concentration of from about 65% (w/w) to about 85% (w/w). In another embodiment, the base is présent in a concentration of from about 70% (w/w) to about 80% (w/w). In another embodiment, the base is présent in a concentration of from about 75% (w/w) to about 80% (w/w).

In another embodiment, the présent invention provides an active agent described herein, or a sait, hydrate or soivate thereof, in a topical formulation which further comprises an antioxidant. In another embodiment, the antioxidant is butylated hydroxytoluene, ascorbic acid, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl2,6-di-tert-butyl phénol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, or tocopherol. In another embodiment, the antioxidant is butylated hydroxytoluene. In another embodiment, the antioxidant is présent in a concentration of about 0.01% (w/w) to about 1% (w/w). In another embodiment, the antioxidant is présent in a concentration of about 0.01% (w/w) to about 0.5% (w/w). In another embodiment, the antioxidant is présent in a concentration of about 0.05% (w/w) to about 0.5% (w/w). In another embodiment, the antioxidant is présent in a concentration of about 0.075% (w/w) to about 0.2% (w/w).

In another embodiment, the topical pharmaceutical formulation further comprises an emulsifying agent. In another embodiment, the emulsifying agent is a glyceride blend. In another embodiment, the emulsifying agent is a glyceride blend, wherein the glyceride blend comprises a monoglyceride and a diglyceride. In another embodiment, the emulsifying agent is a glyceride blend, wherein the glyceride blend comprises a monoglyceride, a diglyceride, and a triglycéride. In another embodiment, the emulsifying agent is a glyceride blend, wherein the glyceride blend comprises a monoglyceride and a diglyceride, and wherein from about 40% (w/w) to about 55% (w/w) ofthe glyceride blend is a monoglyceride. In another embodiment, the emulsifying agent is a glyceride blend, wherein the glyceride blend comprises a monoglyceride, a diglyceride, and

277 a triglycéride, and wherein from about 40% (w/w) to about 55% (w/w) ofthe glyceride blend is a monoglyceride. In another embodiment, the monoglyceride is selected from the group consisting of glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, or combinations thereof. In another embodiment, the monoglyceride is a monoglyceryl ester of a long chain, saturated or unsaturated fatty acid. In an embodiment, the monoglyceride is an alpha-monoglyceride. In a preferred embodiment, the diglyceride is a diglyceryl ester of a long chain, saturated or unsaturated fatty acid. In another embodiment, the glyceride blend is présent in a concentration of about 3.0% (w/w) to about 10.0% (w/w). In another embodiment, the glyceride blend is présent in a concentration of about 5.0% (w/w) to about 10.0% (w/w). In another embodiment, the glyceride blend about 6.0% (w/w) to about 8.0% (w/w).

In another embodiment, the topical pharmaceutical formulation further comprises a stiffening agent. In another embodiment, the stiffening agent is a wax. In another embodiment, the stiffening agent is a wax and the wax is selected from the group consisting of beeswax, paraffin wax, and spermaceti wax. In another embodiment, the stiffening agent is paraffin wax. In another embodiment, the stiffening agent is présent in a concentration of about 3.0% (w/w) to about 7.0% (w/w). In a preferred embodiment, the stiffening agent is présent in a concentration of about 4.0% (w/w) to about 6.0% (w/w). In another embodiment, the stiffening agent is présent in a concentration of about 4.5% (w/w) to about 5.5% (w/w).

In another embodiment, the topical pharmaceutical formulation further comprises a stabilizer. In another embodiment, the stabilizer is ethylenediaminetetraacetic acid, or a pharmaceutically acceptable sait thereof. In another embodiment, the stabilizer is a pharmaceutically acceptable sait of ethylenediaminetetraacetic acid, and this sait is a sodium sait or a potassium sait or a calcium sait, or a combination thereof. In another embodiment, the stabilizer is présent in a concentration of about 0.000010% (w/w) to about 0.0450% (w/w).

The composition of topical formulations for compounds ofthe présent invention include excipients that provide at least one ofthe following functionalities: solvent; base; dispersing agent; emulsifying agent; stiffening agent; rheology modifying agent; stabilizing agent; and antioxidant. For example, suitable topical ointment formulations for Example 4 include, but are not limited to, the formulations listed in Tables 12, 13, 15 and 16. In addition to the ointment formulations listed in Tables 12 and 13, other topical formulations suitable for the compounds of the présent invention include, but are not limited to, creams, lotions, gels, solutions, suspensions, foams, and sprays.

278

Table 12

	Quantity (% w/w)
Example 4	0.001 - 1	0.001 - 1	0.001 - 1	0.001 - 1	0.001 - 1	0.001 - 1
Propylene glycol	2 - 9				MMM\|
Hexylene glycol Transcutol		2-9___ MM	feu A - 2 -V”
Diisopropyl adipate				2 - 20
PEG400 Propylene carbonate	—		111¾¾		2 - 9	2 - 9
White petrolatum	qs	qs	qs	qs	qs	qs
Mono- and diglycerides	0-7	0-7	0-7	0-7	0-7	0-7
Span 60	0-2	0-2	0-2	0-2	0-2	0-2
Span 40	0-2	0-2	0-2	0-2	0-2	0-2
Phospholipid (lecithin)	0-10	0-10	0- 10	0 - 10	0- 10	0 - 10
Butylated Hydroxytoluene	0 - 0.1	0 - 0.1	0-0.1	0 - 0.1	0 - 0.1	0-0.1
Butylated Hydroxyanisole	0-0.1	0 - 0.1	0-0.1	0-0.1	0-0.1	0-0.1
Paraffin Wax	0-5	0-5	0-5	0-5	0-5	0-5
Total (%)	100.0	100.0	100.0	100.0	100.0	100.0

*qs or quantum satis means sufficient amount to make the total = 100%

Topical formulations prepared containing Example 4 that were tested for skin 5 permeability and maximum flux of Example 4 are listed in Table 13.

