RU2793936C2 - Boron-containing pde4 inhibitors - Google Patents

Abstract

FIELD: medicinal chemistry.

SUBSTANCE: boron-containing compound of formula (IA) or formula (IB) or a pharmaceutically acceptable salt thereof. In formula (IA) and formula (IB): B is boron; A₁ and A₂ are independently O or S; R₁, R₂ and R₅ are each independently H, deuterium, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d_1-13, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d_1-13, cyano, halogen or halo(C₁-C₆)alkyl; R₃ and R₄ are each independently (C₁-C₆)alkyl, (C₁-C₆)alkyl-d_1-13, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; R₆, R₇ and R₉ are each independently H, deuterium, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d_1-13 or halo(C₁-C₆)alkyl; p is 0. (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof and (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof and crystalline forms thereof, pharmaceutical composition and use for the drug preparation for the treatment of atopic dermatitis in humans are also provided. The proposed compounds inhibit phosphodiesterase 4 (PDE4).

EFFECT: treating conditions or disorders mitigated by PDE4 inhibition.

20 cl, 12 dwg, 18 tbl, 470 ex

Formula (1A) Formula (1B)

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

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

BACKGROUND OF THE INVENTION

Inflammation is a major component of many diseases, and individuals with such diseases often exhibit high levels of inflammatory regulators, which include, but are not limited to, the following cytokines IL-1α, IL-1β, IL-2, IL-3, IL-4, IL -5, IL-6, IL-7, IL-9, IL-12, IL-13, IL-17, IL-18, IL-23, IL-31, IL-33, TNF-α, IFN-α , IFN-β and IFN-γ. A non-limiting list of disease states that are directly related to inflammatory cytokines include: atopic dermatitis, in which inflammatory cytokines cause inflammation; psoriasis, in which inflammatory cytokines cause dermatitis; arthritis, in which inflammatory cytokines can lead to synovial damage and destruction of articular cartilage and bone; fibrosis, in which inflammatory cytokines can attack injured tissue; lupus, in which inflammatory cytokines can exacerbate immune complex deposition and damage; allergies, in which inflammatory cytokines can cause inflammation, IgE production, and congestion; fibromyalgia, in which patients have elevated inflammatory cytokines; and surgical complications, in which inflammatory cytokines can interfere with healing.

Other diseases associated with chronic inflammation include: cancer; heart attack, in which chronic inflammation contributes to coronary atherosclerosis; Alzheimer's disease, in which chronic inflammation negatively affects brain cells; congestive heart failure, in which chronic inflammation causes wasting of the heart muscle; stroke, in which chronic inflammation contributes to thromboembolic events; and aortic valve stenosis, in which chronic inflammation damages the heart valves. Also associated with inflammation are arteriosclerosis, osteoporosis, Parkinson's disease, bacterial infection, viral infection, inflammatory bowel disease including Crohn's disease and ulcerative colitis, and multiple sclerosis (a typical autoimmune inflammatory disease). Current methods available for the treatment of such inflammatory diseases may be unsatisfactory due to lack of efficacy and/or side effects associated with drugs. Therefore, there is a need for new therapeutic methods that modulate the inflammatory process associated with the diseases, conditions and disorders described herein.

In particular, atopic dermatitis (AD) is an inflammatory skin disease that usually presents in early childhood but may appear in adolescence or adulthood and follows a chronic or recurrent/hard-to-treat progression of the disease. Patients with AD have pruritus and a predisposition to skin secondary bacterial, viral, and fungal infections. Patients with AD may also exhibit impaired barrier function, resulting in the activation of keratinocytes 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 promote the production of various chemoattractants or chemokines that support the recruitment of leukocytes to the disease site. Chemokines that contribute to inflammation in AD patients include, but are 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. Topical application of anti-inflammatory steroids is used in the treatment of AD, especially in the case of an exacerbation of the disease. Steroids inhibit the activation and proliferation of inflammatory cells, as well as keratinocytes and fibroblasts. However, steroids can cause adverse local side effects that include, but are not limited to, skin atrophy, telangiectasia (abnormal dilation of capillaries), disruption of the epidermal barrier, striae, rosacea, acne, hypertrichosis, hypopigmentation, delayed wound healing, and changes in skin elasticity. Emollients, including petroleum jelly and over-the-counter moisturizers, are used to reduce the use of topical steroids. Topical application of mevalonic acid and nicotinamide is used to improve the permeability of the epidermal barrier through the production of cholesterol and ceramide. Topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus are used to treat AD. Cyclosporine A (CyA) is used as an immunosuppressant to inhibit calcineurin phosphatase, resulting in a decrease in IL-2 levels and inhibition of T cell proliferation.

Systemic treatment includes humanized monoclonal antibodies such as Omalizumab, Efalizumab and Etanercept, Dupilumab, which target serum IgE, LFA-1, TNF-α and IL-4, respectively [Rahman, Inf. & All. 2011, 10, 486]. Additional eczema, skin, and disease conditions include hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, dermatomyositis, lichen planus , lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug 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 patchy psoriasis, pustular psoriasis, nail psoriasis, wrinkle psoriasis, guttate psoriasis, psoriasis arthritis, erythrodermic psoriasis, and inverse psoriasis. Spotted psoriasis (psoriasis vulgaris) is the most common form of psoriasis and usually presents as patches of raised red skin covered with scaly white growths. Pustular psoriasis appears as bumps filled with non-infectious pus (pustules). The skin under and around the pustules is red and sore. Pustular psoriasis can be localized, usually on the hands and feet, or generalized with extensive patches on any part of the body. Nail psoriasis causes many changes in the appearance of finger and toe nails. These changes include discoloration under the nail plate, ulceration of the nails, lines on the nails, thickening of the skin under the nail, and weakening (onycholysis) and crumbling of the nail. Fold psoriasis (inverse psoriasis) appears as smooth, inflamed patches of skin. It occurs in the folds of the skin, especially around the genitals (between the thigh and groin), in the armpits, under the overweight abdomen (pannus) and under the breasts (in the folds under the mammary glands). It is aggravated by friction and sweat, and is also prone to fungal infections. Guttate psoriasis is characterized by numerous small oval patches. These patches of psoriasis appear on large areas of the body such as the torso, limbs, and scalp. Psoriatic arthritis involves inflammation of the joints and connective tissue. Psoriatic arthritis can affect any joint, but is most common in the joints of the fingers and toes. Psoriatic arthritis can lead to swelling of the fingers and toes, known as dactylitis. Psoriatic arthritis can also affect the hips, knees, and spine (spondylitis). Erythrodermic psoriasis involves widespread inflammation and scaling of the skin over much of the surface of the body. It may be accompanied by severe itching, swelling and pain. It is often the result of exacerbation of unstable patchy psoriasis, especially after the abrupt cessation of systemic treatment. Current treatments for psoriasis include topical treatments, phototherapy, and systemic applications. The treatment is either cosmetically undesirable, inconvenient for long-term use, or has limited efficacy.

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 recurrent and chronic inflammation and ulcers in the lining of the large intestine (colon). Crohn's disease (CD) is characterized by inflammation of the lining of the gastrointestinal tract and may invade related tissues. Patients with IBD may exhibit diarrhea, abdominal pain, fatigue, and weight loss, and these conditions can be severe and debilitating. Because symptoms vary with the level and duration of inflammation, an agent that modulates said inflammation may be useful in the treatment of IBD.

Phosphodiesterases (PDEs) are 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 levels of cyclic nucleotides in cells and maintain cyclic nucleotide homeostasis by hydrolyzing such cyclic mononucleotides, causing them to cease their messenger role. PDE enzymes can be grouped into families according to their specificity for hydrolysis of cAMP and/or cGMP, their sensitivity to regulation by calcium and calmodulin, and their selective inhibition by various compounds.

The PDE4 enzyme subfamily consists of four genes that produce 4 isoforms of the PDE4 enzyme, designated PDE4A, PDE4B, PDE4C and PDE4D [Wang et al., Biochem. Biophys. Res. Comm., 234, 320 (1997)]. In addition, different splicing variants of each PDE4 isoform have been identified. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5'-monophosphate (AMP). The regulation of cAMP activity plays an important role in many biological processes, including inflammation.

The compounds of the present invention inhibit phosphodiesterases, including PDE4, and modulate levels of inflammatory cytokines and are therefore useful in the treatment of inflammatory diseases such as atopic dermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, ulcerative colitis, Crohn's disease, inflammatory bowel disease, and inflammation resulting from surgical complications.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I) which inhibit PDE4 and are useful in the treatment or prevention of disorders ameliorated by PDE4 inhibition in humans,

X-Y-Z

Formula (I)

or their pharmaceutically acceptable salt, where

X is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, or triazine, each optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently deuterium, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) alkenyloxy, (C ₂ -C ₆ )alkenylthio, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, (C ₂ -C ₆ )alkynyl, (C ₂ -C ₆ )alkynyloxy, (C ₂ -C ₆ )alkynylthio, aryl, aryl(C ₁ -C ₆ )alkoxy, aryl(C ₁ -C ₆ )alkyl, aryl(C ₁ -C ₆ )alkylthio, aryloxy, arylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio, (C ₃ -C ₈ )cycloalkyloxy, (C ₃ -C ₈ )cycloalkylthio, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ - C ₆ )alkyl, halo(C ₁ -C ₆ )alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(C ₁ -C ₆ )alkoxy, (5-6 membered)heteroaryl( C ₁ -C ₆ )alkyl, (5-6-membered)heteroaryl(C ₁ - _{C 6} )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(C ₁ -C ₆ )alkoxy, (4-7-membered)heterocycle( C ₁ -C ₆ )alkyl, (4-7-membered) heterocycle (C ₁ -C ₆ )alkylthio, (4-7-membered) heterocycloxy, (4-7-membered) heterocyclthio, hydroxy, hydroxy(C ₁ - C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, thio(C ₁ -C ₆ )alkyl, -NR _A R _B , NR _A R _B (C ₁ -C ₆ )alkoxy, NR _A R _B (C ₁ -C ₆ )alkyl or (NR _A R _B )carbonyl; R _A and R _B are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, oxadiazole, thiadiazole or triazole, each optionally substituted with 1, 2 or 3 substituents which independently are deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ - C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio , carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, hydroxy, hydroxy (C ₁ -C ₆ ) alkoxy, hydroxy(C ₁ -C ₆ ) alkyl, mercapto, nitro, -NR _C R _D , NR _C R _D (C ₁ -C ₆ ) alkoxy, NR _C R _D (C ₁ - C ₆ )alkyl or (NR _C R _D )carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; Z is

,

,

,

,

where B is boron; R ₁₀ is independently at each occurrence H, deuterium, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio(C ₁ -C ₆ )alkyl; R ₁₁ is independently at each occurrence deuterium, (C ₁ -C ₃ )alkyl, or (C ₁ -C ₃ )alkyl -d _1-7 ; R ₁₂ is independently H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )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 present invention provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of 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 salt thereof.

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

In another aspect, the present invention provides the use of compounds of formula (I) in the manufacture of a medicament for the treatment of inflammatory diseases in mammals, in particular humans.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the X-ray structure (ORTEP image) of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3).

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

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

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

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

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

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

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

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

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

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

Figure 12 shows an X-ray powder diffraction analysis of crystalline 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, the present invention provides compounds of formula (I)

X-Y-Z

formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently deuterium, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkenyloxy, (C ₂ -C ₆ )alkenylthio, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, (C ₂ -C ₆ )alkynyl, (C ₂ -C ₆ )alkynyloxy, (C ₂ -C ₆ )alkynylthio, aryl, aryl( C ₁ -C ₆ )alkoxy, aryl(C ₁ -C ₆ )alkyl, aryl(C ₁ -C ₆ )alkylthio, aryloxy, arylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ ) alkyl, cyano, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio, (C ₃ -C ₈ )cycloalkyloxy, (C ₃ -C ₈ )cycloalkylthio, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(C ₁ -C ₆ )alkoxy, (5-6 membered)heteroaryl (C ₁ -C ₆ )alkyl, (5-6-membered)heteroaryl(C ₁ - _{C 6} )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 (C ₁ -C ₆ )alkoxy, (4-7-membered)heterocycle (C ₁ -C ₆ )alkyl, (4-7-membered) heterocycle (C ₁ -C ₆ )alkylthio, (4-7-membered) heterocycloxy, (4-7-membered) heterocyclthio, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, thio(C ₁ -C ₆ )alkyl, -NR _A R _B , NR _A R _B (C ₁ -C ₆ )alkoxy, NR _A R _B (C ₁ -C ₆ )alkyl or (NR _A R _B )carbonyl; R _A and R _B are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole, each optionally substituted with 1, 2, or 3 substituents that are independently deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto , nitro, -NR _C R _D , NR _C R _D (C ₁ -C ₆ ) alkoxy, NR _C R _D (C ₁ -C ₆ ) alkyl or (NR _C R _D ) carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; Z is as defined in the Summary of the Invention section of this document; R ₁₀ in each case is H, deuterium, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl -d _1-13 or hydroxy(C ₁ -C ₆ )alkyl; R ₁₁ is in each case deuterium, methyl or methyl- d ₃ ; R ₁₂ is independently H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )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.

или

, где B является бором;In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

or

where B is boron;

R ₁₀ in each case is H, methyl or hydroxymethyl; m is 1; and p is equal to 1.

, где B является бором.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (3-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

, where B is boron.

, где B является бором.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

, where B is boron.

, где B является бором.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

, where B is boron.

или

, где B является бором;In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

or

where B is boron;

R ₁₀ in each case is H, methyl or hydroxymethyl; p is equal to 1; and r is 1.

или

, где B является бором; R₁₀ в каждом случае является H, метилом или гидроксиметилом; R₁₂ в каждом случае независимо является H, (C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

or

where B is boron; R ₁₀ in each case is H, methyl or hydroxymethyl; R ₁₂ is independently at each occurrence H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl.

, где B является бором; R₁₂ в каждом случае независимо является H, (C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₂ is independently at each occurrence H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl.

, где B является бором; R₁₂ в каждом случае независимо является H, (C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₂ is independently at each occurrence H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl.

, где B является бором; и R₁₂ в каждом случае независимо является H, (C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; and R ₁₂ is independently at each occurrence H, (C ₁ -C ₆ )alkyl, or hydroxy(C ₁ -C ₆ )alkyl.

, где B является бором; R₁₀ в каждом случае является H, метилом или гидроксиметилом; R₁₁ в каждом случае независимо является (C₁-C₃)алкилом; и n равно 0, 1, 2, 3 или 4.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₀ in each case is H, methyl or hydroxymethyl; R ₁₁ is independently at each occurrence (C ₁ -C ₃ )alkyl; and n is 0, 1, 2, 3, or 4.

, где B является бором; R₁₁ является метилом; и n равно 0 или 1.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ is methyl; and n is 0 or 1.

, где B является бором; R₁₁ является метилом; и n равно 0 или 1.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ is methyl; and n is 0 or 1.

, где B является бором; R₁₁ является метилом; и n равно 0 или 1.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ is methyl; and n is 0 or 1.

или

, где B является бором; R₁₀ в каждом случае является H, метилом или гидроксиметилом; R₁₁ в каждом случае независимо является (C₁-C₃)алкилом; и q равно 0, 1, 2, 3, 4, 5 или 6.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, where each is optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

or

where B is boron; R ₁₀ in each case is H, methyl or hydroxymethyl; R ₁₁ is independently at each occurrence (C ₁ -C ₃ )alkyl; and q is 0, 1, 2, 3, 4, 5, or 6.

, где B является бором; R₁₁ в каждом случае является метилом; и q равно 0, 1, 2 или 3.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ in each case is methyl; and q is 0, 1, 2, or 3.

, где B является бором; R₁₁ в каждом случае является метилом; и q равно 0, 1, 2 или 3.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ in each case is methyl; and q is 0, 1, 2, or 3.

, где B является бором; R₁₁ в каждом случае является метилом; и q равно 0, 1, 2 или 3.In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridine, or pyrimidine, each optionally substituted with 1, 2, or 3 substituents that are independently (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, cyano, (C ₃ -C ₈ )cycloalkyloxy, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, (4-7-membered)heterocycloxy or hydroxy(C ₁ -C ₆ )alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, pyrazole or thiadiazole, each optionally substituted with 1 substituent which is (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

where B is boron; R ₁₁ in each case is methyl; and q is 0, 1, 2, or 3.

In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

; A₁ и A₂ независимо являются O или S; R₁, R₂ и R₅ независимо являются H, дейтерием, циано, галогеном или гало(C₁-C₆)алкилом; R₃ и R₄ независимо являются H, (C₁-C₆)алкилом, (C₁-C₆)алкил-d _1-13, (C₃-C₈)циклоалкилом, гало(C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом; Y является

; A ₁ and A ₂ are independently O or S; R ₁ , R ₂ and R ₅ are independently H, deuterium, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

;

;

R ₆ , R ₇ , R ₈ and R ₉ are independently H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 ,(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ - C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, -NR _C R _D , NR _C R _D (C ₁ - C ₆ alkoxy, NR _C R _D (C ₁ -C ₆ ) alkyl or (NR _C R _D ) carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; Z is as defined in the Summary of the Invention section of this document; R ₁₀ is independently at each occurrence H, deuterium, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio(C ₁ -C ₆ )alkyl; R ₁₁ is independently at each occurrence (C ₁ -C ₃ )alkyl or (C ₁ -C ₃ )alkyl- d _1-7 ; R ₁₂ is independently H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )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.

,

или

; R₁, R₂ и R₅ независимо являются H, циано, галогеном или гало(C₁-C₆)алкилом; R₃ и R₄ независимо являются (C₁-C₆)алкилом, (C₃-C₈)циклоалкилом, гало(C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом; Y являетсяIn another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

,

or

; R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

R ₆ , R ₇ , R ₈ and R ₉ are independently H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl( C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy( C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is as defined in the Summary of the Invention section of this document; R ₁₀ is independently at each occurrence H, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ ) alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio(C ₁ -C ₆ )alkyl; R ₁₁ is independently at each occurrence (C ₁ -C ₃ )alkyl; R ₁₂ is independently H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )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 present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

;

;

R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

или

, где B является бором; R₁₀ в каждом случае независимо является H, (C₁-C₆)алкилом или гидрокси(C₁-C₆)алкилом; m равно 0, 1, 2 или 3; и р равно 0, 1, 2, 3, 4 или 5.R ₆ , R ₇ , R ₈ and R ₉ are independently H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl( C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy( C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; Z is

or

where B is boron; R ₁₀ is independently at each occurrence H, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; m is 0, 1, 2, or 3; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

;

;

R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

, где B является бором.R ₆ , R ₇ , R ₈ and R ₉ are independently H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl( C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy( C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; and Z is

, where B is boron.

In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

;

;

R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

, где B является бором.R ₆ , R ₇ , R ₈ and R ₉ are independently H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl( C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy( C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; and Z is

, where B is boron.

In another embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is

;

;

R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; Y is

, где B является бором.R ₆ , R ₇ , R ₈ and R ₉ are independently H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl( C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy( C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; and Z is

, where B is boron.

In another embodiment, the present invention provides compounds of formula (IA)

formula (IA)

or their pharmaceutically acceptable salt, where B is boron; A ₁ and A ₂ are independently O or S; R ₁ , R ₂ and R ₅ are independently H, deuterium, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkenyloxy, (C ₂ -C ₆ )alkenylthio, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, (C ₂ -C ₆ ) alkynyl, (C ₂ -C ₆ ) alkynyloxy, (C ₂ -C ₆ ) alkynylthio, aryl, aryl (C ₁ -C ₆ ) alkoxy, aryl (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ )alkylthio, aryloxy, arylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio, (C ₃ -C ₈ ) cycloalkyloxy, (C ₃ -C ₈ ) cycloalkylthio, halogen, halo (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkylthio, (5-6- membered)heteroaryl, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkoxy, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkyl, (5-6-membered)heteroaryl(C ₁ - C ₆ )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 (C ₁ -C ₆ )alkoxy, (4-7-membered)heterocycle (C ₁ -C ₆ )alkyl, (4-7-membered)heterocycle (C ₁ - C ₆ )alkylthio, (4-7-membered) heterocycloxy, (4-7-membered) heterocyclthio, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, thio (C ₁ -C ₆ )alkyl, -NR _A R _B , NR _A R _B (C ₁ -C ₆ )alkoxy, NR _A R _B (C ₁ -C ₆ )alkyl or (NR _{A R B} )carbonyl; R _A and R _B are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₃ and R ₄ are independently H, deuterium, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkyl- d _1-13 , (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ - C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo( C ₁ -C ₆ )alkyl, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, -NR _C R _D , NR _C R _D (C ₁ -C ₆ )alkoxy, NR _C R _D (C ₁ -C ₆ ) alkyl or (NR _C R _D ) carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₁₀ at each occurrence is independently deuterium, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , ( C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio (C ₁ -C ₆ )alkyl; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy or hydroxy(C ₁ -C ₆ )alkyl; R ₁₀ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; and p is 0 or 1.

In another embodiment, the present invention provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; R ₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are H; and p is 0.

In another embodiment, the present invention provides compounds of formula (IB)

formula (IB)

or their pharmaceutically acceptable salt, where B is boron; A ₁ and A ₂ are independently O or S; R ₁ , R ₂ and R ₅ are independently H, deuterium, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkenyloxy, (C ₂ -C ₆ )alkenylthio, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, (C ₂ -C ₆ ) alkynyl, (C ₂ -C ₆ ) alkynyloxy, (C ₂ -C ₆ ) alkynylthio, aryl, aryl (C ₁ -C ₆ ) alkoxy, aryl (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ )alkylthio, aryloxy, arylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio, (C ₃ -C ₈ ) cycloalkyloxy, (C ₃ -C ₈ ) cycloalkylthio, halogen, halo (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkylthio, (5-6- membered)heteroaryl, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkoxy, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkyl, (5-6-membered)heteroaryl(C ₁ - C ₆ )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 (C ₁ -C ₆ )alkoxy, (4-7-membered) heterocycle (C ₁ -C ₆ )alkyl, (4-7-membered) heterocycle (C ₁ - C ₆ )alkylthio, (4-7-membered) heterocycloxy, (4-7-membered) heterocyclthio, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, thio (C ₁ -C ₆ )alkyl, -NR _A R _B , NR _A R _B (C ₁ -C ₆ )alkoxy, NR _A R _B (C ₁ -C ₆ )alkyl or (NR _A R _B )carbonyl; R _A and R _B are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₃ and R ₄ are independently H, deuterium, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkyl- d _1-13 , (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ - C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ ) alkyl, mercapto, nitro, -NR _C R _D , NR _C R _D (C ₁ -C ₆ ) alkoxy, NR _C R _D (C ₁ -C ₆ ) alkyl or (NR _C R _D ) carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₁₀ at each occurrence is independently deuterium, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , ( C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio (C ₁ -C ₆ )alkyl; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy, or hydroxy(C ₁ -C ₆ )alkyl; R ₁₀ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; and p is 0 or 1.

In another embodiment, the present invention provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; R ₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are H; and p is 0.

In another embodiment, the present invention provides compounds of formula (IC)

formula (IC)

or their pharmaceutically acceptable salt, where B is boron; A ₁ and A ₂ are independently O or S; R ₁ , R ₂ and R ₅ are independently H, deuterium, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkenyloxy, (C ₂ -C ₆ )alkenylthio, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, (C ₂ -C ₆ ) alkynyl, (C ₂ -C ₆ ) alkynyloxy, (C ₂ -C ₆ ) alkynylthio, aryl, aryl (C ₁ -C ₆ ) alkoxy, aryl (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ )alkylthio, aryloxy, arylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, (C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio, (C ₃ -C ₈ ) cycloalkyloxy, (C ₃ -C ₈ ) cycloalkylthio, halogen, halo (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkylthio, (5-6- membered)heteroaryl, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkoxy, (5-6-membered)heteroaryl(C ₁ -C ₆ )alkyl, (5-6-membered)heteroaryl(C ₁ - C ₆ )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 (C ₁ -C ₆ )alkoxy, (4-7-membered) heterocycle (C ₁ -C ₆ )alkyl, (4-7-membered) heterocycle (C ₁ - C ₆ )alkylthio, (4-7-membered) heterocycloxy, (4-7-membered) heterocyclthio, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, thio (C ₁ -C ₆ )alkyl, -NR _A R _B , NR _A R _B (C ₁ -C ₆ )alkoxy, NR _A R _B (C ₁ -C ₆ )alkyl or (NR _{A R B} )carbonyl; R _A and R _B are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₃ and R ₄ are independently H, deuterium, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkyl- d _1-13 , (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy- d _1-13 , (C ₁ -C ₆ )alkoxy(C ₁ - C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylthio, carboxy, carboxy(C ₁ -C ₆ )alkoxy, carboxy(C ₁ -C ₆ )alkyl, cyano, halogen, halo(C ₁ -C ₆ )alkoxy, halo( C ₁ -C ₆ )alkyl, hydroxy, hydroxy(C ₁ -C ₆ )alkoxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, -NR _C R _D , NR _C R _D (C ₁ -C ₆ )alkoxy, NR _C R _D (C ₁ -C ₆ ) alkyl or (NR _C R _D ) carbonyl; _RC and _RD are independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl; R ₁₀ at each occurrence is independently deuterium, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkyl- d _1-7 , ( C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl- d _1-13 , (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or thio (C ₁ -C ₆ )alkyl; and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds of formula (IC) or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkoxy, or hydroxy(C ₁ -C ₆ )alkyl; R ₁₀ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; and p is 0 or 1.

In another embodiment, the present invention provides compounds of formula (IC) or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; R ₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds of formula (IC) or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IC) or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C ₁ -C ₃ )alkyl; and p is 0.

In another embodiment, the present invention provides compounds of formula (IC) or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are O; R ₁ , R ₂ and R ₅ are H; R ₃ and R ₄ are independently (C ₁ -C ₃ )alkyl; R ₆ , R ₇ and R ₉ are H; and p is 0.

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

(R) 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-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-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-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-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-chloro-5-ethoxy-4-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)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol; (S) 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-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-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-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-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol; 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (R) 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)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'-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-3-propoxy-[1,1'-biphenyl]-2-carbonitrile; (R) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-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-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan- 1-ol; (2S)-2-(5-(4-methoxy-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-6 -propoxy-[2,3'-bipyridine]-5'-yl)-1,2-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)-1,2-oxaborolan-2-ol; (R) 4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-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-(4-methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-thiadiazol-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-oxaborolan-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-yl)-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]-3-yl)-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) 4-(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-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)-4-(6-((S)-1-hydroxyethyl)-2-(4-methoxy-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)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S)-4-(6-((R)-1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (R) 4 -(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile; (S) 6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile; (R) 4-(4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-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-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(3-(4-(cyclopentyloxy)-5-methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(4-(cyclopentyloxy)-5-methoxypyrimidin-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-3-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-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-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)-1,2-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-3-propoxyphenyl)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-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1'-biphenyl]-3-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) 3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile; 4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-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)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; 4-(3'-(cyclopentyloxy)-4'-methoxy-[1,1'-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)-4-methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) ethyl 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate; (S) ethyl 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate; (R) 2-(6-(2-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-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)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)-4-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)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-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-2-yl)-3-methoxybenzonitrile; (S) 2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-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-4-yl)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-5-propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; 4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R) 4-(3',4',5-trimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3',4',5-trimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-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-3-yl)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-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)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-[1,1'-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-2-ol; (R) 4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2,4-dimethoxy-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-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-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)-1,2-oxaborolan-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-(4,5-dimethoxypyridin-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]-2-carbonitrile; (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-4-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)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)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(4'-ethoxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-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-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 3-ethoxy-3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1'-biphenyl]-2-carbonitrile; (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-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-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-(4-methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-2-fluoro-4-methoxyphenyl)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)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(1-(4-methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-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)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-4,6-dimethylpyridin-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'-dimethoxy-5-methyl-[1,1'-biphenyl]-3-yl)-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-2-ol; (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-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-ethoxy-2-fluoro-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-2-fluoro-3-methoxyphenyl)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)-1,2-oxaborolan-2-ol; (S) 4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-methoxy-2-(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-(3,4-dimethoxyphenyl)pyridin-4-yl)-1,2-oxaborol-2(5H)-ol; 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-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-(5-methoxy-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-yl)-1,2-oxaborolan-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 salt thereof.

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

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

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease in a human, comprising topically administering to a 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 salt thereof, in the form of a transdermal patch, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans, comprising administering to a person 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 salt thereof.

In another embodiment, the present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising topical administration to a person in need of such treatment of a therapeutically effective amount of a compound of formula (I), formula (IA), formula (IB), or formula (IC) or a pharmaceutically acceptable salt thereof, in the form of a transdermal patch, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 salt thereof.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 salt thereof, in the form of a transdermal patch, ointment, lotion, cream or 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 a 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 salt thereof.

In another embodiment, the present invention provides the use of a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory disease in a human.

In another embodiment, the present invention provides the use of a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of atopic dermatitis, hand dermatitis, contact dermatitis , allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, rosacea, vitiligo epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma , cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, suppurative hydradenitis, psoriasis, patchy psoriasis, pustular psoriasis, nail psoriasis, fold psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans.

In another embodiment, the present invention provides the use of a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing or inflammation after surgical complications in humans.

In another embodiment, the present invention provides the use of a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammatory bowel disease, ulcerative colitis, or The human crown.

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

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

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

In another embodiment, the present invention provides crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 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 are two theta.

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

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

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

In another embodiment, the present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising administering to a person 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans, comprising topical administration to a person in need of such treatment of 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, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising topical administration to a human in need of such treatment of 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, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method of treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn's disease in a human, comprising administering to a 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 present invention provides the use of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory disease in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, suppurative hidradenitis, psoriasis, patchy psoriasis, pustular psoriasis, nail psoriasis, fold psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory bowel disease, ulcerative colitis, or Crohn's disease in humans.

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

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

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 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 theta.

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 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 are two theta.

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 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 theta.

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 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 theta.

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 3-10 diffraction peaks listed in Table 6.

In another embodiment, the present invention provides crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing the diffraction peaks listed in Table 6.

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

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

In another embodiment, the present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans, comprising administering to a person 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising topical administration to a person in need of such treatment of 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, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising topically administering to a person 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, ointment, lotion, cream or 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 a 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 present invention provides the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory disease in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, suppurative hidradenitis, psoriasis, patchy psoriasis, pustular psoriasis, nail psoriasis, fold psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory bowel disease, ulcerative colitis, or Crohn's disease in humans.

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

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

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

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

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

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

In another embodiment, the present invention provides crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern, containing 3-10 diffraction peaks listed in Table 7.

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

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

In another embodiment, the present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising administering to a person 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising topical administration to a person in need of such treatment of 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, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising topical administration to a human in need of such treatment of 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, ointment, lotion, cream or 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 a 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 present invention provides the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory disease in humans.

In another embodiment, the present invention provides the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, suppurative hidradenitis, psoriasis, patchy psoriasis, pustular psoriasis, nail psoriasis, fold psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans.

In another embodiment, the present invention provides the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in humans.

In another embodiment, the present invention provides the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a medicament for treatment of inflammatory bowel disease, ulcerative colitis, or Crohn's disease in humans.

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

In another embodiment, the present 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 containing diffraction peaks of 12.8 ± 0.2, 20.4 ± 0.2 and 25.7 ± 0.2 degrees two theta.

In another embodiment, the present 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 containing 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 theta.

In another embodiment, the present 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 containing 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 theta.

In another embodiment, the present 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 containing 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 theta.

In another embodiment, the present 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 containing 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 theta.

In another embodiment, the present 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 containing 3-10 diffraction peaks listed in Table 8.

In another embodiment, the present 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 containing the diffraction peaks listed in Table 8.

In another embodiment, the present invention provides crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, having a powder x-ray diffraction pattern shown in figure 8.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (-) 4-(5-(2-(difluoromethyl)-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 of treating or preventing an inflammatory disease in a human, comprising administering to a 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising administering to a person 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans, comprising topical administration to a person in need of such treatment of 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, ointment, lotion, cream or gel.

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

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

In another embodiment, the present invention provides a method of treating or preventing inflammatory bowel disease, ulcerative colitis, or Crohn's disease in a human, comprising administering to a 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 present 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 medicament for the treatment of an inflammatory disease in humans.

In another embodiment, the present 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 medicinal product for the treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis , lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, nevus /Sutton's nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, fold psoriasis, guttate psoriasis psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans.

In another embodiment, the present 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 medicament for the treatment of arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing or inflammation following surgical complications in humans.

In another embodiment, the present 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 medicament for the treatment of inflammatory bowel disease, ulcerative colitis or Crohn's disease in humans.

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

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffraction pattern containing diffraction peaks 21.1 ± 0.2, 22.7 ± 0.2 and 23.8 ± 0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffraction pattern containing 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 are two theta.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffraction pattern containing 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 are two theta.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffraction pattern containing 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 theta.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray a diffraction pattern containing 3-10 diffraction peaks listed in Table 9.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffraction pattern containing the diffraction peaks listed in Table 9.

In another embodiment, the present invention provides crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol having a powder x-ray diffractogram shown in figure 9.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-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 of treating or preventing an inflammatory disease in a human, comprising administering to a 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis or inverse psoriasis in humans, comprising administering to a person 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 present invention provides a method of treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, syndrome Vogt-Koyanagi-Harada, Sutton's nevus/nevi, postinflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, patchy psoriasis, pustular psoriasis, psoriasis of the nails, psoriasis of the folds, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans comprising topical administration to a person in need of such treatment of 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, ointment, lotion, cream or gel.

In another embodiment, the present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising administering to a 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 present invention provides a method for treating or preventing arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing, or inflammation following surgical complications in a human, comprising topical administration to a human in need of such treatment of 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, ointment, lotion, cream or 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 a 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 present invention provides the use of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug agents for the treatment of inflammatory disease in humans.

In another embodiment, the present invention provides the use of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug agents for the treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalary dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis red flat lichen, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada syndrome, Sutton's nevus/nevi , post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis purulent, psoriasis, patchy psoriasis, pustular psoriasis, nail psoriasis, wrinkle psoriasis, psoriasis guttate arthritis, erythrodermic psoriasis or inverse psoriasis in humans.

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

In another embodiment, the present invention provides the use of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug agents for the treatment of inflammatory bowel disease, ulcerative colitis or Crohn's disease in humans.

In another embodiment, the present invention provides topical pharmaceutical combinations comprising a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, in combination with another pharmaceutical agent for the treatment of diseases. , conditions and/or disorders described herein. Suitable pharmaceutical agents that can be used in combination with the topical compounds of the present invention include, but are not limited to: a second compound of formula (I), formula (IA), formula (IB), or formula (IC); an inhibitor of the PDE4 isoenzyme, including, but not limited to, crisaborole, ampremilast, roflumilast, rolipram, and piclamilast; a corticosteroid including, but not limited to, fluocinonide, deoxymethasone, mometasone, triamcinolone, betamethasone, alklomethasone, desonide, hydrocortisone, and mapracorate; a calcineurin inhibitor, including but not limited to tacrolimus, pimecrolimus, and cyclosporine; JAK inhibitor including but not limited to tofacitinib, ATI-502, SNA-152, SHR-0302, JTE052, BMS-986165, filgotinib, baricitinib, upadacitinib, ruxolitinib, pecitinib, PF-04965842, 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; non-steroidal anti-inflammatory drugs, including but not limited to WBI-1001 and MRX-6; a vitamin D analog such as calcipotriene; retinoic acid derivatives, including but not limited to alitretinoin; a selective liver X receptor (LXR) agonist, including but not limited to VTP-38543; H4 receptor antagonists, including but not limited to ZPL-389; NKI receptor antagonists including, but not limited to, Aprepitant and Tradipitant; CRTH2 receptor antagonists including, but not limited to, fevipiprant and OC-459; chymase inhibitors, including but not limited to SUN 13834; GATA-3 inhibitors including but not limited to SB-011 and GR-MD-02; and ROR inverse agonists including but not limited to VTP-43742, ARN6039, TAK-828 and JTE-451; immunomodulators such as PF-06763809 and SYK, BTK and ITK inhibitors including but not limited to R-348, cerdulatinib, ibrutinib, entospletinib, tirabrutinib and JTE-051.

In another embodiment, the present invention provides oral pharmaceutical combinations comprising a compound of formula (I), formula (IA), formula (IB) or formula (IC) or a pharmaceutically acceptable salt thereof in combination with another pharmaceutical agent for the treatment of diseases. , conditions and/or disorders described herein. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention for oral administration include, but are not limited to: oral derivatives of retinoic acid, including, but not limited to, alitretinoin; oral selective liver X receptor (LXR) 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 OC-459; 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, upadacinib, ASNAT-002 , ATI-501, ATI-502, AZD1480, AZD4205, BMS-911543, BMS-986165, INCB-52793, INCB-54707, PF- 04965842 -0302, SNA-125 or TD-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, PRN-1008, BMS-935177, PRN-473, ABBV-105, AS-550, M-7583, WXFL-10230486, LOU-064, AEG-42766, 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 present invention provides pharmaceutical combinations for administration by injection comprising a compound of formula (I), formula (IA), formula (IB) or formula (IC) or a pharmaceutically acceptable salt thereof in combination with another pharmaceutical agent for the treatment of diseases. , conditions and/or disorders described herein. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention for administration by injection include, but are not limited to: TNFα 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 drugs such as dupilumab, lebrikizumab, nemolizumab, tralokinumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omazumilab and CIM-331.

Combination therapy involves the administration of two or more therapeutic agents simultaneously or sequentially. Agents can be entered in any order. Alternatively, multiple therapeutic agents can be combined into a single composition that can be administered to a patient. For example, one pharmaceutical composition may contain a compound or a pharmaceutically acceptable salt, ester or prodrug thereof according to formulas (I), (IA), (IB) and (IC), another therapeutic agent or a pharmaceutically acceptable salt, ester or its a prodrug; and at least one pharmaceutically acceptable excipient or carrier.

When used in the above or other treatment options, a therapeutically effective amount of one of the compounds of the present invention can be used in pure form or, if such forms exist, in the form of a pharmaceutically acceptable salt, ester, amide, or prodrug. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. The phrase "therapeutically effective amount" of a compound of the present invention means a sufficient amount of the compound to treat the diseases, conditions or disorders set forth herein, at a reasonable benefit/risk ratio applicable to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disease being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known in medicine.

Pharmaceutical compositions or formulations

In another embodiment, the present invention provides pharmaceutical compositions or formulations containing a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions or compositions of the present invention may be administered to humans and other mammals topically, orally, parenterally, intracisternally, intravaginally, intraperitoneally, buccally, as an oral spray, as a nasal spray, rectally as a suppository, or as liposomes.

A typical pharmaceutical composition or formulation is prepared by mixing a compound of the present 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 hydrophobic materials, gelatin, oils, solvents, water, and the like. The specific carrier, diluent or excipient used will depend on the means and purpose for which the compound of the present invention is being used. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg PEG400, PEG300), etc. and their mixtures. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, coating agents, glidants, processing aids, colors, sweeteners, flavors, flavorings, and other known additives. to provide an elegant appearance to a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., to be used in the preparation of a drug).

The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., a compound of the present invention or a stabilized form of the compound (e.g., complexed with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The rate of dissolution of poorly water-soluble compounds can be increased by using spray-dried dispersions such as those described in Takeuchi, H., et al. in “Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants” J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786 B1 (US2002/009494), incorporated herein by reference. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controlled dosage of the drug and to provide the patient with an elegant and easily processed product.

The pharmaceutical composition or composition for use may be packaged in various ways depending on the method used to administer the drug. Typically, the product for distribution includes a container that contains the pharmaceutical composition in the appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-resistant assembly to prevent unauthorized access to the contents of the package. In addition, the container has a label that describes the contents of the container. The label may also include appropriate warnings.

The term "pharmaceutically acceptable carrier" refers to a carrier medium that provides for the appropriate delivery of an effective amount of the active agent as defined herein, does not interfere with the efficacy of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Typical carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickeners, penetration enhancers and the like. Additional information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference. Other examples of materials that 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 carboxymethylcellulose, ethylcellulose 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 as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants may also be present in the composition, in the opinion compiler.

The term "pharmaceutically acceptable carrier for topical use" refers to pharmaceutically acceptable carriers, as described herein above, suitable for topical use. An inactive liquid or cream carrier capable of suspending or dissolving the active agent(s) and having non-toxic and non-inflammatory properties when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically acceptable topical carrier. The term is specifically intended to cover carrier materials approved for use in topical cosmetics.

The term "topical administration" refers to the application of a pharmaceutical agent to the outer surface of the skin, nail, hair, claw or hoof such that the agent passes through the outer surface of the skin, nail, hair, claw or hoof and into the underlying tissues. Topical administration includes applying 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 may result in limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, may result in systemic distribution of the agent.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Volatile compounds may require mixing with special formulation agents or special packaging materials to ensure correct dosage. In addition, compounds of the present invention that have poor human skin permeability may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may require a formulation with absorption delaying agents or barriers.

Ointments, pastes, creams, lotions, gels, powders and topical solutions may contain, in addition to the active compound of the present invention, pharmaceutically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, colorants, excipients, non-irritating agents, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surface active agents, emollients, colorants, preservatives, buffering agents, penetration enhancers or mixtures thereof. Excipients for topical application should not affect the effectiveness of the biological activity of the active agent and not be harmful to epithelial cells or their function.