Table 13

	Quantity (% w/w)
Example 4	1	0.1	0.01	0
White petrolatum, USP	77.9	78.8	78.89	78.9
Mono- and diglycerides, NF	7	7	7	7
Butylated Hydroxytoluene (BHT), NF/PhEur	0.1	0.1	0.1	0.1
Paraffin Wax, NF	5	5	5	5
Hexylene Glycol, NF/USP	9	9	9	9
Total (%)	100.0	100.0	100.0	100.0

ln-vitro skin perméation study or Franz cell assay was used to demonstrate the ability of 10 ofthe formulations in Table 13 to enable Example 4 perméation across stratum corneum barrier and mobility through epidermis and dermis by way of flux measurement. The formulations exhibited a concentration dépendent skin flux (Table 14) and may accommodate a broad range

279 of Example 4 concentrations, providing a range of thermodynamic driving forces for Example 4 to permeate skin. A higher driving force can be achieved via incorporation into the formulations of additional pénétration enhancers such as oleyl alcohol.

Table 14

Cumulative Amount Permeated and Maximum Flux of Example 4

Example 4 Formulations From Table 13	N*	Mean, Cumulative Amount in 24 hours, (ng)	Std Error, Cumulative Amount in 24 hours (ng)	Mean, Max. Flux, (ng/cm²/hr)	Std Error, Max. Flux, (ng/cm²/hr)
1% Example 4	15	3357.7	769.6	252.28	49.05
0.1% Example 4	15	1089.9	131.9	73.95	7.53
0.01% Example 4	15	233.0	23.5	20.14	1.75
0% Example 4	6	0	0	0	0

* Number of skin donor = 3; Replicate per donor = 5.

Table 15

	Quantity (% w/w)
Example 4	0.001 - 1	0.001 - 1	0.001 - 1	0.001 - 1
Medium chain triglycérides*	2-20
Crodamol GTCC		2-20
Crodamol GMCC			2 - 20
Triacetin				2-10
White petrolatum	qs	qs	qs	qs
Mono- and diglycerides	0-7	0-7	0-7	0-7
Span 60	0 - 2	0-2	0-2	0-2
Span 40	0-2	0-2	0-2	0-2
Phospholipid (lecithin)	0-10	0 - 10	0-10	0-10
Butylated Hydroxytoluene	0-0.1	0-0.1	0-0.1	0 - 0.1
Butylated Hydroxyanisole	0-0.1	0-0.1	0 - 0.1	0-0.1
Paraffin Wax	0 - 5	0 - 5	0-5	0-5
Total (%)	100.0	100.0	100.0	100.0

* Medium chain triglycérides contain two or three fatty acids having an aliphatic tail of 6-12 carbon atoms.

280

Table 16

Example 4 Topical Ointment Formulations

Component	milligrams/gram (mgs/g)	milligrams/gram (mgs/g)	milligrams/gram (mgs/g)
Example 4	0.100	0.300	0.600
Hexylene Glycol	90.000	90.000	90.000
White Petrolatum	788.900	788.700	788.400
Mono- and Di-Glycerides	70.000	70.000	70.000
Paraffin Wax	50.000	50.000	50.000
Butylated Hydroxytoluene (BHT)	1.000	1.000	1.000
Total	1000.000	1000.000	1000.000

Biological Assays

PDE4 SPA Assay

Phosphodiesterase (PDE) activity is determined by measuring the effect of a test agent on the activity ofthe PDE4B enzyme in a scintillation proximity assay (SPA). At the time of assay, approximately 30 pL of PDE4B (aa 152-484, Uniprot ID Q07343) in 50 mM Tris pH 7.5, 10 1.3 mM MgCI₂, 0.004% Brij 35 is added to a 384 well white clear bottom polystyrène plate (Corning) containing 1 pL of varying concentrations of test compound. After -10 minutes at room température (RT; ~21°C), the assay is initiated by the addition of 20 pL of a mixture of ³Hlabeled (adenosine 3', 5'-cyclic phosphate, ammonium sait, [2,8-³H]; Perkin Elmer) and unlabeled cAMP. The final assay conditions are approximately 81.6 pM PDE4B in 50 mM Tris 15 pH 7.5, 1.3 mM MgCI₂, 0.004% Brij 35, 1 μΜ ³H-labeled/unlabeled cAMP (1425 dpm/pmol) and the indicated final concentration of test compound (approximately 10 μΜ to 9.5 pM by 4-fold dilution). The final concentration of DMSO in the assay is approximately 2.0%. After 30 minutes at RT, the assay is terminated by the addition of approximately 20 pL of an aqueous solution of PDE YSI SPA beads (8 mg/mL in water; Perkin Elmer). The beads are allowed to settle for at 20 least 2 hours and the plate is then counted on a MicroBeta2 (Perkin Elmer). The concentrations and resulting effect values for the tested compound are plotted and the concentration of compound required for 50% effect (IC50) is determined with a four-parameter logistic dose response équation (E-WorkBook, ID Business Solutions Ltd.) and shown in Table 17.