The terms "permeation enhancer" or "penetration enhancer" refers to increasing the permeability of the skin, nails, hair, claws, or hooves for a drug to increase the rate at which the drug penetrates the skin, nail, hair, claw, or hoof. The permeability enhancement achieved by using such enhancers can be observed, for example, by measuring the diffusion rate of the drug through the skin, nail, hair, claw or hoof of an animal or human using a diffusion cell apparatus. The diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The term "permeation enhancer" or "penetration enhancer" means an agent or mixture of agents which, alone or in combination, acts to increase the permeability of skin, nails, hair or hooves to a drug.

The term "transdermal delivery" refers to the diffusion of an agent through the barrier of the skin, nail, hair, claw or hoof as a result of topical administration or other application of the 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 solutes, and therefore absorption of drugs occurs more easily through the skin, nail, hair, claw, or hoof, which is abraded or otherwise stripped of the stratum corneum to expose the epidermis. Transdermal delivery includes injection or other delivery through any part of the skin, nail, hair, claw or hoof or mucous membrane and absorption or penetration through the remainder. Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable carrier prior to application to the skin, nail, hair, claw or hoof. Passive topical administration may consist of applying the active agent directly to the area to be treated, in combination with emollients or penetration enhancers. As used herein, transdermal delivery includes delivery by penetration through or through integument, ie skin, nail, hair, claw or hoof.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) excipients or diluents such as starches, lactose, sucrose, glucose, mannitol and salicylic acid. acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution 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 stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

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

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 art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition from which they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract in a delayed manner. Examples of potting compositions that can be used include polymeric materials and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to active compounds, 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 (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof .

In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors and flavors.

The term "parenteral" as used herein refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. Pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating such as lecithin, while maintaining the required particle size in the case of dispersions, and when using surfactants.

Depot injectable forms are prepared by forming microencapsulated drug matrices in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectables are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues.

Formulations for injection may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

Injectable preparations, for example sterile injectable aqueous or oily suspensions, may be formulated using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

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

The compounds of the present invention can also be administered in the form of liposomes. Liposomes are usually derived from phospholipids or other fatty substances and are formed by mono- or multilayer hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable fat capable of forming liposomes can be used. The present compositions in the form of liposomes may contain, in addition to the compounds of the present invention, stabilizers, preservatives and the like. Preferred fats are natural and synthetic phospholipids and phosphatidylcholines (lecithins), used alone or together. Methods for the formation of liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), pp. 33ff.

Pharmaceutical compositions or formulations of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the use of absorption delaying agents such as aluminum monostearate and gelatin.

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

Pharmaceutical compositions also include solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound represented by formulas (I), (IA), (IB) and (IC), including its pharmaceutically acceptable salts, with one or more solvent molecules. Such solvent molecules, which are commonly used in pharmaceuticals, are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol and the like. "Hydrate" refers to a complex in which the solvent molecule is water. The solvates and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates. Intermediate solvents include, but are not limited to, methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, 1,4-butyndiol, and the like.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may vary to obtain an amount of active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and route of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start dosing the compound at levels lower than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

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

Definitions

In the context of this description and the appended claims, the following terms have the following meanings:

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

The term "(C ₂ -C ₆ )alkenyloxy" as used herein means a (C ₂ -C ₆ )alkenyl group as defined herein attached to the main molecular group via an oxygen atom.

The term "(C ₂ -C ₆ )alkenylthio" as used herein means a (C ₂ -C ₆ )alkenyl group as defined herein attached to the main molecular group via a sulfur atom.

The term "(C ₁ -C ₆ )alkoxy" as used herein means a (C ₁ -C ₆ )alkyl group, as defined herein, attached to the main molecular group via an oxygen atom. Typical examples of (C ₁ -C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "(C ₁ -C ₆ )alkoxy- d _1-13 " as used herein means a (C ₁ -C ₆ )alkyl- d _1-13 group, as defined herein, attached to the main molecular group via an oxygen atom. Representative examples of (C ₁ -C ₆ )alkoxy d _1-13 include, but are not limited to, methoxy d ₃ , ethoxy d ₅ , propoxy d ₇ , 2-propoxy d ₇ , butoxy d ₉ , tert -butoxy- d ₉ , pentyloxy- d ₁₁ and hexyloxy- d ₁₃ .

The term "(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy" as used herein means a (C ₁ -C ₆ )alkoxy group as defined herein attached to the main molecular group through another (C ₁ - C ₆ )alkoxy group as defined herein. Typical examples of (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkoxy include, but are not limited to, t-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.

The term "(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl" as used herein means a (C ₁ -C ₆ )alkoxy group as defined herein attached to the main molecular group via a (C ₁ -C ₆ ) an alkyl group as defined herein. Typical examples of (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term "(C ₁ -C ₆ )alkoxycarbonyl" as used herein means a (C ₁ -C ₆ )alkoxy group as defined herein attached to the main molecular group via a carbonyl group as defined herein. Representative examples of (C ₁ -C ₆ )alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl.

The term "(C ₁ -C ₃ )alkyl" in this document means a straight or branched hydrocarbon containing from 1 to 3 carbon atoms. Typical examples of (C ₁ -C ₃ )alkyl include methyl, ethyl, n-propyl and isopropyl.

The term "(C ₁ -C ₃ )alkyl- d _1-7 " as used herein means a straight or branched hydrocarbon containing from 1 to 3 carbon atoms, where one to seven hydrogen atoms are replaced by deuterium ( ² H or D). Typical examples of (C ₁ -C ₃ )alkyl- d _1-7 include methyl- d ₃ , ethyl- d ₅ , ethyl-2,2,2- d ₃ , propyl- d ₇ and 2-propyl- d ₇ .

The term "(C ₁ -C ₆ )alkyl" in this document means a straight or branched hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of (C ₁ -C ₆ )alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n -hexyl.

The term "(C ₁ -C ₆ )alkyl- d _1-13 " as used herein means a straight or branched hydrocarbon containing from 1 to 6 carbon atoms, where one to thirteen hydrogen atoms are replaced by deuterium ( ² H or D). Typical examples of (C ₁ -C ₆ )alkyl- d _1-13 include, but are not limited to, methyl- d ₃ , ethyl- d ₅ , ethyl-2,2,2- d ₃ , propyl- d ₇ , 2- propyl d ₇ , butyl d ₉ , tert-butyl d ₉ , pentyl d ₁₁ and hexyl d ₁₃ .

The term "(C ₁ -C ₆ )alkylcarbonyl" as used herein means a (C ₁ -C ₆ )alkyl group as defined herein attached to the main molecular group via a carbonyl group as defined herein. Typical examples of (C ₁ -C ₆ )alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term "(C ₁ -C ₆ )alkylthio" as used herein means a (C ₁ -C ₆ )alkyl group, as defined herein, attached to the main molecular group via a sulfur atom. Representative examples of (C ₁ -C ₆ )alkylthio include, but are not limited to, methylthio, ethylthio, t-butylthio, and hexylthio.

The term "(C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl" as used herein means a (C ₁ -C ₆ )alkylthio group as defined herein attached to the main molecular group via a (C ₁ -C ₆ ) an alkyl group as defined herein. Typical examples of (C ₁ -C ₆ )alkylthio(C ₁ -C ₆ )alkyl include, but are not limited to, methylthiomethyl and 2-(ethylthio)ethyl.

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

The term "(C ₂ -C ₆ )alkynyloxy" as used herein means a (C ₂ -C ₆ )alkynyl group as defined herein attached to the main molecular group via an oxygen atom.

The term "(C ₂ -C ₆ )alkynylthio" as used herein means a (C ₂ -C ₆ )alkynyl group as defined herein attached to the main molecular group via a sulfur atom.

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

The term "aryl(C ₁ -C ₆ )alkoxy" as used herein means an aryl group as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkoxy group as defined herein.

The term "aryl(C ₁ -C ₆ )alkyl" as used herein means an aryl group as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkyl group as defined herein. Representative examples of aryl(C ₁ -C ₆ )alkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term "aryl(C ₁ -C ₆ )alkylthio" as used herein means an aryl(C ₁ -C ₆ )alkyl group as defined herein attached to the main molecular group via a sulfur atom as defined herein. Typical examples of aryl(C ₁ -C ₆ )alkylthio include, but are not limited to, benzylthio, phenylethylthio, 3-phenylpropylthio, and 2-naphth-2-ylethylthio.

The term "aryloxy" in this document means an aryl group, as defined herein, attached to the main molecular group through an oxygen atom. Representative 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, attached to the main molecular group via a sulfur atom. Representative examples of arylthio include, but are not limited to, phenylthio and naphtalenylthio.

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(C ₁ -C ₆ )alkoxy" as used herein means a carboxy group as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkoxy group as defined herein.

The term "carboxy(C ₁ -C ₆ )alkyl" as used herein means a carboxy group as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkyl group as defined herein.

The term "cyano" in this document means -CN group.

The term "(C ₃ -C ₈ )cycloalkyl" as used herein means a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, examples of (C ₃ -C ₈ )cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "(C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy" as used herein means a (C ₃ -C ₈ )cycloalkyl group as defined herein attached to the main molecular group via a (C ₁ -C ₆ ) an alkoxy group as defined herein.

The term "(C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl" as used herein means a (C ₃ -C ₆ )cycloalkyl group as defined herein attached to the main molecular group via a (C ₁ -C ₆ ) an alkyl group as defined herein. Typical examples of (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term "(C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkylthio" as used herein means a (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl group as defined herein attached to a basic molecular group through the sulfur atom.

The term "(C ₃ -C ₈ )cycloalkyloxy" as used herein means a (C ₃ -C ₈ )cycloalkyl group as defined herein attached to the main molecular group via an oxygen atom as defined herein. Representative examples of (C ₃ -C ₈ )cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The term "(C ₃ -C ₈ )cycloalkylthio" as used herein means a (C ₃ -C ₈ )cycloalkyl group as defined herein attached to the main molecular group via a sulfur atom as defined herein. Typical examples of (C ₃ -C ₈ )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" in this document means -Cl, -Br, -I or -F.

The term "halo(C ₁ -C ₆ )alkoxy" as used herein means at least one halogen as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkoxy group as defined herein . Representative examples of halo(C ₁ -C ₆ )alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term "halo(C ₁ -C ₆ )alkyl" as used herein means at least one halogen, as defined herein, attached to the main molecular group via a (C ₁ -C ₆ )alkyl group, as defined herein. document. Typical examples of halo(C ₁ -C ₆ )alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term "halo(C ₁ -C ₆ )alkylthio" as used herein means a halo(C ₁ -C ₆ )alkyl group, as defined herein, attached to the main molecular group via a sulfur atom. Typical examples of halo(C ₁ -C ₆ )alkylthio include, but are not limited to, trifluoromethylthio.

The term "(5-6 membered) heteroaryl" as used herein means 5 or 6 membered monocyclic heteroaryl. A 5-membered ring consists of two double bonds and one, two, three or four nitrogen atoms and/or optionally one oxygen or sulfur atom. A 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 molecule through any carbon atom or any nitrogen atom contained in the heteroaryl. Representative 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(C ₁ -C ₆ )alkoxy" as used herein means (5-6 membered)heteroaryl as defined herein attached to the main molecular group via (C ₁ -C ₆ )alkoxy group as defined herein. Representative examples of heteroaryl(C ₁ -C ₆ )alkoxy include, but are not limited to, fur-3-ylmethoxy, 1H-imidazol-2-ylmethoxy, 1H-imidazol-4-ylmethoxy, 1-(pyridin-4-yl)ethoxy , pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, pyridin-4-ylmethoxy, (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(C ₁ -C ₆ )alkyl" as used herein means (5-6 membered)heteroaryl as defined herein attached to the main molecular group via (C ₁ -C ₆ )alkyl group as defined herein. Representative examples of heteroaryl(C ₁ -C ₆ )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-4-yl)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 ₁ -C ₆ )alkylthio" as used herein means a (5-6 membered)heteroaryl(C ₁ -C ₆ )alkyl group as defined herein attached to a basic molecular group through the sulfur atom. Representative examples of heteroaryl(C ₁ -C ₆ )alkylthio include, but are not limited to, fur-3-ylmethylthio, 1H-imidazol-2-ylmethylthio, 1H-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-4-yl) methylthio, (5-(cyano)pyridin-2-yl)methylthio, (2-(chloro)pyridin-4-yl)methylthio, pyrimidin-5-ylmethylthio, 2-(pyrimidin-2-yl)propylthio, thien-2 -ylmethylthio; and thien-3-ylmethylthio.

The term "(5-6 membered)heteroaryloxy" as used herein means (5-6 membered)heteroaryl, as defined herein, attached to the main molecular group via an oxygen atom. Representative examples of heteroaryloxy include, but are not limited to, fur-3-yloxy, 1H-imidazol-2-yloxy, 1H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4- yloxy, (6-(trifluoromethyl)pyridin-3-yl)oxy, (6-(cyano)pyridin-3-yl)oxy, (2-(cyano)pyridin-4-yl)oxy, (5-(cyano) pyridin-2-yl)oxy, (2-(chloro)pyridin-4-yl)oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy and thien-3-yloxy.

The term "(5-6 membered)heteroarylthio" as used herein means (5-6 membered)heteroaryl, as defined herein, attached to the main molecular group via a sulfur atom. Representative examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and quinolin-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. A 4-membered ring contains 1 heteroatom selected from the group consisting of O, N and S. A 5-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The heterocycle is linked to the parent molecular group through any carbon atom or any atom nitrogen contained in the heterocycle. Exemplary heterocycle examples include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithioylanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, изоксазолинил, изоксазолидинил, морфолинил, оксадиазолинил, оксадиазолидинил, оксазолинил, оксазолидинил, пиперазинил, пиперидинил, пиранил, пиразолинил, пиразолидинил, пирролинил, пирролидинил, тетрагидрофуранил, тетрагидротиенил, тиадиазолинил, тиадиазолидинил, тиазолинил, тиазолидинил, тиоморфолинил, 1,1-диоксидотиоморфолинил (тиоморфолин сульфон ), thiopyranil and trithianil.

The term "(4-7 membered)heterocycle (C ₁ -C ₆ )alkoxy" as used herein means a (4-7 membered)heterocycle as defined herein attached to the main molecular group via (C ₁ -C ₆ )alkoxy group as defined herein.

The term "(4-7 membered)heterocycle(C ₁ -C ₆ )alkyl" as used herein means a (4-7 membered)heterocycle as defined herein attached to the main molecular group via (C ₁ -C ₆ )alkyl group as defined herein.

The term "(4-7 membered)heterocycle(C ₁ -C ₆ )alkylthio" as used herein means a (4-7 membered)heterocycle(C ₁ -C ₆ )alkyl group as defined herein attached to a basic molecular group through the sulfur atom.

The term "(4-7 membered) heterocycloxy" as used herein means a (4-7 membered) heterocycle, as defined herein, attached to the main molecular group via an oxygen atom. Typical examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy and pyrimidin-2-yloxy.

The term "(4-7 membered) heterocyclethio" as used herein means a (4-7 membered) heterocycle as defined herein attached to the main molecular group via a sulfur atom. Typical examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and pyrimidin-2-ylthio.

The term "hydroxy" in this document means -OH group.

The term "hydroxy(C ₁ -C ₆ )alkoxy" as used herein means at least one hydroxy group as defined herein attached to the main molecular group via a (C ₁ -C ₆ )alkoxy group as defined herein. document. Representative examples of hydroxy(C ₁ -C ₆ )alkoxy include, but are not limited to, hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy, and 2-ethyl-4-hydroxyheptoxy.

The term "hydroxy(C ₁ -C ₆ )alkyl" as used herein means at least one hydroxy group, as defined herein, attached to the main molecular group via a (C ₁ -C ₆ )alkyl group, as defined herein. document. Representative examples of hydroxy(C ₁ -C ₆ )alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term "mercapto" in this document means -SH group.

The term "nitro" in this document means -NO ₂ group.

The term "thio(C ₁ -C ₆ )alkyl" as used herein means a sulfur atom attached to the main molecular group via a (C ₁ -C ₆ )alkyl group as defined herein. Typical examples of thio(C ₁ -C ₆ )alkyl include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl, and 4-thiobutyl.

The term "-NR _A R _B " in this document means two groups, R _A and R _B attached to the main molecular group through a nitrogen atom. R _A and R _B are each independently hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl. Representative examples of -NR _A R _B include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term "NR _A R _B (C ₁ -C ₆ )alkoxy" as used herein means an NR _A R _B group attached to the parent molecular group via a (C ₁ -C ₆ )alkoxy group.

The term "NR _A R _B (C ₁ -C ₆ )alkyl" as used herein means an NR _A R _B group attached to the parent molecular group via a (C ₁ -C ₆ )alkyl group.

The term "(NR _A R _B )carbonyl" as used herein means an NR _A R _B group as defined herein attached to the main molecular group via a carbonyl group as defined herein. Representative examples of (NR _A R _B )carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.

The term "-NR _C R _D " in this document means two groups, R _C and R _D , attached to the main molecular group through a nitrogen atom. R _C and R _D are each independently hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl. Representative examples of -NR _C R _D include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term "NR _C R _D (C ₁ -C ₆ )alkoxy" as used herein means an NR _C R _D group attached to the main molecular group via a (C ₁ -C ₆ )alkoxy group.

The term "NR _C R _D (C ₁ -C ₆ )alkyl" as used herein means an NR _C R _D group attached to the main molecular group via a (C ₁ -C ₆ ) alkyl group.

The term "(NR _C R _D )carbonyl" as used herein means an NR _C R _D group as defined herein attached to the main molecular group via a carbonyl group as defined herein.

The compounds of the present invention can form boron-oxygen coordinative bonds upon exposure to water, alcohols (ROH, r is alkyl), and diols (ROH, r is hydroxyalkyl) as shown in Scheme A.

Scheme A

If a boron atom is covalently bonded to an oxygen atom and coordinately bonded to a second oxygen atom, the coordinative bond and the covalent bond can interconvert or form a resonant hybrid represented by structures (1), (2), (3), and (4) in Scheme A. The compounds of the present invention, after exposure to water, alcohols and diols, can exist as neutral compounds represented by compounds (1) to (4) or as negatively charged compounds represented by compounds (5) and (6), where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention section herein. In addition to oxygen, boron can form coordinative bonds with sulfur and nitrogen. It should be understood that the present invention covers compounds of formula (I), formula (IA), formula (IB) and formula (IC) which form coordinative bonds with oxygen, sulfur and nitrogen, including, but not limited to, compounds (7) -(12). Suitable counterions include, but are not limited to, lithium, sodium, potassium, ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, calcium, magnesium, and aluminum.

The compounds of the present invention can form oxygen-bonded dimers upon exposure to water. Exemplary dimers of the present invention are shown in Scheme B where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention section herein .

Scheme B

It is to be understood that the present invention encompasses oxygen-bonded 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)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridine-3 -yl)propyl)diboronic acid.

The compounds of the present invention can also form acyclic and cyclic trimers when treated with water. Exemplary acyclic and cyclic trimers of the present invention are shown in Scheme C, where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention » in this document.

Scheme C

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

The present invention covers anhydrides of formula (I), formula (IA), formula (IB) and formula (IC) formed under dehydration conditions. Exemplary anhydrides of the present invention are shown in Scheme D, where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention section of this document.

Scheme D

It is to be understood that the present 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-oxaborolan-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine) and 5,5'-((4R,4'R)-oxybis(1,2-oxaborolan- 2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine).

The compounds of the present invention may form poly- or multivalent compounds assembled from a single compound or from more than one compound of the present invention. Polymer constructs can be "homopolymer" consisting of the same or related constructs, or "heteropolymer" consisting of many different constructs.

The present invention encompasses compounds that can be formulated with excipients such that one or more excipients react with a compound of the present invention to give mono-, poly-, or multivalent compounds, including, for example, compounds such as esters, dimers, trimers, tetramers and higher homologues. For example, compounds of formula (I), formula (IA), formula (IB), and formula (IC) can form boron esters with propylene glycol or hexylene glycol under appropriate conditions. Exemplary esters of the present invention are shown in Scheme E, where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention section of this document.