Cytokine Assays

Cytokine inhibitory activity is determined by measuring the effect of test agent on the release ofthe cytokines IL-4, IL-13 and IFNy from human peripheral blood mononuclear cells (PBMCs) stimulated with the T-cell mitogen phytohemagglutinin-L (PHA-L). At the time of assay, human PBMCs (Astarte Biologics) are removed from cryopreservation, thawed quickly at 30 37°C, diluted in assay medium (RPMI - Gibco 1640 medium, 10 % heat inactivated fêtai bovine

281

I sérum (HIFBS), 2 mM glutamine and 10 mM HEPES pH 7.4) and then centrifuged at 250 x g for minutes. The resulting cell pellet is re-suspended in assay medium to a concentration of approximateiy 5 x10^s cells/mL and 50 pL of this cell suspension (approximateiy 250,000 cells) is added to each well of a 384-well cell culture microtiter plate (Perkin Elmer). Varying concentrations of test compound are then diluted in assay medium and added to the assay plate wells in a volume of 25 pL. After ~10 minutes at room température (~21°C) the cells are stimulated by the addition of 25 pL of PHA-L (14 pg/mL; Millipore) and the assay plate is placed in an incubator at 37°C in a humidified environment in 5% carbon dioxide. The final assay conditions are approximateiy 250,000 human PBMCs per well in assay medium containing 3.5 10 pg/mL PHA-L and the indicated final concentration of test compound (approximateiy 10 μΜ to .5 pM by 4-fold dilution). The final concentration of DMSO in the assay is approximateiy 0.25%. After 48 hours, the assay plate is removed from the incubator and centrifuged at 250 x g for 5 minutes. A portion ofthe resulting cell supematant is then used to détermine the amount of IL4, IL-13 and IFNy in each well. Cytokine measurements are made using human IL-4, IL-13 or

IFNy HTRF assay kits (CisBio) following the manufacturées assay protocol. The concentrations and resulting effect values for tested compounds are plotted and the concentration of compound required for 50% effect (IC50) is determined with a four-parameter logistic dose response équation (E-WorkBook, ID Business Solutions Ltd.) and shown in Table 17.

Table 17

Example number	PDE4B2 IC50 nM	IL13 IC50 nM	IL4 IC50 nM	IFNy IC50 nM
1	3.16	284	14.34	2.98
2	0.67	1346	210.39	2.73
3	1.14	165	3.54	0.70
4	0.50	135	4.11	1.06
5	0.93	2394	36.33	4.04
6	1.05	283	17.58	0.72
7	0.97	289	7.76	0.71
8	2.42	25	0.76	1.20
9	1.26	265	3.63	1.87
10	6.92	438	2.39	1.62
11	33.49	10000	141.16	68.33
12	1.08	162	2.32	0.99
13	0.97	166	5.98	4.89
14	1.50	91	3.21	1.85
15	1.57	136	1.41	0.71
16	0.05	126	0.54	0.82
17	0.28	138	0.65	0.47
18	0.74	218	1.91	2.23
19	2.96	1482	2.56	1.68
20	26.91	8793	86.83	102.97
21	0.64	159	0.84	1.35
22	7.89	257	1.75	1.43
23	0.97	132	0.61	0.85

282

Example number	PDE4B2 IC50 nM	IL13 ICso nM	IL4 IC50 nM	IFNy IC50 nM
24	0.99	163	2.24	1.33
25	2.40	2315	67.79	9.17
26	399.28	10000	1668.34	3302.07
27	73.39	10000	3786.25	208.88
28	10.85	8013	1036.85	200.54
29	10.47	3470	9.51	4.82
30	15.54	10000	70.71	11.61
31	4.20	5726	3.92	2.96
32	12.96	2249	64.00	8.47
33	1.25	181	39.82	1.44
34	0.52	309	14.34	1.39
35	1.17	230	6.98	1.55
36	0.98	476	5.25	1.27
37
38
39	1.63	182	13.78	1.82
40	0.37	175	29.25	1.28
41	6.85	397	6.20	1.87
42	0.35	205	90.39	1.55
43	8.23	10000	232.92	76.01
44	2.50	167	7.22	1.34
45	2.29	450	12.38	3.88
46	3.46	317	11.80	3.77
47	3.01	143	4.11	1.54
48	0.12	252	0.82	0.98
49	1.59	166	4.40	3.21
50	0.79	234	1.04	1.52
51	1.27	337	3.73	1.64
52	9.25	2607	14.59	5.74
53	1.41	115	4.87	0.60
54	7.77	1487	5.58	4.20
55	2.21	576	3.94	2.27
56	2.81	446	68.04	3.62
57	10.17	239	7.54	2.29
58	0.72	103	162.84	1.81
59
60	0.34	308	2.04	0.53
61	0.53	499	0.73	2.12
62	0.28	2573	2.66	1.44
63	1.62	312	57.89	2.75
64	18.49	325	8.04	4.44
65	9.53	814	185.58	5.34
66	2.15	327	86.50	0.71
67	4.02	759	99.92	12.61
68	0.47	369	4.85	1.50
69	4.39	373	6.51	3.84
70	3.00	890	4.31	2.85
71	11.01	1908	42.00	18.84
72	0.85	375	102.82	6.21
73	2.19	384	49.87	1.66
74	3.04	768	10.91	2.71
75	4.52	395	125.12	5.98