Scheme E

It should be understood that the present invention encompasses boron esters of formula (I), formula (IA), formula (IB) and formula (IC), including, but not limited to, 1-hydroxypropan-2-yl hydro-((R) -3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-1-hydroxypropan-2-yl hydro-((R)-3-hydroxy -2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-1-hydroxypropan-2-yl hydro-((R)-3-hydroxy-2-( 5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 2-hydroxypropyl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridine) -3-yl)propyl)boronate, (S)-2-hydroxypropyl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate , (R)-2-hydroxypropyl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-2-methylpentane -2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-2-methylpentane -2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-2-methylpentane -2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-4-methylpentan-2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-4-methylpentan-2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-4-methylpentan-2-yl hydro-((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 1-hydroxypropan-2-yl hydro-((S)-3 -hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-1-hydroxypropan-2-yl hydro-((S)-3-hydroxy-2 -(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-1-hydroxypropan-2-yl hydro-((S)-3-hydroxy-2-(5- (4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 2-hydroxypropyl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridine-3 -yl)propyl)boronate, (S)-2-hydroxypropyl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, ( R)-2-hydroxypropyl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-2-methylpentan-2 -yl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-2-methylpentan-2 -yl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (R)-4-hydroxy-2-methylpentan-2 -yl hydro-((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, 4-hydroxy-4-methylpentan-2-yl hydro- ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate, (S)-4-hydroxy-4-methylpentan-2-yl hydro- ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate and (R)-4-hydroxy-4-methylpentan-2-yl hydro- ((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate.

The present invention also encompasses cyclic esters formed by the reaction of formula (I), formula (IA), formula (IB) and formula (IC) with certain diols, which include, but are not limited to, propylene glycol and hexylene glycol. Representative cyclic ethers are shown in Scheme F, where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p are as defined in the Summary of the Invention section herein .

Scheme F

It should be understood that the present 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)propan-1-ol, (R)-2-(5 -(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol, (2R)- 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-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-3-yl)-3-((R)-4,4,6-trimethyl-1, 3,2-dioxaborinan-2-yl)propan-1-ol, (2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4-methyl-1, 3,2-dioxaborolan-2-yl)propan-1-ol, (S)-2-(5-(4-methoxy-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)propan-1-ol, (2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3 -(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol, (S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridine-3- yl)-3-((S)-4,4,6-trimethyl-1,3,2-dioxaborinan-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 shown in Schemes A-F are prodrugs that can be hydrolyzed to parent compounds under aqueous conditions, which include in vivo conditions that reform the oxaborol ring.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. By "pharmaceutically acceptable salt" is meant those salts which, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or the like, and which 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 in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66:1-19, herein incorporated by reference. Salts can be generated in situ during the final isolation and purification of the compound of the present invention, or separately by reacting the free base (basic nitrogen) with a suitable organic or inorganic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide , 2-hydroxyethanesulfonate (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 agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. In this way, products soluble or dispersible in water or oil are obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. .

The compounds of the present invention may exist as stereoisomers where asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon. The terms "R" and "S" as 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 formulas (I), (IA) and (IB), may independently be either (R) or (S), unless specifically indicated otherwise. Enantiomers of the present invention, designated (R), (S) or *, essentially do not contain the 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%. In the context of enantiomeric excess, the term "about" means ±1.0%. The symbol * denotes a chiral carbon atom in either (R) or (S) stereochemistry depending on the configuration of the substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of this invention. Stereoisomers include enantiomers and mixtures of enantiomers. The individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers, or by preparing racemic mixtures, followed by resolution, well known to those skilled in the art. These separation methods include, but are not limited to, (1) adding a chiral auxiliary to a mixture of enantiomers, separating the resulting mixture of diastereomers by recrystallization or chromatography and isolating an optically pure product from the auxiliary, or (2) directly separating the mixture of optical enantiomers on chiral chromatographic columns.

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

The compounds of the present invention may exist in a variety of stable conformational forms that can be separated. Torsion asymmetry due to limited rotation around an asymmetric single bond, such as due to steric hindrances or ring deformation, may allow separation of different conformers. The compounds of the present invention further include each conformational isomer of the compound of formula (I), (IA), (IB) and (IC) and mixtures thereof.

Tautomers may exist in the compounds of the present invention, and are specifically included within the scope of the present invention. The term "tautomer" in this document means the shift of a proton from one atom of a molecule to another atom of the same molecule, where two or more structurally different compounds are in equilibrium with each other. The compounds of the present invention may exist as tautomers. The present invention considers tautomers due to shifts of protons from one atom to another atom of the same molecule to form two or more different compounds in equilibrium with each other.

The compounds of the present invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts. In accordance with the present invention, compounds with several basic nitrogen atoms can form salts with different numbers of equivalents ("eq.") acid. Practitioners will appreciate that all such salts are within the scope of the present invention.

The compounds of the present invention may exist in more than one crystalline form. Polymorphs of the compounds of formula (I), (IA), (IB) and (IC) and their salts (including solvates and hydrates) form part of the present invention and can be obtained by crystallizing the compound of the present invention under various conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; various cooling modes, from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compounds of the present invention, followed by gradual or rapid cooling. The presence of polymorphs can be determined using solid-state nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, X-ray powder diffraction, or other similar methods.

This invention also includes isotopically labeled compounds which are identical to those described by formulas (I), (IA), (IB) and (IC), but due to the fact that one or more atoms are replaced by an atom having an atomic mass or mass a number other than the atomic mass or mass number normally found in nature. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, iodine and fluorine, such as ² H, ³ H ^{, 13 C, 14 C, 15 N , 18} O, ¹⁷ O, ³⁵ S, ³⁶ Cl, ¹²⁵ I, ¹²⁹ I, ¹⁸ F, and ¹⁹ F, respectively. Certain isotopically labeled compounds of the present invention, for example, in which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore , may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following the procedures outlined 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 present invention includes deuterated compounds of formula (I), (IA), (IB) and (IC). Any of the hydrogen atoms contained in the compounds of the present invention can be replaced by deuterium. Typical examples of deuterated compounds of the present invention include, but are not limited to, the compounds listed below, where D is deuterium.

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

The compounds of the present invention have been named Chemdraw Professional version 15.0 or 16.0, or have been given names that appear to be consistent with the Chemdraw nomenclature.

The present invention includes compounds of formulas (I), (IA), (IB) and (IC) obtained using synthetic processes or metabolic processes. The preparation of the compounds of the invention by metabolic processes includes processes occurring in the human or animal body (in vivo) or processes occurring in vitro.

The present invention also contemplates pharmaceutically active metabolites formed by in vivo biotransformation of compounds of formulas (I), (IA), (IB) and (IC). The term pharmaceutically active metabolite as used herein refers to a compound formed in vivo by biotransformation of compounds of formula (I), (IA), (IB) and (IC). A detailed discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, MacMillan Publishing Company, New York, NY, (1985)).

The compounds of the present invention can be synthesized by synthetic methods that include processes similar to those well known in the field of chemistry, especially in light of the description contained herein. Starting materials are usually available from commercial sources or can be easily 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 appendices (also available through the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide possible routes for the synthesis of the compounds of the present invention, as well as intermediates for obtaining the compounds of the present invention. A more detailed description of the individual reaction steps is provided in the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. While specific starting materials and reagents are depicted in the diagrams and discussed below, other starting materials and reagents may be substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds obtained by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

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

The reactions are carried out in a solvent suitable for the reagents and materials used and suitable for the transformations to be carried out. Those skilled in the art of organic synthesis will appreciate that the functionality present in the molecule must be consistent with the proposed transformations. Sometimes this will require a decision to change the order of the steps in the synthesis or choose one particular process scheme over another in order to obtain the desired compound of the present invention.

It will also be understood that another important factor in planning any synthetic route in this area is the judicious choice of the protecting group used to protect the reactive functional groups present in the compounds described in the present invention. The authoritative document describing the many alternatives for 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 hydrochloric acid, and the SES protecting group may be removed with a fluoride such as cesium fluoride or tetrabutylammonium fluoride. The protecting groups CBZ and Bn can be removed by catalytic hydrogenation. Additional suitable protecting groups for hydroxy substituents include, but are not limited to, t-butyldimethylsilyl (TBDMS), tetrahydropyranyl (THP), or isopropyl (i-Pr) protecting groups. The TBDMS and THP protecting groups can be removed by treatment with an acid such as acetic acid or hydrochloric acid, while the i-Pr protecting group can be removed with aluminum trichloride.

Isolation and purification of the compounds and intermediates described herein, if desired, can be carried out using any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative liquid chromatography low, medium or high pressure, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be found in the following examples throughout this document. However, other equivalent separation or separation procedures may also be used.

The compounds of the invention may be prepared by any method known in the art to obtain compounds of similar structure. In particular, the compounds of the present invention can be obtained using the procedures described with reference to the schemes that follow, or using specific methods described in the examples, or using methods similar to any of them.

The skilled artisan will appreciate that the experimental conditions set forth in the following Schemes illustrate suitable conditions for carrying out the transformations shown and that it may be necessary or desirable to modify the exact conditions used to prepare compounds of formula (I), (IA), (IB) and (IC ). It will also be appreciated that it may be necessary or desirable to perform transformations in a different order from that described in the Schemes, or to change one or more of the transformations in order to obtain the desired compound of the invention.

Derivatives of formulas (I), (IA), (IB) and (IC) can be obtained using the procedures described in the General methods below, or by their usual modifications. The present invention also includes one or more of these methods for obtaining derivatives of formulas (I), (IA), (IB) and (IC) in addition to any new intermediates used in this document. One skilled in the art will appreciate that the following reactions can be heated thermally or by exposure to microwave radiation.

The routes below, including those indicated in the Examples and Preparations, illustrate methods for the synthesis of compounds of formulas (I), (IA), (IB) and (IC). One skilled in the art will appreciate that the compounds of the invention and intermediates thereto may be prepared by methods other than those specifically described herein, for example, by adapting the methods described herein, for example, by methods known in this document. the field of technology. Suitable guidelines for 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); "Guidebook to 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, one skilled in the art will appreciate that at any stage in the synthesis of the compounds of the invention, it may be necessary or desirable to protect one or more sensitive groups to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect the alcohol, amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in the usual manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter GM Wuts, fifth edition, (John Wiley and Sons, 2014), incorporated herein by reference, which also describes how to remove such groups.

In the general synthesis methods below, unless otherwise indicated, substituents have the meanings given above with reference to compounds of formula (I) above. When ratios of solvents are given, they are by volume unless otherwise indicated.

The compounds of the invention may be prepared by any method known in the art to obtain compounds of similar structure. In particular, the compounds of the present invention can be obtained using the procedures described with reference to the schemes that follow, or using specific methods described in the examples, or using methods similar to any of them.

One skilled in the art will appreciate that the experimental conditions set forth in the following Schemes illustrate suitable conditions for carrying out the transformations shown, and that it may be necessary or desirable to change the exact conditions used to prepare the compounds of formula (I).

According to the first method, the compounds of formula (1D) (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ and p such as defined in the section "Summary of the invention" in herein and v=0, 1, 2, 3, 4, 5) can be obtained from a compound of formula (II) and (III) as shown in Scheme 1.

Scheme 1

In Scheme 1, compounds of formula (II) where R ₁₄ is an appropriate protecting group (preferably TBS) are converted to a compound of formula (III) where R ₁₅ is boronic acid (preferably) or 4,4,5,5-tetramethyl -1,3,2-dioxaborolane (Bpin) by treatment with a suitable hydroborating source such as catecholborane or bis(pinacolato)diboron in the presence of a suitable catalyst (bis(1,5-cyclooctadiene)di-µ-methoxydiiridium(I) or a dimer ( 1,5-cyclooctadiene)(methoxy)iridium(I)) and ligand (ethylenebis(diphenylphosphine), in a suitable solvent such as DCE or THF at a suitable temperature (15°C - 70°C). also knows that alternative methods of alkene hydroboration are achievable using alternative reagents, solvents and temperatures A compound of formula (III) is converted to a compound of formula (1D) under aqueous acidic conditions by treatment with a suitable acid (acetic or hydrochloric) at a suitable temperature. It is well understood in the art that the compound of formula (III) is prepared and isolated as described above, or prepared in situ without isolation in a sequential reaction strategy to give compound (1D). In the case where compounds of formula (III) and (1D) result in the presence of a chiral center, it is well understood by one skilled in the art that the individual enantiomers can be obtained using a suitable separation method such as HPLC or SLC chromatography to obtain both (+) and (-) enantiomer of the compound of formula (III) and (1D). It is well understood by one skilled in the art that the individual enantiomer of a compound of formula (III) and (1D) is prepared and isolated as described above, or isolated using an alternative separation technique such as HPLC or SLC using an appropriate chiral stationary phase eluted with a suitable mobile phase that is determined to be necessary to isolate the desired enantiomers.

According to the second method, compounds of formula (1E) or (1F) can be obtained from formula (II) as shown in scheme 2.

Scheme 2

In Scheme 2, compounds of formula (1E) or (1F) can be prepared according to the procedure depicted in Scheme 1 using suitable chiral ligands such as (S, S)-[2-(4'-n-propyloxazoline-2 -yl)ferrocinyl]diphenylphosphine or (R,R)-[2-(4'-i-propyloxazolin-2-yl)ferrocinyl]diphenylphosphine to give a chiral compound of formula (IV). One skilled in the art will recognize that alternative chiral ligands, catalysts, boron sources, solvent and temperature combinations can be used in chiral hydroboration strategies. It will be well understood by one skilled in the art that a compound of formula (IV) may be prepared and isolated as described above, or prepared in situ without isolation in a sequential reaction yielding a compound of formula (1E) or (1F). The person skilled in the art also knows that compounds of formula (1E) or (1F) can be further enriched by crystallization or chiral chromatography (HPLC or SLC) techniques using an appropriate chiral stationary phase, eluting with an appropriate mobile phase as determined to be necessary. to isolate the desired enantiomers.

According to the third method, the compounds of formula (1G) can be obtained from formula (II) as shown in scheme 3.

Scheme 3

In Scheme 3, compounds of formula (II) are converted to compounds of formula (V) by treatment with a halogenating agent such as pyridinium tribromide in a suitable solvent such as DCM at a suitable temperature such as 0°C. The person skilled in the art also knows that alternative methods for the specific introduction of a suitable halogen group, such as Br, are carried out using alternative reagents, solvents and temperatures. Compounds of formula (VI) can be synthesized by this method or by reacting a compound of formula (V) using DBU with a suitable solvent such as DCM at a suitable temperature such as 25°C. Compounds of formula (VI) may be converted to compounds of formula (VII) (wherein R ₁₅ =Bpin) using Miyaura borylation conditions. Typical boronate ester preparation conditions include Pd(dppf)Cl ₂ .DCM and potassium acetate with bispinacolatoboron in 1,4-dioxane at a suitable temperature such as 55°C. A compound of formula (VII) can be converted to a compound of formula (1G) under aqueous acidic conditions by treatment with a suitable acid (acetic or hydrochloric) at a suitable temperature.

Compounds of formula (II) can be prepared from compounds of formulas (VIII), (IX), (X) and (XI) as shown in Scheme 4.

Scheme 4

In Scheme 4, compounds of formula (X) where R ₁₇ is chlorine, bromine, or iodine can be prepared from compounds of formulas (VIII) and (IX) using a suitable organometallic cross-coupling reaction, such as the Suzuki cross-coupling reaction, which precedes, if necessary, the preparation of boronic acid or ester. Typical Suzuki cross-coupling conditions include a palladium catalyst containing suitable phosphine ligands in the presence of an inorganic base, in aqueous dioxane or methanol, at elevated temperatures, either thermally or under microwave irradiation. Preferred conditions include Pd(OAc) ₂ , Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ with sodium, cesium or potassium carbonate, in aqueous dioxane or methanol at room temperature to 120°C. One skilled in the art will recognize that organometallic cross-coupling reactions can be used, including alternative combinations of metals, catalysts, ligands, bases, solvents, and temperatures. Typical boronic ester preparation conditions include Pd(dppf)Cl ₂ and potassium acetate with bispinacolate diboron with a compound of formula (VIII) where R ₁₆ =chlorine, bromine or iodine in dioxane at reflux. Compounds of formula (VIII) can also be obtained commercially or synthesized by a person skilled in the art according to the literature or in analogy with the methods described herein.

Compounds of formula (II) can be prepared from compounds of formula (X) and (XI) (wherein R ₁₈ =boronic acid or Bpin) by an organometallic cross-coupling reaction similar to those described above. One skilled in the art will recognize that alternative organometallic cross-coupling reaction strategies may also be employed, including alternative combinations of metals, catalysts, ligands, bases, solvents, and temperatures. Preferred Suzuki conditions include Pd(dppf)Cl ₂ with potassium carbonate and potassium acetate in dioxane from room temperature to 120°C.

Alternatively, compounds of formula (II) may be prepared from compounds of formulas (VIII), (IX), (XI) and (XII) in reverse order to that shown in Scheme 4 shown in Scheme 5.

Scheme 5

Compounds of formula (XII) can be prepared from compounds of formula (XI) (where R ₁₈ = boronic acid or pinacol) and (IX) (where R ₁₇ is chlorine, bromine or iodine) using an organometallic cross-coupling reaction as described on scheme 4. Preferred conditions include Pd(dppf)Cl ₂ with potassium carbonate in aqueous dioxane at room temperature to 120°C. Compounds of formula (XI) can be synthesized by those skilled in the art according to the literature or by analogy with the methods described herein. Compounds of formula (XII) can be converted to compounds of formula (II) using a method similar to that described earlier in Scheme 4, the Suzuki cross-coupling reaction, which may be preceded, if necessary, by the preparation of boronic acid or ester. One skilled in the art will recognize that alternative organometallic cross-coupling reaction strategies may also be employed, including alternative combinations of metals, catalysts, ligands, bases, solvents, and temperatures.

According to the sixth method, compounds of formula (1H) can be obtained from formulas (XIII) and (XIV) as shown in scheme 6.

Scheme 6

Compounds of formula (1H) where A is carbon or nitrogen can be prepared analogously to compounds of formula (1D), (1E) or (1F) as described in Schemes 1-5. It will be well understood by one skilled in the art that the individual enantiomers can be obtained using a suitable separation method, such as HPLC or SLC chromatography, to give both the (+) and (-) enantiomers of the compound of formula (XIV) and (1H). It is also well understood by one skilled in the art that the individual enantiomer of a compound of formula (XIV) and (1H) is prepared and isolated as described above or isolated using an alternative separation method such as HPLC or SLC using the appropriate elution of the chiral stationary phase with the appropriate mobile phase, as determined as necessary to isolate the desired enantiomers. Additionally, compounds of formula (1H) in which the central ring is substituted with a substituted 5-membered heterocycle (represented by Y in formula (1)) can also be synthesized in a similar manner by a person skilled in the art.

The compounds and methods of the present invention will be better understood in connection with the following examples, which are intended to illustrate and not limit the scope of the invention as defined in the appended claims.

The following abbreviations have been used in the description of the schemes and in the following examples: Ac is acetyl; AcOH is acetic acid; Ac ₂ O is acetic anhydride; Adam's catalyst is platinum(IV) oxide; Br ₂ is bromine; n-BuLi is n-butyllithium; °C are degrees Celsius; CDCl ₃ is deutero-chloroform; CD ₃ OD is deuteromethanol; CO ₂ is carbon dioxide; Cs ₂ CO ₃ is cesium carbonate; δ is the 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; DXM is dichloromethane or methylene chloride; DEA is diethylamine; DMAP is 4-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; DMSO- d ₆ is deuterodimethyl sulfoxide; Et ₂ O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et ₃ N is triethylamine; Fe is iron; g is a gram; HCl is hydrochloric acid; HCO ₂ H is formic acid; HMTA is hexamethylenetetramine; HPLC is high pressure liquid chromatography; H ₂ is hydrogen; H ₂ O is water; h is the hour; Hr is hours; Hz is hertz; IPA is isopropyl alcohol; IPAM: is isopropylamine; [Ir(COD)Cl] ₂ is bis(1,5cyclooctadiene)diiridium(I) dichloride; [Ir(COD)OMe] ₂ is a dimer of (1,5-cyclolctadiene)(methoxy)iridium(I); K ₂ CO ₃ is potassium carbonate; K ₃ PO ₄ is tribasic potassium phosphate; KBr is potassium bromide; KMnO ₄ is potassium permanganate; KOAc is potassium acetate; L is a liter; LCMS is liquid chromatography mass spectrometry; DAL is lithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide; LiOH is lithium hydroxide monohydrate; TMPL is lithium tetramethylpiperidine; m is molar; m -CPBA is meta-chloroperoxybenzoic acid; MeCN is acetonitrile; MeOH is methanol; MeNH ₂ is methylamine; mg is a milligram; MgSO ₄ is magnesium sulfate; MHz is megahertz; min is minutes; ml is a milliliter; mm is a millimeter; mmol is a millimol; a mole is a mole; MS m/z is the peak of the mass spectrum; MTBE is tert- butyl methyl ether; MsCl is mesyl chloride; NaBH ₄ is sodium borohydride; Na ₂ CO ₃ is sodium carbonate; NaOH is sodium hydroxide; NaOMe is sodium methoxide; Na ₂ SO ₄ is sodium sulfate; NBS is N-bromosuccinimide; NH ₃ is ammonia; NH ₄ Cl is ammonium chloride; NH ₂ OH∙HCl is hydroxylamine hydrochloride; NH ₄ OH is ammonium hydroxide; nM is nanomolar; PCl ₅ is phosphorus pentachloride; Pd/C is palladium on carbon; Pd(dppf)Cl ₂ is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl ₂ ^. DCM is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane; Pd(dppf)-tBu is [1,1'-bis(n-t-butylphosphino)ferrocene]dichloropalladium (II); Pd(OAc) ₂ is palladium acetate; PPh ₃ is triphenylphosphine; pet. ether is petroleum ether; pH is a hydrogen ion; Pin ₂ B ₂ is bis(pinacolato)diboron; PinBO-iPr is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; f./sq.d. is pounds per square inch; ppm is parts per million; POCl ₃ is phosphorus oxychloride; PrOH is 1-propanol; PtO ₂ is platinum (IV) oxide; kt is room temperature, RT is the hold time; SEM-Cl is 2-(trimethylsilyl)ethoxymethyl chloride; SLC is supercritical liquid chromatography; TBS is t -butyldimethylsilyl; TBS-Cl is t -butyldimethylsilyl chloride; tBu ₃ P is tri- t -butylphosphine; TFA is trifluoroacetic acid; TFUA is trifluoroacetic anhydride; TiCl ₄ is titanium tetrachloride; TfO is trifluoromethanesulfonyl; Tf ₂ O is trifluoromethanesulfonic anhydride; pTsOH is p-toluenesulfonic acid; Turbo Grignard is a solution of an isopropyl magnesium chloride-lithium chloride complex; 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(II ).

¹ H and ¹⁹ F spectrum of nuclear magnetic resonance (NMR) in all cases corresponds to the proposed structures. Characteristic chemical shifts (δ) are given in parts per million down from tetramethylsilane (for ¹ H-NMR) and up from trichlorofluoromethane (for ¹⁹ F NMR) using the usual abbreviations for major peaks: i.e. s, singlet; e, doublet; t, triplet; square, quartet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; m, multiplet; w, wide. The following abbreviations apply to common solvents: CDCl ₃ , deuterochloroform; DMSO- d ₆ , deuterodimethyl sulfoxide; and CD ₃ OD, deuteromethanol. If applicable, tautomers may be recorded in the NMR data; and some exchanged protons may be invisible.

The mass spectrum, MS (m/z), is recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI).

Where applicable and unless otherwise indicated, m/z data provided refer to ¹⁹ F, ³⁵ Cl, ⁷⁹ Br and ¹²⁷ I isotopes.

If using preparative TLC or column chromatography (silica), the person skilled in the art can choose any combination of suitable solvents to purify the desired compound.

The specific rotation based on the equation [α] = (100 ^. α)/(l ^. c) is represented as a dimensionless number, where the concentration c is given in g/100 ml and the path length l is given in decimetres. Units of specific rotation, (gr ^. ml) / g. dm) are implicit and are not included in the resulting value.

The following are analytical and preparative chromatography methods used to analyze and purify the compounds of the invention.

Preparative FLC Methods

Prep LC Method A: Column: Chiralpak IC-H, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH, 60/40 (v/v); Flow rate: 65 ml/min

Prep FLC Method B: Column: Lux Amylose-1 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH+0.2% (7N ammonia in MeOH) 80/20 (v/v); Flow rate: 150 ml/min

Prep LC Method C: Column: Chiralpak IC-H, 250 mm x 50 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /IPS 85/15 (v/v); Flow rate: 250 ml/min

Prep LC Method D: Column: Chiralcel OJ, 250 mm X 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /IPS, 65/35 (v/v); Flow rate: 50ml/min)

Prep LC Method E: Column: Daicel Chiralpak AD, 250 mm X 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 60/40 (v/v); Flow rate: 50 ml/min

Prep LC Method F: Column: Daicel Chiralpak IC, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 60/40 (v/v); Flow rate: 200ml/min)

Prep LC Method G: Column: Daicel Chiralpak AD, 250 mm x 50 mm, 10 µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 55/45 (v/v); Flow rate: 200 ml/min

Prep LC Method H: Column: Chiralpak IC-H, 250 mm X 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 75/25 (v/v); Flow rate: 200 ml/min

Prep SLC Method I: Column: Chiralpak IC, 250 mm x 30 mm, 10µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 60/40 (v/v); Flow rate: 60.0 ml/min

Prep FLC Method J: Column: Chiralpak IC 250 mm x 30 mm, 10µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 80/20 (v/v); Flow rate: 60 ml/min

Prep LC Method K: Column: Chiralpak AD, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH (0.1% NH ₄ OH), 75/25 (v/v); Flow rate: 50.0 ml/min

Prep LC Method L: Column: Chiralpak AD, 250 mm x 30 mm, 10µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH (0.1% NH ₄ OH), 75/25 (v/v); Flow rate: 200.0 ml/min

Prep SLC Method M: Column: Chiralpak IC, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 55/45 (v/v); Flow rate: 50.0 ml/min

Prep LC Method N: Column: Chiralpak IC, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 75/25 (v/v); Flow rate: 60.0 ml/min

Prep FLC Method O: Column: Daicel Chiralpak AD, 250 mm x 50 mm, 10µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH, 60/40 (v/v); Flow rate: 200 ml/min

Prep SLC Method P: Column: Chiralcel OJ-H, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH ₄ OH), 85/15 (v/v); Flow rate: 50 ml/min

Prep LC Method Q: Column: Daicel Chiralpak AD, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /IPS (0.1% NH ₄ OH), 75/25 (v/v); Flow rate: 60 ml/min

Prep LC Method R: Column: Chiral Technologies AD-H, 250 mm x 21 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH (0.2% NH ₄ OH), 80/20 (v/v); Flow rate: 75 ml/min

Prep FLC Method S: Column: Princeton PPU, 250 mm x 30 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /MeOH, 80/20 (v/v); Flow rate: 80 ml/min

Analytical SLC Methods

Analytical SLC Method A: Column: Chiralpak IC, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: EtOH (0.05% isopropylamine); Gradient: A:B=65:35; Flow rate: 2.5 ml/min

Analytical SLC Method B: Column: Lux Amylose-1, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% MeNH ₂ ); 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 SLC Method C: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method D: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method E: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method F: Column: Chiralpak AD-3, 50 mm x 3.0 mm, 3µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.0 ml/min

Analytical SLC Method G: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method H: Column: Chiralcel OJ-3, 100 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method I: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method J: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method K: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% NH ₄ OH); Gradient elution (time, %A, %B): (5 min, 60%A, 40%B, [Flow rate: 1.5 ml/min

Analytical SLC Method L: Column: ChiralCel OJ-H, 150 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , 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 SLC Method M: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , 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 SLC Method N: Column: Chiralcel OJ-H 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: IPA (0.05% IPAm), Gradient elution: B and A from 10% to 40% in 10 minutes, Flow rate: 2.5 ml/min

Analytical FLC Method O: Column: ChiralPak AY-3 150 mm × 4.6 mm, 3 µ; Mobile phase: A: CO ₂ , 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 SLC Method P: Column: Chiralcel OJ-3 100 mm × 4.6 mm, 3 µ; Mobile phase: A: CO ₂ , 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 SLC Method Q: Column: ChiralCel OD-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method R: Column: Chiralpak AD-3, 100 mm x 4.6 mm, 3µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.08 ml/min

Analytical SLC Method S: Column: Chiral Technologies OJ-H, 100 mm x 4.6 mm, 5µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.2% NH ₄ OH), 95/5 (v/v); Flow rate: 3.0 ml/min

Analytical SLC Method T: Column: Chiralpak IC, 100 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method U: Column: Lux Amylose-2, 100 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% NH ₄ OH); 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 SLC Method V: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , 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 SLC Method W: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , 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 SLC Method X: Column: ChiralPak AY, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method Y: Column: Chiral Tech OJ-H, 100 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% NH ₄ OH); Gradient elution (time, %A, %B): (0 min, 95%A, 5%B), (10 min, 95%A, 5%B), Flow rate: 1.5 ml/min

Analytical SLC Method Z: Column: Chiralcel OJ-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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

Analytical SLC Method AA: Column: ChiralPak AD-3 100 mm × 4.6 mm, 3 µ; Mobile phase: A: CO ₂ , 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 SLC Method BA: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3µ; Mobile phase A: CO ₂ , 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 SLC Method CA: Column: Lux Cellulose 100 mm x 4.6 mm, 5 µ; Mobile phase: A: CO ₂ , Mobile phase B: MeOH (0.2% NH ₄ OH); Gradient elution: (time, %A, %B): (0 min, 70%A, 30%B), (5 min, 70%A, 30%B), Flow rate: 1.5 ml/min

Analytical SLC Method DA: Column: Lux Cellulose-2, 150 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , 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 SLC Method EA: Column: Chiralcel OJ-3, 150 mm x 4.6 mm, 3µ; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.5 ml/min

Analytical SLC Method FA: Column: ChiralPak AD-3, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: EtOH (0.05% IPAM); Gradient elution (time, %A, %B): (0 min, 65%A, 35%B), Flow rate: 2.5 ml/min

Analytical SLC Method GA: Column: Chiral Tech IC, 250 mm x 4.6 mm, 5µ; Mobile phase A: CO ₂ , Mobile phase B: IPA (0.2% NH ₃ in MeOH); Gradient elution (time, %A, %B): (0 min, 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

Preparative HPLC Methods

HPLC prep Method A: Column: Xtimate C18, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B MeCN; B%: 18%-58%, 12 min; Flow rate: 25 ml/min

HPLC prep Method B: Column: Phenomenex XB-C18, 250 mm x 21.2 mm, 5µ; Mobile phase A: water (0.1% HCO ₂ H), Mobile phase B: MeCN (0.1% HCO ₂ H); 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

HPLC Prep 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

HPLC Prep 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

HPLC prep Method E: Column: Waters Xbridge, 150 mm x 25 mm, 5µ; Mobile phase A: water (10 mM NH ₄ HCO ₃ ), Mobile phase B: MeCN; B%: 20%-50%, 12 min

HPLC prep 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

HPLC prep 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

HPLC Prep Method H: Column: Boston Green ODS, 150 mm x 30 mm, 5µ; Mobile phase A: water (0.225% HCO ₂ H), Mobile phase B: MeCN; B%: 5%-53%, 11 min, Flow rate: 25 ml/min

HPLC prep Method I: Column: Agela Durashell C18, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.225% HCO ₂ H), Mobile phase B: MeCN; B%: 9%-39%, 12 min, flow rate: 25 ml/min

HPLC prep 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

HPLC prep Method K: Column: Agela Durashell C18, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.225% HCO ₂ H), Mobile phase B: MeCN; B%: 0%-32%, 11 min, Flow rate 25 ml/min

HPLC Prep Method L: Column: Xtimate C18, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 15%-55%, 12 min, Flow rate: 25 ml/min

HPLC prep Method M: Column: Agela Durashell 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 30%-60%, 2.5 min, Flow rate: 25 ml/min

HPLC prep 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

HPLC Prep Method O: Column: Agela Durashell, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 25%-55%, 10 min, Flow rate: 25 ml/min

HPLC prep Method P: Column: Agela Durashell, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 30%-60%, 10 min, flow rate: 25 ml/min

HPLC Prep Method Q: Column: Agela Durashell, 150 mm x 25 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 23%-53%, 10 min, flow rate: 25 ml/min

HPLC Prep Method R: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0 min, 90%A, 10%B), (15 min, 60%A, 40%B), (18 min, 0%A, 100%B) , flow rate: 110ml/min)

HPLC prep Method S: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH 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: 110ml/min

HPLC Prep Method T: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 20%-40%, 15 min, flow rate 110 ml/min

HPLC prep Method U: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH 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: 110ml/min

HPLC prep Method V: Column: Phenomenex Synergi Max-RP, 150 mm x 50 mm, 10µ; Mobile phase A: Water (0.225% HCO ₂ H), Mobile phase B: MeCN; B%: 0%-30%, 25 min, flow rate 120 ml/min

HPLC Prep Method W: Column: Xtimate C18, 150 mm x 25 mm, 5µ; Mobile phase A: Water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 17%-57%, 12 min, Flow rate: 25 ml/min

HPLC prep 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: 25ml/min

HPLC prep Method Y: Column: Boston Green ODS, 150 mm x 30 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 45%-65%, 9 min, Flow rate 25 ml/min

HPLC Prep Method Z: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH 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: 110ml/min

HPLC prep Method AA: Column: Gemini C18, 15 mm x 21.2 mm, 5 µ; Mobile phase A: water (0.1% HCO ₂ H) Mobile phase B: MeCN (0.1% HCO ₂ H); B% 25% - 35%; 25 ml/min

HPLC prep Method BA: Column: Agela Durashell C18, 150 mm x 30 mm, 5µ; Mobile phase A: water (0.05% NH ₄ OH v/v), Mobile phase B: MeCN; B%: 20%-55%, 15 min, Flow rate: 25 ml/min

HPLC Prep Method CA: Column: Phenomenex Gemini C18, 250 mm x 50 mm, 10µ; Mobile phase A: Water (0.05% NH ₄ OH 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

Production Example 1 5-(3,4-dimethoxyphenyl)pyridine

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl )-5-(3,4-dimethoxyphenyl)pyridine (Preparation Example 2, 1.6 g, 3.13 mmol) in EtOAc (50 ml) was added with Pd/C (0.5 g, 10% loading). The mixture was stirred under H ₂ (5 psig) at 20° C. for about 3 hours. The mixture was filtered and concentrated to give 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (1.2 g), which is used immediately without further cleaning. ¹ H NMR (CDCl _3, 400 MHz): δ 8.69 (d, J =7.6 Hz, 1H), 8.48 (s, 1H), 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] ⁺ .

Production Example 2 -yl)-5-(3,4-dimethoxyphenyl)pyridine

3-(1-Bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine solution (Preparation Example 37, 0.83 g, 1 .79 mmol), Pd(dppf)Cl ₂ ∙DCM (73 mg, 89 µmol), KOAc (263 mg, 2.68 mmol) and Pin ₂ B ₂ (CAS 73183-34-3, 681 mg, 2.68 mmol) in 1,4-dioxane (10 ml) was heated to 55° C. under N ₂ 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 give 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop -1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (900 mg, 98%). ¹ H NMR (CDCl _3, 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] ⁺ .

Production Example 3 5-(3-ethoxy-4-methoxyphenyl)pyridine

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

Production Example 4 -yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)- 5-(3-ethoxy-4-methoxyphenyl)pyridine (7.5 g, 97%) was prepared in a manner analogous to Preparation 2 using 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop- 1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (Production Example 38, 7.0 g, 14.6 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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 (kv, 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).

Production Example 5 5-(4-methoxy-3-propoxyphenyl)pyridine

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl )-5-(4-methoxy-3-propoxyphenyl)pyridine (Preparation Example 8, 4.00 g, 7.41 mmol) in EtOAc (100 mL) Pd/C (1.0 g, 10% loading) was added under _N2 . The mixture was stirred under H ₂ (14 psig) at about 25° C. for about 3 hours. The mixture was filtered and concentrated to give 3-(1-((tert-butyldimethylsilyl)oxy)-3-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (3.44 g, 86%) which is used without further purification.

Production Example 6 : (R)-(3-((t-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid

Method A:

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Production Example 50, 50.00 g, 120, 9 mmol), [Ir(COD)Cl] ₂ (CAS 12112-67-3, 2.03 g, 3.02 mmol) and (S, S)-[2-(4'-i-propyloxazoline-2- yl)ferrocinyl]diphenylphosphine (CAS 163169-29-7, 3.20 g, 6.65 mmol) anhydrous THF (403 mL) was added. The mixture is stirred for about 15 minutes at about 20° C. under N ₂ . The flask is cooled in an ice water bath until the temperature of the solution is about 0°C. Catecholborane (181.48 mL, 181 mmol, 1.0 M in THF) was added dropwise over 1 h. drops of methanol (25 ml) at about 0°C (ice bath). The solution is removed from the ice bath and stirred for approximately 30 minutes. The solution was concentrated to give (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (88 g), which applied immediately 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 1,4-dioxane (19 mL) and stirred at about 20° C. for about 1 hour. 3-(1-((t-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Preparation Example 42, 46.8 g, 86.5 mmol) in anhydrous THF (270 ml) which is stirred at about 20° C. for about 20 minutes. A solution of trimethyl borate (96.4 ml, 865 mmol) in THF (107 ml) was added dropwise and stirred at about 20° C. for about 30 minutes. The mixture was concentrated and partitioned between water (500 ml) and EtOAc (200 ml). The aqueous layer was extracted with EtOAc (3×100 ml). The combined EtOAc layers are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (80:20-0:100) followed by EtOAc/MeOH (100:0-90:10) to give (R)-(3-((tert-butyldimethylsilyl )hydroxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (29.0 g, 73%). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.51 (d, J =2.3 Hz, 1H), 8.30 (d, J =2.0 Hz, 1H), 7.85 (br , 1H), 7.14-7.17 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 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] ⁺ .

Production Example 7 : (S)-(3-((t-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Production Example 50, 1.0 g, 2, 42 mmol), [Ir(COD)Cl] ₂ (CAS 12112-67-3, 44.2 mg, 0.06 mmol) and (R, R)-[2-(4'-i-propyloxazoline-2- yl)ferrocinyl]diphenylphosphine (CAS 541540-70-9, 58.2 mg, 0.12 mmol) anhydrous THF (8.1 ml) was added. The mixture is stirred at about 20° C. for about 10 minutes. The reaction mixture is cooled to about 0°C and catecholborane (6.04 ml, 6.04 mmol, 1.0 M in THF) is added dropwise. The reaction mixture is heated to about 20° C. and stirred for about 8 hours. The reaction mixture is cooled to about 5° C. and quenched with MeOH. The mixture was concentrated and purified by column chromatography (silica) and eluted with DCM/MeOH (100:0-90:10) to give (S)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4- methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (889 mg, 80%). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.51 (d, J =2.3 Hz, 1H), 8.30 (d, J =2.0 Hz, 1H), 7.85 (br , 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 ( e, J =12.9 Hz, 6H). LCMS m/z =460 [MH] ⁺ .

Production Example 8 -yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

3-(1-Bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Production Example 39, 5.60 g, 11.37 mmol), Pd(dppf)Cl ₂ (415.98 mg, 568.50 µmol), Pin ₂ B ₂ (4.33 g, 17.06 mmol) and KOAc (2.23 g, 22.74 mmol) in dioxane (100 ml) is heated to about 60°C under N ₂ for about 16 hours the Mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop -1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (6.10 g, 99%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 4.06 (t, J= 6.8 Hz, 2H), 3.93 (s, 1H), 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).

Production Example 9 5-(3-isopropoxy-4-methoxyphenyl)pyridine

Bis(1,5-cyclooctadiene)di-µ-methoxydiiridium(I) (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) was stirred for about 15 min under N ₂ at about 15°C. 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine (Preparation Example 51, 600 mg, 1.45 mmol) was added to the mixture under N ₂ at about 15°C. After stirring for about 5 minutes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 25015-63-9, 913 mg, 7.13 mmol) is added at about 70° C. and stirred at for another 15 min. The reaction mixture is quenched with MeOH and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether: EtOAc (100:0-85:15) to give 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)propan-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine (750 mg, 96%). LCMS m/z =542 [MH] ⁺ .

Production Example 10 5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3 -cyclopropoxy-4-methoxyphenyl)pyridine (750 mg, 95%) was prepared in a similar manner to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5 -(3-cyclopropoxy-4-methoxyphenyl)pyridine (Preparation Example 52, 600 mg, 1.46 mmol). LCMS m/z=540 [MH] ⁺ .

Production Example 11 5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

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

Production Example 12 5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3 -(3-((t-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12.0 g, 97%) was prepared in a similar manner to Preparation 9 using 3-(3-((t-butyldimethylsilyl) hydroxy)prop-1-en-2-yl)-5-(3-(3-((t-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Production Example 54, 10.0 g, 18.4 mmol). LCMS m/z =671 [MH] ⁺ .

Production Example 13 5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3 -(2-fluoroethoxy)-4-methoxyphenyl)pyridine (700 mg, 89%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene-2- yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (Preparation Example 55, 600 mg, 1.4 mmol). LCMS m/z=433 [MH] ⁺ .

Production Example 14 : 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

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 was prepared in a manner analogous to Preparation 9 using 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-( 3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine (Production Example 56).

Production Example 15 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)propan-2-yl)-5-(2 -(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (300 mg, 46%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en- 2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 57, 361 mg, 1.13 mmol). LCMS m/z=578 [MH] ⁺ .

Production Example 16 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)propan-2-yl)-5-(3 -ethoxy-5-fluoro-4-methoxyphenyl)pyridine (650 mg, 75%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene-2- yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine (Preparation Example 58, 660 mg, 1.58 mmol). LCMS m/z =546 [MH] ⁺ .