283

Example number	PDE4B2 IC50 nM	IL13 IC50 nM	IL4 IC50 nM	IFNy IC50 nM
76	10.00	403	5.75	2.17
77	2.40	415	40.81	2.61
78	0.55	416	19.09	1.35
79	1.38	748	13.33	0.82
80	1.34	2153	19.75	4.62
81	2.36	858	54.35	1.62
82	0.55	426	7.14	1.07
83	6.64	439	9.42	4.73
84	1.24	444	0.90	0.44
85	0.29	541	0.90	0.56
86	7.26	1334	104.66	5.00
87	5.03	444	19.12	3.02
88	2.64	609	63.68	6.14
89	1.21	449	26.43	3.50
90	4.33	2793	289.67	13.67
91	3.00	460	5.90	3.92
92	1.79	947	3.36	2.70
93	0.50	460	9.87	1.66
94	12.49	606	9.58	3.88
95	4.87	461	7.36	2.87
96	1.69	965	48.92	5.27
97	3.17	465	34.01	2.81
98	1.13	2800	219.37	2.67
99	1.37	957	44.33	9.42
100	1.68	472	32.73	4.32
101	2.70	2652	26.02	13.33
102	5.85	1236	2.07	3.01
103	1.43	487	0.83	0.76
104	3.58	750	29.41	5.46
105	3.20	490	14.20	5.46
106	1.83	2085	16.08	3.42
107	2.41	613	27.06	4.17
108	4.23	493	22.10	4.35
109	4.18	1270	22.69	6.24
110	0.61	496	48.41	5.10
111	0.97	496	3.01	2.95
112	1.41	588	79.88	8.10
113	1.38	497	36.10	3.81
114	3.00	2914	32.74	21.49
115	1.10	509	38.43	1.68
116	0.87	508	42.02	2.45
117	1.80	520	64.17	10.03
118	0.90	531	9.78	2.65
119	0.72	1188	5.74	7.34
120	1.11	2089	171.18	7.85
121	0.69	533	57.39	1.50
122	5.63	567	362.45	7.49
123	3.11	1635	34.10	3.58
124	2.20	1664	9.48	10.12
125	1.70	577	11.31	2.43
126	0.85	680	7.21	0.79
127	5.30	585	62.56	2.84

284

Example number	PDE4B2 IC50 nM	IL13 IC50 nM	IL4 IC50 nM	IFNy IC50 nM
128	5.74	667	53.10	2.25
129	4.04	3337	34.48	24.60
130	1.60	587	120.36	3.21
131	8.10	591	11.55	5.70
132	2.63	604	12.95	2.42
133	1.91	628	1.37	1.92
134	7.46	1108	1.79	3.04
135	10.31	668	15.32	7.24
136	2.86	670	11.66	2.43
137	2.21	1087	37.16	2.52
138	2.04	988	1.08	0.90
139	0.25	788	0.78	0.40
140	2.70	3449	3.47	3.20
141	0.95	701	3.35	2.24
142	2.53	1035	4.50	2.04
143	2.71	1165	4.11	3.68
144	0.58	706	83.91	5.02
145	6.77	2239	103.33	52.07
146	1.21	757	24.35	23.83
147	0.44	1257	2.69	1.57
148	0.24	759	4.92	1.68
149	0.49	793	20.22	0.87
150	4.05	827	168.67	18.89
151	5.98	813	39.11	3.48
152	1.38	828	160.96	6.02
153	3.24	860	50.73	2.57
154	14.13	893	31.39	15.18
155	1.81	2602	292.55	5.64
156	0.82	901	127.25	1.56
157	2.96	906	189.65	5.62
158	12.04	929	59.12	10.23
159	15.08	931	467.60	25.05
160	10.09	2301	25.97	15.92
161	11.26	960	419.00	38.63
162	14.52	975	56.31	8.29
163	3.71	2512	31.09	14.15
164	5.58	986	41.11	7.87
165	2.11	990	127.75	3.25
166	0.97	1006	49.25	5.46
167	1.98	2786	1.37	1.13
168	0.88	1260	1.17	0.64
169	2.85	2017	32.95	5.84
170	3.78	1069	48.55	2.83
171	1.73	1351	2.43	3.22
172	1.76	1112	269.26	27.48
173	10.03	1132	77.06	30.17
174	8.57	1137	278.94	14.36
175	5.03	2307	14.32	4.35
176	5.51	1141	6.51	2.98
177	2.71	1225	154.73	8.49
178	2.02	1284	1.81	0.91
179	0.98	2730	0.72	0.74

285

Example number	PDE4B2 IC50 nM	IL13 IC50 nM	IL4 IC50 nM	IFNy IC50 nM
180	3.01	1288	6.33	6.65
181	0.68	1299	2.23	3.17
182	5.14	1329	245.20	19.59
183	2.72	1367	102.50	6.40
184	0.80	1402	79.25	4.48
185	3.38	2984	5.75	1.30
186	4.43	1402	31.42	5.13
187	4.28	1420	41.13	8.84
188	12.46	1532	135.44	12.25
189	2.61	1457	7.72	1.46
190	1.43	1476	40.33	5.01
191	3.84	1502	175.98	4.42
192	2.15	1500	14.63	5.43
193	0.63	1529	73.11	2.16
194	3.63	1539	2.85	14.71
195	0.72	2190	0.36	0.33
196	0.34	1543	0.29	0.81
197	22.04	1575	106.85	12.18
198	14.28	1576	14.15	4.85
199	10.44	1586	90.38	4.55
200	12.88	1599	128.17	14.09
201	2.13	1661	105.21	9.51
202	4.29	1668	5.20	8.51
203	14.99	2185	176.06	114.15
204	6.07	1707	22.71	21.78
205	0.52	1772	1.06	1.09
206	2.65	1793	113.37	27.80
207	10.33	1802	389.57	53.50
208	0.22	1805	4.06	1.98
209	6.55	1819	308.43	21.72
210	1.92	2390	17.58	2.40
211	2.95	1839	27.81	1.83
212	2.27	1895	102.59	3.29
213	6.32	1980	80.86	3.36
214	4.92	1995	20.71	13.67
215	2.58	2052	62.71	2.18
216	4.05	2864	19.63	1.94
217	5.50	2067	20.53	10.33
218	1.45	2836	3.24	2.30
219	0.82	2130	4.10	1.67
220	3.29	2131	539.65	2.37
221	2.21	2426	47.35	9.35
222	1.14	2370	1.44	1.17
223	6.67	2689	30.93	22.52
224	2.17	2494	8.94	8.12
225	3.79	2376	21.22	4.36
226	8.72	2522	24.68	17.78
227	7.94	2541	285.17	9.16
228	6.32	2574	7.78	14.24
229	2.64	2733	194.76	2.90
230	17.09	2780	140.71	26.53
231	1.98	2954	1.25	1.72

286

•	Example number	PDE4B2 IC50 nM	IL13 IC50 nM	IL4 IC50 nM	IFNy IC50 nM
232	4.65	583	197.03	17.92
233	8.74	508	103.58	2.94

PDE4B is a major PDE4 isoform in neutrophils and in monocytes, and the PDE4B2 variant is a major subtype found in these cells associated with inflammation. Interferon gamma (IFNy), interleukin 4 (IL4), and interleukin 13 (IL13) are cytokines that are primarily produced by 5 T cells in addition to certain innate immune cell populations. Production of these cytokines has been associated with inflammatory skin diseases, such as atopie dermatitis and with other immune and inflammatory diseases. Inhibition of release of these inflammatory cytokines would modulate the inflammatory response.

It is understood that the foregoing detailed description and accompanying Examples are 10 merely illustrative and are not to be taken as limitations upon the scope ofthe invention, which is defined by the appended claims. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the Chemical structures, substituents, dérivatives, intermediates, synthèses, formulations and/or methods of use of the invention, may be made 15 without departing from the spirit and scope thereof.

Powder X-Ray Diffraction analysis for crystalline (4-methoxy-3-propoxyphenyl)boronic acid, 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine, and 3-(3-((tertbutyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-α average). The divergence slit was set at 15 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 2.99 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the

Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1.0 second. The antiscatter screen was set to a fixed distance of 1.5 mm. Samples were rotated at 15 rotations /min during collection. Samples were prepared by placing them in a Silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.

Data analysis was performed by EVA diffract plus software (version 4.2.1). The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked and peak positions were adjusted to the peak maximum.

Peaks with relative intensity of > 3% were generally chosen. The peaks which were not resolved

287 or were consistent with noise were not selected. A typical error associated with the peak position of crystalline material, from PXRD, stated in USP, is up to +/- 0.2° 2-Theta (USP-941).

Table 18

PXRD peak list for (4-methoxy-3-propoxyphenyl)boronic acid.

^H0 'oh

Angle 2-Theta °	Relative Intensity %
8.3	9.2
9.6	19.5
9.9	3.0
10.6	8.1
12.0	4.9
14.8	100.0
15.4	39.1
16.6	7.9
17.0	7.5
18.3	3.5
18.9	23.7
19.3	24.6
20.4	3.9
21.1	6.4
21.5	6.5
21.7	7.1
22.0	3.9
23.1	35.9
23.5	73.6
23.8	32.0
24.5	15.7
25.0	16.5
25.5	39.7
26.2	10.4
27.3	14.4
27.9	22.0
28.2	17.0
28.5	4.6
29.2	6.8
31.0	12.4
31.3	6.4
31.7	6.1
32.7	4.1
34.4	4.0
34.7	2.7

288

35.8	5.4
38.7	5.6
39.3	7.5

Table 19

PXRD peak list for 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine.