Production Example 17 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)propan-2-yl)-5-(3 -chloro-5-ethoxy-4-methoxyphenyl)pyridine (800 mg, 77%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2- yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 59, 800 mg, 1.8 mmol). LCMS m/z =562 [MH] ⁺ .

Production Example 18 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)propan-2-yl)-5-(5 -ethoxy-2-fluoro-4-methoxyphenyl)pyridine (2.0 g, 85%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en- 2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (Preparation Example 60, 1.80 g, 4.31 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.56 (t, J =1.7 Hz, 1H), 8.44 (d, J =2.0 Hz, 1H), 7.71 (m, 1H ), 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), 3.07-3.14 (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] ⁺ .

Production Example 19 5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2 -chloro-5-ethoxy-4-methoxyphenyl)pyridine (2.05 g, 73%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene- 2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 61, 2.17 g, 5.0 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.44 (m, 2H), 7.63 (t, J =2.0 Hz, 1H), 6.95 (s, 1H), 6.77 ( s, 1H), 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).

Production Example 20 5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

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

Production Example 21 5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4 -(difluoromethoxy)-3-propoxyphenyl)pyridine (2.25 g, 88%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2- yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine (Preparation Example 63, 2.0 g, 4.5 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.61 (d, J =2.2 Hz, 1H), 8.57 (d, J =2.1 Hz, 1H), 7.73 (t, J= 2.1Hz, 1H), 7.24(d, J =8.0Hz, 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] ⁺ .

Production Example 22 : 5'-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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)propan-2-yl)-3-fluoro -5-methoxy-6-propoxy-2,3'-bipyridine (4.02 g, quant.) 1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (Preparation Example 64, 3.1 g, 7.17 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.03 (s, 1H), 8.45 (d, J =2.3 Hz, 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] ⁺

Production Example 23 : 5'-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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)propan-2-yl)-6-methoxy -5-propoxy-3,3'-bipyridine (2.55 g, 81%) was prepared in a manner analogous to Preparation 9 using 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene- 2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine (Preparation Example 65, 2.4 g, 5.8 mmol). LCMS m/z =543 [MH] ⁺ .

Production Example 24 3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine

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

Production Example 25 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)propan-2-yl)-2-(4 -methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (0.94 g, 59%) was prepared in a manner analogous to Preparation 9 using 4-(3-((tert-butyldimethylsilyl)oxy)prop-1- en-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (Preparation Example 67, 1.27 g, 2.63 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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), 0.80-0.82 (s, 9H), -0.04 (t, J =3.1 Hz , 3H), -0.08 (t, J =3.1 Hz, 3H). LCMS m/z =611 [MH] ⁺

Production Example 26 6-(3-ethoxy-4-methoxyphenyl)pyrazine

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

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

Ethyl 2-(6-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)- 2-(4-Methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Preparation Example 28, 758 mg, 1.21 mmol) was dissolved in MeCN (10 ml) and water (10 ml). LiOH∙H ₂ O (101 mg, 2.41 mmol) was added to the solution in portions. The mixture is stirred at about 25° C. for about 1 hour. The mixture is concentrated. The reaction mixture was used immediately in the next step without further purification. LCMS m/z =519 [MH] ⁺ .

Production Example 28 : Ethyl 2-(6-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2 -yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

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

Production Example 29 : 4-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(( (tert-Butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (1.0 g, 58%) was prepared in a manner analogous to Preparation 9 using 4-(((tert-butyldimethylsilyl) hydroxy)methyl)-6-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (Production Example 70, 1.4 g , 2.5 mmol). LCMS m/z =687 [MH] ⁺ .

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

Methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate mixture (Preparation Example 40, 15.00 g, 30.03 mmol), Pd(dppf)Cl ₂ (1.10 g, 1.50 mmol), Pin ₂ B ₂ (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 hours under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to give methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (13.6 g, 94%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.52 (s, 1H), 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).

Production Example 31 : 2-(4-((t-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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-2-yl)-6-(4 -methoxy-3-propoxyphenyl)pyridine (140 mg, 12%) was prepared in a manner analogous to Preparation 9 using 2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6 -(4-methoxy-3-propoxyphenyl)pyridine (Preparation Example 71, 900 mg, 2.10 mmol). LCMS m/z =556 [MH] ⁺ .

Production Example 32 : (E)-3-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-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 N ₂ . N-BuLi (2.56 ml, 6.41 mmol, 2.5 M in hexane) is added dropwise to the solution and stirred for about 30 minutes at about 0°C. Solution of 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (Preparation Example 149, 1810 mg, 6.41 mmol) in THF (2 ml) is added dropwise, then stirred for about 5 minutes, then cooled to about -78°C. 2-((tert-Butyldimethylsilyl)oxy)-1-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)ethan-1-one solution (Preparation Example 75, 666 mg, 1.60 mmol) in THF (3.0 ml) was added dropwise and stirred under N ₂ at about -78°C for about 1 hour. The reaction mixture was placed in an ice bath and stirred for another hour. The reaction mixture is quenched with water and diluted with EtOAc. EtOAc is separated, washed with brine and dried over MgSO ₄ . The solution is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (9:1) to give (E)-3-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl -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] ⁺ .

Production Example 33 : Ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) propanoate

To a mixture of ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (Production Example 110, 249 mg, 0.625 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 114, 357 mg, 1.22 mmol) in 1,4-dioxane (8.5 ml) was added a solution of K ₃ PO ₄ in water (2.0 M, 0.625 ml, 1.25 mmol). The mixture is degassed using N ₂ at about 20° C. for about 10 minutes. Bis(tri-t-butylphosphine)palladium(0) (CAS 53199-31-8, 16.0 mg, 0.03 mmol) is added and the mixture is stirred at about 20° C. for 2 hours. The mixture is diluted with EtOAc, dried over Na ₂ SO ₄ , filter and concentrate. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0-0:100) to give ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (134 mg, 44%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 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= 7.4 Hz, 7H). LCMS m/z =399 [MH] ⁺ .

Production Example 34 3-(4-methoxy-3-propoxyphenyl)pyridazine

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

Production Example 35 5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3 -ethoxy-4-methoxyphenyl)-4-methylpyridine (0.28 g, 26%) was prepared in a manner analogous to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene-2 -yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (Preparation Example 73, 0.8 g, 1.93 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.36 (s, 1H), 8.22 (s, 1H), 6.92 (d, J =8.3 Hz, 1H), 6.75- 6.78 (m, 1H), 6.73 (d, J = 2.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 3.74-3.78 (m, 1H), 3.64-3.68 (m, 1H), 3.38-3.46 (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] ⁺

Production Example 36 : 4-(1-((t-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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)propan-2-yl)-2-(3 -ethoxy-4-methoxyphenyl)thiazole (0.41 g, 39%) was prepared in a manner analogous to Preparation 9 using 4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl) -2-(3-ethoxy-4-methoxyphenyl)thiazole (Preparation Example 74, 0.8 g, 1.97 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (d, J =2.0 Hz, 1H), 7.46 (dd, J =2.0, 8.5 Hz, 1H), 6, 91 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.88-3.92 (s, 4H ), 3.77-3.81 (m, 1H), 3.27-3.34 (m, 1H), 1.51 (t, J=7.0Hz, 3H), 1.27-1.30 (m, 2H), 1.15 (d, J =13.6, 12H), 0.85 (s, 9H), -0.03 (s, 6H). LCMS m/z =534 [MH] ⁺ .

Production Example 37 : 3-(1-bromo-3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (Preparation Example 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 is stirred at about 20°C for about 1 h and poured into cold aqueous Na ₂ SO ₃ (100 ml). The mixture is extracted with DCM (3×50 ml). The combined DCM extracts were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. DBU (CAS 6674-22-2, 58.64 ml, 389.1 mmol) is added to the above mixture in DCM (500 ml) at about 20°C. The mixture is stirred at about 20°C for about 16 h and poured into aqueous NH ₄ Cl (500 ml). The mixture is extracted with DCM (3×200 ml). The combined DCM extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (15:1) to give 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (27 .0 g, 75%), ¹ H NMR (CDCl _3, 400 MHz): δ 8.74 (d, J= 2.4 Hz, 1H), 8.55 (d, J= 3.0 Hz, 1H ), 7.88 (t, J= 2.0 Hz, 1H), 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).

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

3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine mixture (Production Example 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 hours. The mixture was washed with 1N HCl (300 ml), brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (7.0 g, 74%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

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

To a mixture of 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Production Example 47b, 10.0 g, 17.44 mmol) in DCM (150 mL) was added DBU (CAS 6674-22-2, 5.26 mL, 34.88 mmol) followed by stirring at about 25° C. for about 16 hours under N ₂ . The mixture was washed with 1N HCl (400 ml), brine (400 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (5.60 g, 65%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 6, 57 (s, 1H), 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).

Production Example 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)-3-hydroxyacrylate (Production Example 41, 14.5 g, 39, 47 mmol) in toluene (500 ml) LiOH (11.59 g, 276.27 mmol) in water (30 ml) was added. Tf ₂ O (CAS 358-23-8, 15.63 ml, 94.72 mmol) was added dropwise to the mixture at about 0°C. The mixture was stirred at about 0° C. for about 1 hour. The reaction mixture was quenched with water (500 ml) and extracted with EtOAc (2×500 ml). The combined EtOAc extracts were washed with brine (2×300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (15:1) to give methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(((trifluoromethyl) sulfonyl)oxy)acrylate (15.00 g, 74%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 41 : Methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-hydroxyacrylate

To a mixture of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)acetate (Preparation Example 85, 12.0 g, 35.36 mmol) and ethyl formate (11.39 ml, 141.43 mmol) in DCM (150 ml) TiCl ₄ (13.41 g, 70.72 mmol, 7.62 ml) and Et ₃ N (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 hour. Water (150 ml) was added and the mixture was extracted with DCM (2×150 ml). The combined DCM extracts were washed with brine (150 ml), dried over Na ₂ SO ₄ and concentrated to give methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]- 3-yl)-3-hydroxyacrylate (14.50 g), which was used immediately without further purification. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

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

(R)-3-((tert-Butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl methanesulfonate mixture (Production Example 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 mixture is heated to about 50°C for about 45 minutes. The mixture is cooled to about 20°C and concentrated to remove acetone. The residue is diluted with DCM and washed with water (2×100 ml). The DCM extract is dried over MgSO ₄ , filtered and concentrated. The residue was triturated in heptane/EtOAc (1:1, 100 mL) for about 45 minutes. The solid product is filtered and purified by column chromatography (silica) and eluted with heptane/EtOAc (85:15 to 30:70) to give (R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropane-2 -yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (41.2 g, 85%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.71 (d, J =2.3 Hz, 1H), 8.43 (d, J =2.0 Hz, 1H), 7.71 (t, J =2.0Hz, 1H), 7.09-7.15(m, 2H), 6.98(d, J =8.2Hz, 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), 3.09-3.15(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] ⁺ .

Production Example 43 : (R)-3-((t-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl methanesulfonate

To an ice-cold solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol (Production Example 44, 42, 8 g, 99.2 mmol) in DCM (600 ml) was added Et ₃ N (25.1 ml, 178 mmol) and stirred for about 30 minutes. MsCl (9.98 ml, 129 mmol) is added dropwise and heated and stirred at about 20° C. overnight. The mixture was washed with water, dried over MgSO ₄ , filtered, passed through a silica gel pad and concentrated to give (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl) methanesulfonate )pyridin-3-yl)propyl (45.5 g) used in Preparation 42. LCMS m/z =510 [MH] ⁺ .

Production Example 44 : (S)-3-((t-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol

To an ice-cold solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (Production Example 45, 45.7 g, 96 .5 mmol) in THF (400 ml) was added aqueous NaOH (154 ml, 1 N). The mixture is heated and stirred at about 20°C for 2 days. The organic phase is separated and concentrated. The residue is dissolved in DCM (300 ml). The aqueous layer is extracted with DCM. The combined DCM extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl )pyridin-3-yl)propan-1-ol (42.8 g), which was used in Preparation 43. LCMS m/z =432 [MH] ⁺ .

Production Example 45 : (S)-3-((t-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate

To an ice-cold solution of (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (Preparation Example 46, 43.4 g, 121 mmol) in 2-MeTHF ( 1400 ml) DCM (800 ml), imidazole (41.1 g, 604 mmol) and TBS-Cl (91.0 g, 604 mmol) are added. The reaction mixture is heated to about 20°C and stirred overnight. The mixture is filtered and the solids are washed with EtOAc. The combined filtrates are washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0-60:40) to give (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3 -propoxyphenyl)pyridin-3-yl)propyl acetate (48.3 g, 85%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.70 (d, J =2.0 Hz, 1H), 8.45 (d, J =2.3 Hz, 1H), 7.74 (t, J = 2.3 Hz, 1H), 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), 3.17-3.23 (m, 1H), 2.04 (s, 3H), 1.67-1.96(m, 2H), 1.08(t, J =7.4Hz, 3H), 0.87(s, 9H), 0.01(d, J =2 .3 Hz, 6H). LCMS m/z =474 [MH] ⁺ .

Production Example 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)propan-1,3-diol (Preparation Example 82, 38.3 g, 121 mmol) in 2-MeTHF (1088 ml) immobilized Rhizomucor miehei lipase (1.53 g, Lipozyme® RM IM, Novozymes A/S, Denmark) is added. The mixture is stirred at about 20° C. for about 5 minutes. 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 hours. The mixture was filtered and the filter cake was washed with 2-MeTHF (50 ml). The combined filtrates were concentrated to give (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (36.0 g, 83%), which was used in Preparation Example 45 .

Production Example 47a : 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (Production Example 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 N ₂ . The mixture was stirred at about 25° C. for about 3 hours. The mixture was washed with aqueous Na ₂ SO ₃ (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (11 00 g) which is taken immediately at the next stage. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72-8.74 (m, 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= 8.0 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).

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

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Production Example 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 N ₂ . The mixture was stirred at about 25° C. for about 3 hours. The mixture was washed with aqueous Na ₂ SO ₃ (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (10 00 g), which is taken immediately at the next stage. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 48 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

3-(3,4-Dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine mixture (Preparation Example 91a, 2.0 g, 5.86 mmol), 2-bromoallyloxy-tert-butyldimethylsilane (Preparation Example 227, 1.47 g, 5.86 mmol), Pd(dppf)Cl ₂ ^. DCM (239.34 mg, 293 µmol), Na ₂ CO ₃ (621.26 mg, 5.86 mmol) and KOAc (1.15 g, 11.72 mmol) in 1,4-dioxane (50 ml) and water (5 ml) is heated to about 90° C. for about 12 hours. The mixture is filtered and the filtrate is concentrated. The residue was purified by column chromatography (silica) and eluted with DCM/MeCN (5:1) to give 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3.4 -dimethoxyphenyl)pyridine (2.10 g, 5.45 mmol, 93%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72 (d, J= 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).

Production Example 49 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-Bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine mixture (Preparation Example 92, 20 g, 64.9 mmol), t-butyldimethyl ((2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Preparation Example 146, 23.23 g, 77.88 mmol), Pd(dppf)Cl ₂ (1.42 g, 1.95 mmol), K ₂ CO ₃ (17.94 g, 129.8 mmol) and KOAc (9.55 g, 97.35 mmol) in 1,4-dioxane (300 ml) and water (10 ml) are degassed and heated to about 90 °C for about 16 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (3:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (18.0 d, 69%). ¹ H NMR (CDCl ₃ , 400 MHz): 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= 8.0 Hz, 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).

Production Example 50 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

3-Bromo-5-(4-methoxy-3-propoxyphenyl)pyridine mixture (Preparation Example 93a, 15.0 g, 46.55 mmol), t-butyldimethyl ((2-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Preparation Example 146, 18.05 g, 60.51 mmol), Pd(dppf)Cl ₂ (1.70 g, 2.33 mmol ), K ₂ CO ₃ (12.87 g, 93.10 mmol) and KOAc (6.85 g, 69.83 mmol) in 1,4-dioxane (250 ml) and water (5 ml) are degassed and heated to about 90°C for about 16 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (3:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (13.50 d, 70%). ¹ H NMR (CDCl ₃ , 400 MHz): 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), 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).

Production Example 51 : 3-(3-((t-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-4-methoxyphenyl)pyridine (1.1 g, 75%) was obtained by a method similar to Preparation 50 using 3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (Production Example 94, 1.15 g, 3.6 mmol) at about 90° C. for about 2 hours. LCMS m/ z =414 [MH] ⁺ .

Production Example 52 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (730 mg, 76%) was prepared in a manner analogous to Preparation Example 50 using 3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (Preparation Example 95, 0.75 g, 2.34 mmol). ¹ H NMR (CDCl ₃ , 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] ⁺ .

Production Example 53 )pyridine

3-(3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (6 .7 g, 62%) was prepared in a manner analogous to Preparation 50 using 3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine (Preparation 96, 9.3 g, 21 mmol). ¹ H NMR (CDCl ₃ , 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] ⁺ .

Production Example 54 )pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12 .9 g, 99%) was prepared in a manner analogous to Preparation 50 using 3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Preparation 97, 10.8 g, 23.8 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.71 (d, J= 2.5 Hz, 1H), 8.60 (d, J= 2.0 Hz, 1H), 7.83 (t, J= 2.2Hz, 1H), 7.11-7.16(m, 2H), 6.98(d, J= 8.3Hz, 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] ⁺ .

Production Example 55 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (1.6 g, 78%) was obtained in a similar manner to Preparation 50 using 3-bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (Preparation 98, 1.4 g, 4.7 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.92 (d, J= 2.5 Hz, 1H), 8.70-8.73 (m, 1H), 7.73 (t, J= 8 .6 Hz, 1H), 6.84-6.90 (m, 1H), 6.07 (d, J= 1.5 Hz, 1H), 5.76 (d, J= 1.5 Hz, 1H ), 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] ⁺ .

Production Example 56 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared in a manner analogous to Preparation Example 50 using 3-bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine (Production Example 99)

Production Example 57 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

A solution of 2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol (Preparation Example 76, 321 mg, 0.71 mmol) and imidazole (97.2 mg, 1.43 mmol) in DCM (20 ml) TBS-Cl (129 mg, 0.86 mmol) was added at about 0°C. The reaction mixture is stirred at about 20°C for about 15 hours. Additional TBS-Cl (129 mg, 0.86 mmol) is added and the reaction mixture is stirred at about 20°C for about 20 hours. The reaction mixture is concentrated and purified by column chromatography (silicon dioxide) and elute pet. ether/EtOAc (100:0 to 60:40) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy -4-methoxyphenyl)pyridine (361 mg, 75%). ¹ H NMR (CDCl ₃ .400 MHz): δ 8.66 (d, J= 2.0 Hz, 1H), 8.51 (d, J= 2.0 Hz, 1H), 7.71 (t, J= 2.3 Hz, 1H), 7.05-7.10 (m, 1H), 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 (kv, 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] ⁺ .

Production Example 58 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine

3-Bromo-5-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine mixture (Preparation Example 86, 795 mg, 2.42 mmol), 2-(3-ethoxy- 5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 132, 652 mg, 2.2 mmol), Pd(dppf)Cl ₂ ^. DCM and K ₂ CO ₃ (760 mg, 5.5 mmol) are suspended in 1,4-dioxane (20 ml) and water (0.7 ml). The mixture is degassed and heated to about 85° C. under N ₂ for about 9 hours. The mixture is concentrated and MTBE (50 ml) is added with stirring for about 20 minutes. The mixture is filtered and the filtrate is concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4 -methoxyphenyl)pyridine (660 mg, 72%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.66 (dd, J= 2.2, 15.4 Hz, 2H), 7.82 (t, J= 2.0 Hz, 1H), 6, 94 (dd, J= 2.2, 11.0 Hz, 1H), 6.88 (t, J= 1.7 Hz, 1H), 5.50-5.57 (m, 2H), 4.54 -4.57(m, 2H), 4.18(kv, J= 7.0Hz, 2H), 3.98(s, 3H), 1.50(t, J= 7.1Hz, 3H) , 0.92 (s, 9H), 0.12 (s, 6H). LCMS m/z =418 [MH] ⁺ .

Production Example 59 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine (840 mg, 61%) was obtained according to the method , analogous to Preparation 58 using 2-(3-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 133, 1.0 g, 3.2 mmol). ¹ H NMR (CDCl ₃ .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(kv, J= 7.2Hz, 2H), 3.94(s, 3H), 1.51(t, J= 6.9Hz , 3H), 0.90-0.97 (m, 9H), 0.08-0.15 (m, 6H).

Production Example 60 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (400 mg, 89%) was obtained according to the method analogous to Preparation 50 using 3-bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (Preparation 101, 350 mg, 1.07 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.66 (t, J =1.7 Hz, 1H), 8.62 (d, J =2.2 Hz, 1H), 7.84-7, 86 (m, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 11.7 Hz, 1H), 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] ⁺ .