Angle 2-Theta °	Relative Intensity %
5.5	100
11.0	5.1
16.4	4.4
21.2	6.6
22.1	78.7
25.2	11.1
25.3	10.7
26.1	11.6
26.2	6.8
27.7	22
30.0	16.0
30.1	7.1
30.9	15.9
33.3	14.2
33.4	7.1
39.1 39.2	7.7 3.8

Table 20

PXRD peak list for 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3propoxyphenyl)pyridine

Angle 2-Theta °	Relative Intensity %
5.5	34.3
7.7	43.6
9.4	8.6
11.0	19.7
13.4	100.0
15.3	32.2
15.6	2.6
16.3	95.0

289

18.1	20.9
18.8	92.4
20.5	7.9
21.0	3.4
21.8	6.2
22.0	17.5
22.5	4.1
23.0	38.0
23.3	5.5
23.6	38.0
23.7	77.7
23.9	4.6
24.8	2.9
25.5	35.5
26.8	16.5
27.1	3.4
27.5	3.0
28.4	6.7
28.5	7.9
31.1	4.9
31.3	9.1
31.6	2.8
32.0	5.2
32.8	5.1
33.2	3.4
33.9	8.7
34.0	11.6
34.1	10.3
35.2	4.3

290

or a pharmaceutically acceptable sait thereof, wherein

B is boron;

Ai and A₂ are independently O or S;

Ri, R₂, and Rs are independently H, deuterium, (C₂-C6)alkenyl, (C₂-C6)alkenyloxy, (C₂-C6)alkenylthio, (Ci-Cejalkoxy, (Ci-C6)alkoxy-di-i₃, (Ci-C6)alkoxy(Ci-C6)aIkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C6)alkoxycarbonyl, (Ci-Ce)alkyl, (Ci-Cejalkyl-di-is, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, (C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C2-C₆)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C6)alkoxy, carboxy(Ci-C6)alkyl, cyano, (C3-C₈)cycloalkyl, (C3-C8)cycloalkyl(CiC₆)alkoxy, (C₃-C₈)cycloalkyl(Ci-C₆)alkyl, C3-C8)cycloalkyl(Ci-C₆)alkylthio, (C₃-C₈)cycloalkyloxy, (C3-C₈)cycloalkylthio, halogen, halo(Ci-C6)alkoxy, halo(Ci-C6)alkyl, halo(Ci-C6)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C₆)alkyl, (5-6 membered)heteroaryl(Ci-C6)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C6)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-C6)alkoxy, hydroxy(Ci-C6)alkyI, mercapto, nitro, thio(Ci-C₆)alkyl, -NRaRb, NR_ARB(Ci-C₆)alkoxy, NRAR_B(Ci-C₆)alkyl, or (NR_AR_B)carbonyl;

Ra and Rb are independently hydrogen, (Ci-Cejalkyl, or (Ci-Cejalkylcarbonyl;

R₃ and R4 are independently H, deuterium, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di.7, (Ci-Cejalkyl, (Ci-C₆)alkyl-c/i-i₃, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl;

R₆, R7, and Rg are independently, H, deuterium, (Ci-Cejalkoxy, (Ci-C6)alkoxy-di-i₃, (Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-c/i-7, (Ci-Cejalkyl, (Ci-C6)alkyl-di-i3, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy,

291 hydroxy(Ci-C6)alkyl, mercapto, nitro, -NRcRd, NRcRD(Ci-C6)alkoxy, NRcRD(Ci-C6)alkyl, or (NRcRo)carbonyl;

Rc and Rd are independently hydrogen, (Ci-C₈)alkyl, or (Ci-Cejalkylcarbonyl;

Rio at each occurrence is independently deuterium, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di.₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylthio(Ci-C₆)alkyl, hydroxy(Ci-C6)alkyl, or thio(Ci-C6)alkyl; and p is 0, 1,2, 3, 4, or 5.

Claims

1/12

FIG. 1

2/12

FIG. 2

C7

2. The compound of claim 1 of Formula (IA)

Formula (IA) or a pharmaceutically acceptable sait thereof, wherein B is boron;

Ai and A₂ are independently O or S;

Ri, R₂, and R₅ are independently H, deuterium, (C₂-C6)alkenyl, (C₂-C6)alkenyloxy, (C₂-C₆)alkenylthio, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-c/i-i₃, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alky[, (Ci-C₆)alkoxycarbonyl, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, (C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C6)alkoxy, carboxy(CrCe)alkyl, cyano, (C₃-C₈)cycloalkyl, (C3-C₈)cycloalkyl(CiC₆)alkoxy, (C₃-C₈)cycloalkyl(Ci-C₆)alkyl, C₃-C₈)cycloalkyl(Ci-C6)alkylthio, (C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(Ci-C6)alkoxy, halo(Ci-C6)alkyl, halo(Ci-C6)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C₆)alkoxy, (5-6 membered)heteroaryl(Ci-C6)alkyl, (5-6 membered)heteroaryl(Ci-C6)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(Ci-C₆)alkoxy, (4-7 membered)heterocycle(Ci-C₆)alkyl, (4-7 membered)heterocycle(Ci-C6)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-Ce)alkoxy, hydroxy(Ci-C6)alkyl, mercapto, nitro, thio(Ci-C₈)alkyl, -NRaRb, NR_ARB(Ci-C₆)alkoxy, NR_ARB(Ci-C6)alkyl, or (NR_ARB)carbonyl;

292

Ra and Rb are independently hydrogen, (Ci-Ce)alkyl, or (Ci-Cejalkylcarbonyl;

R₃ and R₄ are independently H, deuterium, (Ci-Cs)alkyl, (Ci-C3)alkyl-di.₇, (Ci-C₆)alkyl, (Ci-C6)alkyl-di-i₃, (Cs-Csjcycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl;

Re, R₇, and Rg are independently, H, deuterium, (Ci-Ce)alkoxy, (Ci-Ce)alkoxy-c/i-i3, (Ci-Ce)alkoxy(Ci-Ce)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C6)alkoxycarbonyl(Ci-Ce)alkyl, (Ci-Cs)alkyl, (Ci-C₃)alkyl-c/i-₇, (Ci-Ce)alkyl, (Ci-Cejalkyl-cG-is, (Ci-Ce)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-Ce)alkyl, cyano, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-Ce)alkyl, mercapto, nitro, -NRcRd, NRcRD(Ci-Ce)alkoxy, NRcRD/Ci-Cejalkyl, or (NRcRo)carbonyl;

Rc and Rd are independently hydrogen, (Ci-Ce)alkyl, or (Ci-Cejalkylcarbonyi;

Rio at each occurrence is independently deuterium, (Ci-Ce)alkoxy(Ci-Ce)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-di-₇, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylthio(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, or thio(Ci-C₆)alkyl; and p is 0, 1,2, 3, 4, or 5.

3/12

FIG. 3

3. The compound of claim 2, or a pharmaceutically acceptable sait thereof, wherein B is boron;

Ai and A₂ are O;

Ri, R₂, and R₅ are independently H, cyano, halogen, or halo/Ci-Cejalkyl;

R₃ and R₄ are independently (Ci-C₃)alkyl, (Ci-Cejalkyl, (Cs-Csjcycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl;

R₆, R₇, and Rg are independently, H, (Ci-Ce)alkoxy, (Ci-Cejaikoxy/Ci-Cejalkyl, (Ci-C6)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-C₆)alkyl;

Rio is (Ci-C₆)alkyl or hydroxy(Ci-C₆)alkyl; and p is 0 or 1.

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

2Theta

4/12

FIG. 4

4. The compound of claim 2, or a pharmaceutically acceptable sait thereof, wherein B is boron;

Ai and A₂ are O;

Ri, R₂, and R₅ are H;

R₃ and R₄ are independently (Ci-C₃)alkyl, (Ci-Cejalkyl, (Cs-Csjcycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C6)alkyl;

293

R₆, R?, and Rg are independently H or (Ci-C₃)alkyl; Rio is methyl; and p is 0, 1, or 2.

5/12

FIG. 5

1oooooi

Counts

80000

60000

40000

20000

Ï0.........20.........30 .....40

2Theta (Coupled Two Theta/Theta) WL=1.54060

5. The compound of claim 2, or a pharmaceutically acceptable sait thereof, wherein B is boron;

Ai and A₂ are O;

Ri, R₂, and Rs are H;

Ra and R₄ are independently (Ci-C₃)alkyl;

R₆, R?, and Rg are independently H or (Ci-C₃)alkyl; and p is 0.

6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

2Theta

6/12

FIG. 6

Counts

110001

100001

90001 80001

7000 î

6000 j 5000] 4000] 3000 i d

2000]

10001

0^

2Theta Scale

6. The compound of claim 1 of Formula (IB)

Formula (IB) or a pharmaceutically acceptable sait thereof, wherein

B is boron;

Ai and A₂ are independently O or S;

Ri, R₂, and Rs are independently H, deuterium, (C₂-C6)alkenyl, (C₂-C6)alkenyloxy, (C₂-C₆)alkenylthio, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy-di-i_3> (Ci-C6)alkoxy(Ci-C₆)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Ci-Ce)alkyl, (Ci-C6)alkyl-di-i₃, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, (C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl, aryl(Ci-C₆)alkoxy, aryl(Ci-C₆)alkyl, aryl(Ci-C₆)alkylthio, aryloxy, arylthio, carboxy, carboxy(Ci-C6)alkoxy, carboxy(Ci-Ce)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-Cs)cycloalkyI(CiC₆)alkoxy, (C₃-C8)cycloalkyl(Ci-C₆)alkyl, C₃-C₈)cycloalkyl(Ci-C₆)alkylthio, (C₃-C₈)cycloalkyloxy, (Cs-Csjcycloalkylthio, halogen, halo(Ci-C6)alkoxy, halo(Ci-C₈)alkyl, halo(Ci-C6)alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(Ci-C6)alkoxy, (5-6 membered)heteroaryl(Ci-C6)alkyl, (5-6 membered)heteroaryl(Ci-C6)alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N,

294 and S, (4-7 membered)heterocycle(Ci-C6)alkoxy, (4-7 membered)heterocycle(Ci-C6)alkyl, (4-7 membered)heterocycIe(Ci-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(Ci-Ce)alkoxy, hydroxy(Ci-Ce)alkyl, mercapto, nitro, thio(Ci-C₆)alkyl, -NRaRb, NR_ARB(Ci-C₆)alkoxy, NR_ARB(Ci-C₆)alkyl, or (NR_ARB)carbonyl;

Ra and Rb are independently hydrogen, (Ci-Ce)alkyl, or (Ci-Ce)alkylcarbonyl;

Rs and R4 are independently H, deuterium, (Ci-Csjalkyl, (Ci-C3)alkyl-di.7, (Ci-Ce)alkyl, (Ci-C6)alkyl-di-i3, (C₃-C₈)cycloalkyl, halo(Ci-C₆)alkyl, or hydroxy(Ci-C₆)alkyl;