Production Example 61 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine (2.1 g, 48%) was obtained in the same manner as in Preparation 58 using 2-(2-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 135, 3.13 g, 10.0 mmol). LCMS m/z =434 [MH] ⁺ .

Production Example 62 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (5.0 g, 99%) was obtained in a similar manner to Preparation 50 using 3-bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (Preparation 102, 7.0 g, 9.0 mmol). ¹ H NMR (CDCl ₃ .400 MHz): δ 8.66 (s, 1H), 8.62 (d, J= 2.0 Hz, 1H), 7.85 (d, J= 1.5 Hz, 1H), 6.92 (d, J= 7.3 Hz, 1H), 6.76 (d, J= 11.7 Hz, 1H), 5.52 (d, J= 9.8 Hz, 2H) , 4.55 (s, 2H), 4.00 (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] ⁺ .

Production Example 63 : 3-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine (2.1 g, 62%) was obtained according to the method , analogous to Preparation 58 using 2-(4-(difluoromethoxy)-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Production Example 142, 2.46 g, 7, 5 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.66-8.71 (m, 2H), 7.85 (d, J =2.1 Hz, 1H), 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] ⁺ .

Production Example 64 : 5'-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine

To a mixture of 5'-chloro-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (Production Example 103, 3.0 g, 10.11 mmol) and tert-butyldimethyl ((2-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Preparation Example 146, 12.1 g, 40.4 mmol) in 1,4-dioxane (300 ml ) add Xphos Pd G2 (CAS 1310584-14-5, 0.64 g, 0.81 mmol), Pd(dppf)-tBu (0.66 g, 1.01 mmol), K ₂ CO ₃ (2.79 g, 20.2 mmol) and KOAc (0.50 g, 5.06 mmol). The mixture is degassed, heated to about 70° C. for about 16 hours under N ₂ . The mixture was diluted with EtOAc (50 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to give 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy -2,3'-bipyridine (3.1 g, 71%). ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺

Production Example 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 according to in the same manner as in Preparation 58 using 2-methoxy-3-propoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 124, 3.95 g, 13.5 mmol). ¹ H NMR (CDCl ₃ .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, 1H), 7.23 (d, J= 2.0 Hz, 1H), 5.47-5.60 (m, 2H), 4.56 (t, J = 1.3 Hz, 2H), 4.03-4.08 (m, 5H), 1.90-1.99 (m, 2H), 1.04-1.13 (m, 3H), 0, 92 (s, 9H), 0.10-0.13 (m, 6H).

Production Example 66 : 5-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine

3-Bromo-5-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine (Preparation Example 87, 1.28 g, 3.7 mmol) and 2-( 3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 113, 1.25 g, 4.49 mmol), Pd(dppf)Cl ₂ (274 mg, 0.374 mmol) and K ₂ CO ₃ (1.29 g, 9.35 mmol) are suspended in 1,4-dioxane (60 ml) and water (2 ml). The mixture is degassed and heated to about 80° C. under N ₂ for about 5 hours. The mixture is concentrated and MTBE (100 ml) is added to the residue, then stirred for about 20 minutes. The mixture is filtered and the filter cake washed with MTBE (50 ml). The combined filtrates are dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0-85:15) to give 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)- 2-methylpyridine (640 mg, 41%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.54 (d, J= 2.5 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 6.94-6, 97(m, 1H), 6.85-6.88(m, 1H), 6.83-6.84(m, 1H), 5.48(d, J= 1.5Hz, 1H), 5 .43-5.45 (m, 1H), 4.52 (t, J= 1.5 Hz, 2H), 4.12 (kv, 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] ⁺ .

Production Example 67 : 4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine

To a mixture of 4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine (Preparation Example 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 (Production Example 114, 1.32 g , 4.52 mmol), K ₃ PO ₄ (3.01 g, 11.3 mmol) and Pd(dppf)Cl ₂ (0.41 g, 0.57 mmol). The mixture is degassed and heated to about 90° C. for about 5 hours under N ₂ . 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 give 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)- 6-(trifluoromethyl)pyrimidine (1.27 g, 70%). ¹ H NMR (CDCl ₃ , 400 MHz): 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), 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] ⁺

Production Example 68 : 2-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine (1.26 g, 65%) was obtained by a method similar to Preparation 50 using 2-bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine (Preparation 104, 1.5 g, 4.9 mmol). ¹ H NMR (CDCl ₃ , 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, 1H), 6.99 (d, J =8.3 Hz, 1H), 6.07 (kv, J= 1.4 Hz, 1H ), 5.77 (kv, J= 1.9 Hz, 1H), 4.80 (t, J= 1.7 Hz, 2H), 4.23 (kv, J= 7.0 Hz, 2H), 3.96 (s, 3H), 1.53 (t, J= 7.0 Hz, 3H), 0.90-0.98 (m, 9H), 0.13-0.18 (m, 6H) . LCMS m/z =401 [MH] ⁺ .

Production Example 69 : Ethyl 2-(6-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

Ethyl 2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (5.6 g, 82%) prepared in a manner analogous to Preparation 50 using ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Preparation 105, 5 g, 13 .7 mmol). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.05 (dd, J= 2.1, 8.4 Hz, 1H), 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, 1H), 4.81 (t, J= 1.6 Hz, 2H), 4.21 (kv, 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] ⁺ .

Production Example 70 : 4-(((t-butyldimethylsilyl)oxy)methyl)-6-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3 -propoxyphenyl)pyrimidine

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (1 g, 77%) was prepared in a manner analogous to Preparation 58 using 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en- 2-yl)-2-chloropyrimidine (Preparation Example 89, 2.0 g, 5.2 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (Preparation Example 114, 0.817 g, 2.8 mmol) at about 90° C. and replacing K ₃ PO ₄ (1.55 g, 5.80 mmol) with K ₂ CO ₃ . ¹ H NMR (CDCl ₃ , 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), 1.91-1.98 (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] ⁺ .

Production Example 71 : 2-(4-((t-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine

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

Production Example 72 : 5-(3-((t-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-(3-((tert-Butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine (3.0 g, 89%) was obtained by a method similar to Preparation 50 using 5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (Production Example 107, 2.2 g, 7.9 mmol) and t-butyldimethyl ((3-(4.4.5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane (Preparation Example 147, 4.9 g, 15.8 mmol). ¹ H NMR (CDCl ₃ , 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, 1H), 5.58 ( s, 1H), 5.53 (s, 1H), 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] ⁺ .

Production Example 73

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (0.8 g, 77%) was prepared according to in a manner analogous to Preparation 50 using 3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (Preparation 108, 0.81 g, 3.28 mmol) and t-butyldimethyl ((2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Preparation Example 146, 0.98 g, 3.28 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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 =7.0Hz, 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] ⁺ .

Production Example 74 : 4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole

4-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole is obtained (0.8 g, 91%) by a method similar to Preparation 50 using 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (Production Example 109, 0.68 g, 2.16 mmol) and t-butyldimethyl ((2-(4.4.5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (Preparation Example 146, 0.84 g, 2.81 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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), 4.60- 4.61(m, 1H), 4.22(kv, 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] ⁺ .

Production Example 75 : 2-((t-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)ethan-1-one

To a mixture of 1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one (Preparation Example 88, 1270 mg, 4.36 mmol), K ₂ CO ₃ (1000 mg , 7.27 mmol), KOAc (357 mg, 3.63 mmol), Pd(dppf)Cl ₂ ^. DCM (151 mg, 0.182 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (Preparation Example 114, 1200 mg, 3.633 mmol) in 1,4-dioxane (24 ml) water (2.4 ml) is added. The mixture is degassed and heated to about 90° C. for about 16 hours under N ₂ . The reaction mixture is filtered through a pad of MgSO ₄ 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 give 2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3- propoxyphenyl)pyridin-2-yl)ethan-1-one (1.21 g, 80%). ¹ H NMR (CDCl ₃ , 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] ⁺ .

Production Example 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 a manner analogous to Preparation 50 using 3-bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 100, 558 mg, 1.56 mmol) at about 100° C. for about 15 hours. ¹ H NMR (CDCl ₃ , 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 = 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, 1H), 1.43 (t, J =7.0 Hz, 3H). LCMS m/z =336 [MH] ⁺ .

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

To a solution of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (Preparation Example 78, 140 mg, 0 .30 mmol) in acetone (1.20 ml) lithium iodide (201 mg, 1.50 mmol) is added. The solution is stirred at about 50° C. for about 16 hours. The reaction mixture is cooled to about 50° C., diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to give 3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)- 5-(4-methoxy-3-propoxyphenyl)pyridine (138 mg, 92%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.74 (d, J= 2.0 Hz, 1H), 8.45 (d, J= 2.3 Hz, 1H), 7.66 (t, J= 2.0Hz, 1H), 7.08-7.17(m, 2H), 7.00(d, J= 8.2Hz, 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 (qvd, J= 7.2, 14.3 Hz, 2H), 1.49 (d, J= 18.3 Hz, 6H), 1.08 (t, J= 7.4 Hz, 3H) . LCMS m/z =498 [MH] ⁺ .

Production Example 78 : (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate

To a mixture of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol (Preparation Example 79, 128 mg, 0 .33 mmol) in DCM (7.0 ml) Me ₃ N (84 μl, 0.60 mmol) was added followed by MsCl (33 μl, 0.43 mmol). The solution was stirred at about 20° C. for about 3.5 hours. The mixture was concentrated and the residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to give (5-(5-(4 -methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (144 mg, 94%). ¹ H NMR (CDCl ₃ , 400 MHz): 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= 7.4 Hz, 3H).

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

To a solution of 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3-diol (Preparation Example 80, 406 mg, 1.17 mmol) in DCM (12 ml) 2,2-dimethoxypropane (0.43 ml, 3.51 mmol) and pTSOH (33 mg, 0.18 mmol) are added. The solution is stirred at about 40° C. for about 24 hours and at about 20° C. for about 4 days. The solution was concentrated and the residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100 gradient) to give (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl) -2,2-dimethyl-1,3-dioxan-5-yl)methanol (129 mg, 28%). ¹ H NMR (CDCl ₃ , 400 MHz): 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 (kvd, 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] ⁺ .

Production Example 80 : 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3-diol

To a solution of methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (Preparation Example 81, 250 mg, 0.67 mmol) in methanol ( 2.0 ml) add LiBH ₄ (17.5 mg, 0.80 mmol). The solution is stirred at about 20° C. for about 21 hours. The mixture is treated with saturated aqueous NH ₄ Cl and extracted with DCM. The DCM extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3 -diol (55 mg, 24%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.49 (br, 1H), 8.28 (br, 1H), 7.90 (br, 1H), 6.83-7.00 (m, 2H ), 6.77 (d, J= 8.6 Hz, 1H), 4.78 (brs, 2H), 4.04 (brs, 5H), 3.74-3.99 (m, 6H), 1 .74-1.91 (m, 2H), 1.26 (s, 1H), 1.00 (t, J = 7.4 Hz, 3H). LCMS m/z =348 [MH] ⁺ .

Production Example 81 : Methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate

Paraformaldehyde (6.81 g, 227 mmol), then DMSO (300 ml). NaOMe (2.23 g, 41.2 mmol) is added, followed by another 100 ml of DMSO. The mixture was stirred at about 20° C. for about 18 hours. The mixture was diluted with water (1200 ml) and extracted with diethyl ether and EtOAc. The combined extracts of diethyl ether and EtOAc are washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The residue is stirred with EtOH (200 ml) at about 65°C until the residue is dissolved. The solution is cooled to about 20° C. with stirring for about 2 hours. The mixture is cooled to about 0° C. (ice water bath) for another 1 hour. The mixture is filtered and the filter cake is washed with ice-cold EtOH. The combined EtOH filtrates are concentrated and the residue is purified by column chromatography (silica) eluting with EtOAc/MeOH (95:5) to give methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridine -3-yl)propanoate (5.46 g, 7%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 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 ).

Production Example 82 : 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3-diol

To an ice-cold solution of methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (Preparation Example 83, 26.4 g, 73.5 mmol) in MeOH (350 mL) add LiBH ₄ (3.2 g, 147 mmol) in 3 portions. The mixture is stirred for about 1 hour. The mixture is concentrated and diluted with DCM. The mixture is washed with 2N NaOH. The DCM layer is separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) to give 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3- diol (20.3 g, 87%). ¹ H NMR (DMSO- d ₆ , 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), 7.06 (d, J = 8.2 Hz, 1H), 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] ⁺ .

Production Example 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 (Preparation Example 84, 30.0 g, 95 mmol), paraformaldehyde (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 hours. The mixture was diluted with water (1200 ml) and extracted with diethyl ether and EtOAc. The combined extracts of diethyl ether and EtOAc are washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in hot EtOH (120 ml). The solution is cooled to about 20°C with stirring. Further cooling to about 0°C (ice bath) gave a precipitate which was filtered to give methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (15.6 g ). The filtrate was concentrated and purified by column chromatography (silica) to give an additional solid (10.8 g). The solids are combined to give methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (26.4 g, 78%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72 (d, J =2.0 Hz, 1H), 8.45 (d, J =2.3 Hz, 1H), 7.76 (t, J =2.0Hz, 1H), 7.07-7.12(m, 2H), 6.97(d, J =8.6Hz, 1H), 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, 1H), 1.67-1.95 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). LCMS m/z =346 [MH] ⁺ .

Production Example 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-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (Preparation Example 114, 84.7 g, 290 mmol) and anhydrous Na ₂ CO ₃ (51.1 g, 482 mmol) in 1,4-dioxane (700 ml) and water (180 ml) degassed and stirred at about 20°C for about 20 min under N ₂ . Pd(dppf)Cl ₂ (9.85 g, 12.1 mmol) was added to the mixture, then heated to about 85° C. for about 18 h under N ₂ . The reaction mixture is cooled to about 20°C and concentrated. The residue is partitioned between water and EtOAc. The aqueous layer is extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) eluting with heptane/EtOAc (85:15 to 40:60) to give methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (75.4 g , 88%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72 (d, J= 2.0 Hz, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.77 (t, J= 2.0Hz, 1H), 7.13(dd, J =2.3, 8.6Hz, 1H), 7.09(d, J =2.3Hz, 1H), 6.98( d, J= 8.6 Hz, 1H), 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] ⁺ .

Production Example 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 (Preparation Example 171, 10.0 g, 37.02 mmol), (3-(2-methoxy-2-oxoethyl)phenyl)boronic acid (7.18 g , 37.02 mmol), Pd(dppf)Cl ₂ (1.35 g, 1.85 mmol), KOAc (3.63 g, 37.02 mmol) and Na ₂ CO ₃ (7.85 g, 74, 04 mmol) in 1,4-dioxane (100 ml) and water (5 ml) is degassed and heated to about 90°C for about 5 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (4:1) to give methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl) acetate (12.0 g, 96 %). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 86 : 3-bromo-5-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine

tert-Butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane mixture (Production Example 146, 14.9 g, 50 mmol), 3,5-dibromopyridine (12.4 g, 52.5 mmol), Pd(dppf)Cl ₂ (1.83 g, 2.5 mmol) and K ₂ CO ₃ (20.7 g, 150 mmol) are suspended in 1,4-dioxane (300 ml) and water (20 ml). The mixture is degassed and heated to about 85° C. for about 5 hours under N ₂ . The mixture is taken out of the heat and aged over the weekend. The mixture is concentrated, MTBE (100 ml) is added and stirred for about 20 minutes. The mixture is filtered and the filter cake washed with MTBE (50 ml). The combined MTBE filtrates are dried and concentrated. The residue was purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:0 to 95:5) to give 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (8.5 g, 51, 8%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.55-8.63 (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] ⁺ .

Production Example 87 : 3-bromo-5-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine

tert-Butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane mixture (Production Example 146, 4.2 g, 14.08 mmol ), 3,5-dibromo-2-methylpyridine (3.71 g, 14.8 mmol), Pd(dppf)Cl ₂ (1030 mg, 1.41 mmol) and K ₂ CO ₃ (5.84 g, 42 .2 mmol) is suspended in 1,4-dioxane (150 ml) and water (5 ml). The mixture is degassed and heated to about 80° C. for about 5 hours under N ₂ . The mixture is concentrated and MTBE (100 ml) is added with stirring for about 20 minutes. The mixture is filtered and the filter cake washed with MTBE (50 ml). The combined MTBE filtrates are concentrated and the residue is purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:0 to 95:5) to give 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine (930 mg, 19 .3%). ¹ H NMR (CDCl ₃ , 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).

Production Example 88 : 1-(6-bromopyridin-2-yl)-2-((t-butyldimethylsilyl)oxy)ethan-1-one

A solution of 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one (Preparation Example 237, 977 mg, 4.52 mmol) and DCM (30 mL) was cooled to about 0°C, imidazole (770 mg, 11.3 mmol) and TBS-Cl (750 mg, 4.97 mmol). The mixture is stirred at about 0° C. for about 2.5 hours. The reaction mixture is quenched with water and the layers are separated. The DCM layer was washed with water and brine. DCM layer is passed through a layer of MgSO ₄ and silica gel. The filtrate was concentrated to give 1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one (1.35 g, 90%). ¹ H NMR (CDCl ₃ , 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).

Production Example 89 : 4-(((t-butyldimethylsilyl)oxy)methyl)-6-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine (0.9 g, 34%) prepared in a manner analogous to Preparation 50 using 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine (Preparation 230, 1.65 g, 5.5 mmol) and K ₃ PO ₄ in as a basis. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.63 (s, 1H), 6.23 (d, J= 1.5 Hz, 1H), 5.87 (d, J= 1.5 Hz, 1H), 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] ⁺ .

Production Example 90 : 4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine

4-(3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine (1.33 g, 66%) was prepared in a manner analogous to Preparation Example 50 using 2,4-dichloro-6-(trifluoromethyl)pyrimidine (CAS 16097-64-6, 1.24 g, 5.72 mmol) and replacing K ₃ PO ₄ (4.57 g, 17.1 mmol) to K ₂ CO ₃ . ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

Preparation Example 91a : 3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-5-(3,4-dimethoxyphenyl)pyridine mixture (Preparation 91b, 12.20 g, 41.48 mmol), Pin ₂ B ₂ (21.07 g, 82.96 mmol), KOAc (8 .14 g, 82.96 mmol) and Pd(dppf)Cl ₂ (607 mg, 830 μmol) in 1,4-dioxane (500 ml) are degassed and stirred at about 110° C. for about 4 h under N ₂ . The mixture was concentrated and the residue was purified by column chromatography (silica) eluting with pet. ether/EtOAc (100:1 to 10:1) to give 3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.00 g, 42%). ¹ H NMR (CDCl _3, 400 MHz): δ 8.97 (d, J =2.3 Hz, 1H), 8.71 (d, J =1.0 Hz, 1H), 8.14 (s, 1H), 7.27 (s, 1H), 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).

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

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), Na ₂ CO ₃ (10.92 g, 103.0 mmol), KOAc (10.11 g, 103.03 mmol) and Pd(dppf)Cl ₂ (1.01 g, 1.37 mmol) in 1,4-dioxane (20 ml) degassed and stirred at about 90°C for about 8 hours under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (20:1 to 1:1) to give 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (20.2 g, 59%). ¹ H NMR (DMSO- d _{6 ,} 400 MHz): δ 8.88 (d, J =1.8 Hz, 1H), 8.61 (d, J =1.8 Hz, 1H), 8.35 ( t, J = 2.0 Hz, 1H), 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] ⁺ .

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

2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane mixture (Preparation Example 113, 20.0 g, 71.9 mmol), 3,5- dibromopyridine (34.07 g, 143.8 mmol), K ₂ CO ₃ (19.87 g, 143.8 mmol), KOAc (10.58 g, 107.9 mmol) and Pd(dppf)Cl ₂ (2 , 10 g, 2.88 mmol) in 1,4-dioxane (600 ml) and water (10 ml) is degassed and heated to about 100° C. for about 5 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to give 3-bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine (20 g, 90%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 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 (kv, J= 6.8 Hz, 2H), 3.92 (s, 3H), 1.49 (t, J= 6.8 Hz, 3H).

Preparation Example 93a : 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 114, 28.00 g, 95.83 mmol), 3,5-dibromopyridine (45.40 g, 191.66 mmol), K ₂ CO ₃ (19.87 g, 143.75 mmol), KOAc (14.11 g, 143.75 mmol) and Pd(dppf)Cl ₂ (3, 51 g, 4.79 mmol) in 1,4-dioxane (600 ml) and water (10 ml) are degassed and heated to about 100° C. for about 5 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (5:1) to give 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine (15.00 g, 49%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72 (d, J= 2.0 Hz, 1H), 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, 1H), 6.98 ( d, J= 8.4 Hz, 1H), 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).