R₆, R7, and R9 are independently, H, deuterium, (Ci-C₈)alkoxy, (Ci-C₈)alkoxy-c/i-i3, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (Ci-C₆)alkoxycarbonyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkyl, (Ci-Cs)alkyl, (Ci-C3)alkyl-di-7, (Ci-Ce)alkyl, (Ci-Csjalkyl-di-is, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkylthio, carboxy, carboxy(Ci-C₆)alkoxy, carboxy(Ci-C₆)alkyl, cyano, halogen, halo(Ci-C₆)alkoxy, halo(Ci-C₆)alkyl, hydroxy, hydroxy(Ci-C₆)alkoxy, hydroxy(Ci-Cs)alkyl, mercapto, nitro, -NR_cRd, NR_cRD(Ci-C₆)alkoxy, NR_cRD(Ci-C₆)alkyl, or (NRcRo)carbonyl;

Rc and Rd are independently hydrogen, (Ci-Cs)alkyl, or (Ci-C₈)alkylcarbonyl;

R10 at each occurrence is independently deuterium, (Ci-C6)alkoxy(Ci-C₈)alkyl, (Ci-C₃)alkyl, (Ci-C₃)alkyl-c/i.7, (Ci-C₆)alkyl, (Ci-C₆)alkyl-di-i₃, (Ci-C₆)alkylthio(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, orthio(Ci-C₆)alkyl; and p is 0, 1,2, 3, 4, or 5.

7/12

FIG. 7

Counts

2Theta (Coupled Two Theta/Theta) WL=1.54060

7. The compound of claim 6, or a pharmaceutically acceptable sait thereof, wherein

B is boron;

Ai and A₂ are O;

Ri, R₂, and R₅ are independently H, cyano, halogen, or halo(Ci-C₆)alkyl;

R3 and R4 are independently (Ci-Csjalkyl, (Ci-Cs)alkyl, (C3-C₈)cycloalkyl, halo(Ci-Ce)alkyl, or hydroxy(Ci-Ce)alkyl;

R₆, R7, and Rg are independently, H, (Ci-C₈)alkoxy, (Ci-Ce)alkoxy(Ci-C6)alkyl, (Ci-C₆)alkoxycarbonyl(Ci-C₆)alkyl, (Ci-C₃)alkyl, (Ci-Ce)alkyl, carboxy(Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy(Ci-C₆)alkoxy, or hydroxy(Ci-Ce)alkyl;

R10 is (Ci-Ce)alkyl or hydroxy(Ci-C₈)alkyl; and p is 0 or 1.

8/12

FIG. 8

Counts

8. The compound of claim 6, or a pharmaceutically acceptable sait thereof, wherein B is boron;

295

Ai and A₂ are O;

Ri, R₂, and R₅ are H;

Rs and R₄ are independently (Ci-C₃)alkyl, (Ci-Cs)alkyl, (C₃-C8)cycloalkyl, halo(Ci-C6)alkyl, or hydroxy(Ci-Ce)alkyl;

R₆, R₇, and R₉ are independently H or (Ci-Cs)alkyl;

R10 is methyl; and p is 0, 1, or 2.

9/12

Counts

150000; 120000; 90000^ 60000' 30000; FIG. 9 jujuJL-jL wuvU 10 .........20 .........30 .........40

2Theta (Coupled Two Theta/Theta) WL=1.54060

9. The compound of claim 6, or a pharmaceutically acceptable sait thereof, wherein

B is boron;

Ai and A₂ are O;

Ri, R₂, and R5 are H;

R₃ and R₄ are (Ci-C₃)alkyl;

R₆, R_7j and R₉ are independently H or (Ci-C₃)alkyl; and p is 0.

10/12

FIG. 10

1200001

100000

Counts

80000 J

60000 ]

40000 '

20000 '

......................r......I...............................................p.....P................!.........p.....P'!....... ψ.τ_τ,_Ί......................................................... !......... !.........,........._t.........,.........!

10. The compound of claim 1 that is (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol or a pharmaceutically acceptable sait thereof.

11/12

FIG. 11

Counts

60000j

40000

200001

OA

AJ

11. The compound of claim 1 of structure

12. The compound of claim 1 that is Crystalline (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

13. The crystalline compound of claim 12 having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 22.9 ± 0.2, and 25.1 ± 0.2 degrees two thêta.

14. The crystalline compound of claim 12 having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 18.8 ± 0.2, 22.9 ± 0.2, 25.1 ± 0.2, and 26.4 ± 0.2 degrees two thêta.

296

15. The compound of claim 1 that is (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol or a pharmaceutically acceptable sait thereof.

16. The compound of daim 1 of structure

17. The compound of claim 1 that is Crystalline (S)-4-(5-(4-methoxy-3- propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

10

18. The crystalline compound of claim 17 having an X-ray powder diffraction pattern comprising diffraction peaks 18.7 ± 0.2, 22.8 ± 0.2, and 25.0 ± 0.2 degrees two thêta.

19. The crystalline compound of claim 17 having an X-ray powder diffraction pattern comprising diffraction peaks 11.0 ± 0.2, 11.4 ± 0.2, 13.2 ± 0.2, 18.7 ± 0.2, 22.8 ± 0.2, and 25.0 ± 15 0.2, degrees two thêta.

ABSTRACT

The present invention relates to boron containing compounds of Formula (I)

X-Y-Z

Formula (I) that inhibit phosphodiesterase 4 (PDE4). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating diseases, conditions, or disorders ameliorated by inhibition of PDE4.

12/12

FIG. 12

Counts

2Theta