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

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 114, 10.6 g, 36.3 mmol), 2,6-dibromopyridine (9.0 g, 38.0 mmol), K ₃ PO ₄ (16.1 g, 76.0 mmol) and Pd(dppf)Cl ₂ (1.55 g, 1.90 mmol) in dioxane (6 ml ) and water (1.5 ml) degassed and heated to about 80° C. overnight. The mixture was diluted with brine (150 ml) and EtOAc (150 ml). The layers are separated and the EtOAc layer is washed with brine (75 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 3:1) to give 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine (5.34 g, 44%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.81-8.72 (m, 2H), 7.51-7.57 (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).

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

3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (1.15 g, 52%) was prepared in a similar manner to Preparation 93a using 2-(3-isopropoxy-4-methoxyphenyl)-4.4 ,5,5-Tetramethyl-1,3,2-dioxaborolane (Preparation Example 115, 2 g, 6.8 mmol) at about 120° C. for about 2 hours. ¹ H NMR (CDCl ₃ , 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] ⁺ .

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

3-Bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (860 mg, 52%) was prepared in a similar manner to Preparation 93a using 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolane (Preparation Example 117, 1.5 g, 5.2 mmol) at about 120° C. for about 2 hours. ¹ H NMR (CDCl ₃ , 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] ⁺ .

Production Example 96 )ethoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)- 4-Methoxyphenyl)pyridine (6.8 g, 32%) was prepared in a similar manner to Preparation 93a using t-butyl(2-(2-methoxy-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)ethoxy)dimethylsilane (Preparation Example 120, 20 g, 49 mmol) at about 120° C. for about 3 hours. ¹ H NMR (CDCl ₃ , 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 (kvd, 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] ⁺ .

Production Example 97 : 3-bromo-5-(3-(3-((t-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (12.4 g, 64%) was prepared in a similar manner to Preparation 93a using tert-butyl (3-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane (Preparation Example 121, 18 g, 42.6 mmol ). ¹ H NMR (CDCl ₃ , 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= 2.0 Hz, 1H), 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] ⁺ .

Production Example 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 a manner analogous to Preparation 93a using 2-(3-(2-fluoroethoxy)- 4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 122, 2.2 g, 7.4 mmol) at about 120°C for about 2 hours ¹ H NMR (CDCl ₃ , 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, 1H), 4.72-4.81 (m, 1H), 4.37-4.44 (m, 1H), 4.25-4.36 (m, 1H), 3.88-3.97 (m, 3H). LCMS m/z =325 [MH] ⁺ .

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

3-Bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared in a manner analogous to Preparation 93a using 2-(3-(3-fluoropropoxy)-4-methoxyphenyl)-4,4, 5,5-tetramethyl-1,3,2-dioxaborolane (Production Example 123)

Preparation Example 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 a manner analogous to Preparation 93a using 2-(2-(difluoromethyl)-3- ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 127, 4.09 g, 12.46 mmol) heated to about 100° C. for about 15 hours ¹ H NMR (400 MHz, CDCl ₃ ): 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 (kv, J= 7.4 Hz, 2H), 3.93 (s, 3H), 1 .42 (t, J= 7.0 Hz, 3H). LCMS m/z =359 [MH] ⁺ .

Production Example 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 in a manner analogous to Preparation 93a using 2-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 134, 1.2 g, 4.05 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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 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] ⁺ .

Preparation Example 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 in a manner analogous to Preparation 93a using 2-(2-fluoro-4-methoxy- 5-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 138, 10 g, 32 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.68 (t, J= 1.5 Hz, 1H), 8.63 (d, J= 2.4 Hz, 1H), 7.99 (q, J= 2.0 Hz, 1H), 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] ⁺ .

Production Example 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 a manner analogous to Preparation 93a using 3-fluoro-2-iodo- 5-methoxy-6-propoxypyridine (Preparation Example 220, 4.18 g, 13.44 mmol) and (5-chloropyridin-3-yl)boronic acid (2.11 g, 13.4 mmol) at about 90°C ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

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

2-Bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine (2.9 g, 52%) was prepared in a similar manner to Preparation 93a using 2-(3-ethoxy-2-fluoro-4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 113.5 g, 18 mmol) and 2,6-dibromopyrazine (6.4 g, 27 mmol) at about 110° C. ¹ H NMR (CDCl ₃ , 400 MHz): 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 (kv, J= 6 .9 Hz, 2H), 3.95 (s, 3H), 1.53 (t, J= 7.0 Hz, 3H). LCMS m/z =309 [MH] ⁺ .

Production Example 105 : Ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

POCl ₃ (253 ml, 2716 mmol) was added to ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate (Production Example 106, 42.98 g, 124.08 mmol), then pyridine hydrochloride (14.3 g, 124 mmol) at about 25°C. The resulting mixture is heated to about 80° C. for about 0.5 h. The mixture is diluted with EtOAc (200 ml) and added dropwise to water. The EtOAc layer is treated with NaHCO ₃ . The EtOAc layer was washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase column chromatography eluting with MeCN/water (0:100 to 100:0) to give ethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl) acetate (22.07 g, 49%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 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] ⁺ .

Production Example 106 : Ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate

A mixture of 4-methoxy-3-propoxybenzimidamide (Preparation Example 233, 25.3 g, 121 mmol), NaHCO ₃ (12.2 mg, 146 mmol) and diethyl 1,3-acetone dicarboxylate (CAS 105-50-0, 29, 4 g, 146 mmol) in EtOH (500 ml) was stirred at about 100°C for about 24 hours. The mixture was filtered and the filter cake washed with MTBE (200 ml), MeOH (100 ml) and DCM (50 ml) to obtain ethyl 2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate (34.34 g, 82%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 12.44 (br, 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), 1.92-1.97 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.10 (t, J= 7.5 Hz , 3H). LCMS m/z =346 [MH] ⁺ .

Preparation Example 107 : 5-Chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-Chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (2.9 g, 52%) was prepared in a similar manner to Preparation 93a using 2-(4-methoxy-3-propoxyphenyl)-4.4 ,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 114, 4.3 g, 14.7 mmol) and 3,5-dichloropyridazine (2.3 g, 15.5 mmol). ¹ H NMR (CDCl ₃ , 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] ⁺ .

Preparation Example 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 a manner analogous to Preparation 93a using 2-(3-ethoxy-4-methoxyphenyl)- 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (Preparation Example 113, 2.0 g, 7.19 mmol) and 3,5-dibromo-4-methylpyridine (2.71 g, 10 8 mmol) at about 120° C. for about 2 hours. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.61 (s, 1H), 8.32 (s, 1H), 6.94 (d, J =8.0Hz, 1H), 6.81-6.83(m, 1H), 6.78(d, J =2.3Hz, 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] ⁺ .

Preparation Example 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 approx. 10 minutes, add 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 113, 1.0 g, 3.60 mmol), 2,4-dibromothiazole (0.83 g, 3.42 mmol) and K ₃ PO ₄ (2.44 g, 11.5 mmol). The combined mixture is degassed and heated to about 60° C. for about 16 hours. The mixture is concentrated and the residue is purified by column chromatography (silica) eluting pet. ether: EtOAc (100:0 to 85:15) to give 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (0.68 g, 60%). ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

Production Example 110 : Ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-1,3,2-dioxaborolane (187 mg , 1.06 mmol) and stirred at about 20° C. for about 30 minutes. The mixture is filtered through a pad of Celite® and the filtrate is concentrated. The residue is dissolved and concentrated with anhydrous THF (3×5 ml). The residue was dissolved in THF (6.0 mL) and added to a cold suspension of NaH (60% dispersion in mineral oil, 349 mg, 8.73 mmol) and ethyl 2-(6-bromopyridin-2-yl)propanoate (Production Example 111 , 1.502 g, 5.819 mmol) in THF (13.0 ml) which is degassed under N ₂ . The combined mixture was stirred at about 20° C. for about 18 hours. The mixture was treated with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined EtOAc extracts are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in DMSO (5 ml) and purified by preparative HPLC (Biotage C18 RP column, 60 g) eluting with MeCN (0.1% NH ₄ CO ₂ H)/water (0:100 to 100:0) to give ethyl 2- (6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (339 mg, 14%). ¹ H NMR (CDCl ₃ , 500 MHz): δ 7.44-7.48 (m, 1H), 7.31 (m, 1H), 7.25-7.29 (m, 2H), 4.15 (kv, 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] ⁺ .

Preparation Example 111 : Ethyl 2-(6-bromopyridin-2-yl)propanoate

To a solution of ethyl 2-(6-bromopyridin-2-yl)acetate (Preparation Example 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 is stirred for about 1 hour and iodomethane (3.33 g, 23.4 mmol, 1.46 ml) is added dropwise. The reaction mixture is heated to about 20° C. for about 19 hours. The reaction mixture is diluted with EtOAc. The mixture was washed with saturated aqueous NH ₄ Cl, brine, dried over MgSO ₄ and Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 80:20) to give ethyl 2-(6-bromopyridin-2-yl)acetate (5.06 g, 84%). ¹ H NMR (CDCl ₃ , 400 MHz,): 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, 1H), 1.57 (d, J= 7.4 Hz, 3H), 1.25 (t, J= 7.0 Hz, 3H). LCMS m/z =259 [MH] ⁺ .

Preparation Example 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 N ₂ was added a solution of DAL in THF (2 .0 M, 59 ml, 118 mmol) with slow stirring. The solution is stirred at about -78° C. for about 30 minutes. Diethyl carbonate (8.6 ml, 70.9 mmol) was added to the mixture at about -78°C. The mixture is heated to about 20°C overnight. The reaction mixture is cooled to about 0°C and diluted with saturated aqueous NH ₄ Cl. The aqueous layer is extracted with DCM and the combined DCM extracts are washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 60:40) to give ethyl 2-(6-bromopyridin-2-yl)acetate (7.7 g, 53%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.55 (t, J= 7.8 Hz, 1H), 7.42 (d, J= 8.2 Hz, 1H), 7.28-7 .34 (m, 1H), 4.21 (q, J= 7.2 Hz, 2H), 3.85 (s, 2H), 1.26-1.34 (m, 3H). LCMS m/z =245 [MH] ⁺ .

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

4-Bromo-2-ethoxy-1-methoxybenzene mixture (Preparation Example 150, 48.0 g, 207.7 mmol), Pd(dppf)Cl ₂ (4.56 g, 6.23 mmol), Pin ₂ B ₂ (58.0 g, 228.5 mmol) and KOAc (40.8 g, 415.4 mmol) in 1,4-dioxane (500 ml) are degassed and heated to about 90°C for about 16 h under N ₂ . The mixture is filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 g, 86%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

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

4-Bromo-1-methoxy-2-propoxybenzene mixture (Preparation Example 151, 43.00 g, 175.43 mmol), KOAc (34.43 g, 350.86 mmol), Pin ₂ B ₂ (49.00 g , 192.97 mmol) and Pd(dppf)Cl ₂ ^. DCM (4.30 g, 5.26 mmol) in 1,4-dioxane (500 mL) was degassed and stirred at about 80° C. for about 16 hours. 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 give 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51.0 g, 99%). ¹ H NMR (CDCl _3, 400 MHz): δ 7.40-7.42 (m, 1H), 7.30 (d, J= 1.2 Hz, 1H), 6.89 (d, J= 8 .0 Hz, 1H), 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= 7.4 Hz, 3H).

The following compounds are prepared using the appropriate bromide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) by the method described in Get example 114 .

Receipt Example No. Structure/name Source Analytical data 115

2-(3-изопропокси-4-метоксифенил)-4,4,5,5-тетраметил-1,3,2-диоксаборолан

2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 152 ¹ H NMR (CDCl ₃ , 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

2-(3-isobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 153 ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.41 (dd, J= 1.2, 8.1 Hz, 1H), 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 ), 1.33-1.37 (m, 12H), 1.05 (d, J= 6.4 Hz, 6H). LCMS m/z =307 [MH] ⁺ . 117

2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 154 ¹ H NMR (CDCl ₃ , 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] ⁺ . 118

2-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 155 ¹ H NMR (CDCl ₃ , 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, 39-2.47 (m, 1H), 2.04-2.07 (m, 1H), 1.34 (s, 12H). LCMS m/z =337 [MH] ⁺ . 119

2-(4-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 156 ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.41-7.48 (m, 1H), 7.32 (d, J= 1.5 Hz, 1H), 6.86-6.93 (m , 1H), 4.26-4.37(m, 1H), 3.86(s, 3H), 2.87-3.01(m, 2H), 2.51-2.62(m, 2H ), 2.13-2.25 (m, 2H), 1.98-2.10 (m, 2H), 1.29-1.36 (m, 12H). 120

tert-butyl (2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)dimethylsilane Receiving Example 157 ¹ H NMR (CDCl ₃ , 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), 0.90-0.92 (m, 9H), 0.09-0.11 (m, 6H). LCMS m/z =409 [MH] ⁺ . 121

tert-Butyl(3-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane Receiving Example 158 ¹ H NMR (CDCl ₃ , 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), 0.05-0.06 (m, 6H). LCMS m/z =423 [MH] ⁺ . 122

2-(3-(2-fluoroethoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 159 ¹ H NMR (CDCl ₃ , 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), 4.34-4.38(m, 1H), 4.27-4.31 (m, 1H), 3.90 (s, 3H), 1.34 (s, 12H). LCMS m/z = 297 [MH] ⁺ . 123

2-(3-(3-fluoropropoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 160 ¹ H NMR (CDCl ₃ , 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), 2.20-2.23 (m, 1H), 1.32 -1.37 (m, 12H). LCMS m/z = 311[MH] ⁺ . 124

2-methoxy-3-propoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Receiving example 215 ¹ H NMR (CDCl ₃ , 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), 1.85-1.94 (m, 2H), 1.35 (s, 12H), 1.05 (t, J= 7.5 Hz , 3H). LCMS m/z =294 [MH] ⁺ . 125

2,3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile Receiving example 162 1H NMR (CDCl ₃ , 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

2-(3-ethoxy-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 170a ¹ H NMR (CDCl ₃ , 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

2-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 168 ¹ H NMR (CDCl _3, 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). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -114.25 (br, 1F). LCMS m/z =296 [MH] ⁺ . 128

2-(2-fluoro-4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receive example 170b LCMS m/z =311 [MH] ⁺ . 129

3-methoxy-2-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile Receiving Example 171 ¹ H NMR (CDCl _3, 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), 1.03-1.08 ( m, 3H). LCMS m/z =318 [MH] ⁺ . 130

2-(2,4-dimethoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 210 ¹ H NMR (CDCl _3, 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), 3.82-3.87 (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

2-(cyclopentyloxy)-3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile Receiving Example 207 ¹ H NMR (CDCl _3, 400 MHz): δ 7.52 (d, J= 8.3 Hz, 1H), 7.00-7.10 (m, 1H), 4.98-5.11 (m , 1H), 3.88 (s, 3H), 1.91-2.01 (m, 4H), 1.65-1.76 (m, 2H), 1.53-1.64 (m, 2H ), 1.37 (s, 12H). LCMS m/z =344 [MH] ⁺ . 132

2-(3-ethoxy-5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 172 ¹ H NMR (CDCl _3, 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

2-(3-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 177 ¹ H NMR (CDCl _3, 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

2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 182 ¹ H NMR (CDCl _3, 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

2-(2-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 183 ¹ H NMR (CDCl _3, 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] ⁺ . 136

2-(5-ethoxy-4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 187 ¹ H NMR (CDCl _3, 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

2-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 193 ¹ H NMR (CDCl _3, 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

2-(2-fluoro-4-methoxy-5-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 188 ¹ H NMR (CDCl ₃ , 400 MHz): 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

2-(4-ethoxy-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 198 ¹ H NMR (CDCl _3, 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] ⁺ . 140

2-(4-ethoxy-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 199 ¹ H NMR (CDCl _3, 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

2-(3,4-diethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving Example 197 ¹ H NMR (400 MHz, CDCl ₃ ) 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

2-(4-(difluoromethoxy)-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 223 ¹ H NMR (CDCl _3, 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

2-(3-methoxy-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receiving example 203 ¹ H NMR (CDCl _3, 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] ⁺ . 144

2-(3-ethoxy-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receive example 204 ¹ H NMR (MeOD- d ₃ , 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

2-(3-(cyclopentyloxy)-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receive example 205 ¹ H NMR (CDCl _3, 400 MHz): δ 7.39 (dd, J= 1.0, 7.8 Hz, 1H), 7.22 (s, 1H), 7.06-7.11 (m , 1H), 4.94-4.98 (m, 1H), 2.41 (s, 3H), 1.82-1.96 (m, 6H), 1.61-1.67 (m, 2H ), 1.32-1.37 (m, 12H). LCMS m/z =335 [MH] ⁺ .

Production Example 146 : tert-Butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane

Method A:

Five reactions are carried out in parallel. Mixture of ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane (Preparation Example 227, 300 g, 1.19 mol), KOAc (234 g, 2.39 mol), 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (333 g, 1.31 mol) and Pd(PPh ₃ ) ₂ Cl ₂ (16.7 g , 0.023 mol) in 1,4-dioxane (1.5 L) is degassed and stirred at about 80° C. for about 16 hours. The solids are removed by filtration and the filtrate is concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (1:0) to give tert-butyldimethyl((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 µm film thickness; injection temperature 250°C; split ratio 100:1; ion source temperature 230°C; cutoff temperature. 250°C ; column temperature 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 ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Method B:

To a mixture of tert-butyldimethyl (prop-2-in-1-yloxy)silane (250 mg, 1.47 mmol), sodium tert-butoxide (21.2 mg, 0.220 mmol), 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 N ₂ is added dropwise a solution of tBu ₃ P (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 dropwise to the mixture and the mixture was stirred at about 20° C. overnight. The reaction mixture 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 give tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane ( 2.2 g, 50%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.97 (br s, 1H), 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).

Production Example 147 : tert-Butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane

To a mixture of (but-3-yn-2-yloxy)(tert-butyl)dimethylsilane (CAS 193812-02-1, 10 g, 54.24 mmol), sodium tert-butoxide (782 mg, 8.41 mmol), copper chloride (I) (537 mg, 5.42 mmol) and Pin ₂ B ₂ (15.2 g, 59.7 mmol) in toluene (120 ml) under N ₂ add a solution of tBu ₃ P (13.2 g, 6.51 mmol) in anhydrous toluene (10 ml) dropwise. MeOH (3.48 g, 108 mmol) is added dropwise and the mixture is stirred at about 20° C. for about 16 hours. The reaction mixture is 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 give tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en- 2-yl)oxy)silane (8.2 g, 48.4%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.88-6.02 (m, 1H), 5.79 (dd, J= 1.5, 3.5 Hz, 1H), 4.40-4 .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).

Production Example 148 : tert-Butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane

Mixture of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (Preparation Example 229, 2.0 g, 7.54 mmol), Pin ₂ B ₂ (2.87 g, 11 .3 mmol) and KOAc (0.74 g, 7.54 mmol) are suspended in anhydrous 1,4-dioxane (10 ml). The mixture is degassed for about 10 minutes at about 18° C. under N ₂ . Pd(PPh ₃ ) ₂ Cl ₂ (106 mg, 0.15 mmol) is added and the mixture is heated to about 90°C for 16 hours. The reaction mixture is cooled to about 20°C and filtered. The filter cake is washed with 1,4-dioxane and the combined filtrates are concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 80:20) to give t-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)but-3-en-1-yl)oxy)silane (1.15 g, 49%). LCMS m/z =313 [MH] ⁺ .

Preparation Example 149 : 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-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) is suspended in DMF (150 ml) under N ₂ . Additional lithium methoxide (5.0 g, 2.43 ml) in DMF (10 ml) was added to the mixture. The reaction mixture is heated to about 40°C and stirred for about 48 h under N ₂ . The solution is cooled to about 20°C and extracted with heptane (3×300 ml). The heptane extracts were washed with water (100 ml), brine (100 ml) and passed through a pad of MgSO ₄ and silica gel. The layer was washed with DCM (100 ml). The combined filtrates are concentrated. The residue was purified by column chromatography (silica) and eluted with DCM to give 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3,6 d, 48%) ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.23 (d, J= 3.1 Hz, 24H), 1.05 (d, J= 7.4 Hz, 3H), 0.72 (kv, J= 7.0 Hz, 1H).

Preparation Example 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 Cs ₂ CO ₃ (96.3 g, 295.5 mmol) in DMF (350 ml) was stirred at about 25° C. for about 16 hours. The mixture was filtered and water (500 ml) was added to the filtrate. The mixture is extracted with EtOAc (2×400 ml). The combined EtOAc extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 4-bromo-2-ethoxy-1-methoxybenzene (48.0 g) which is used immediately in the next step. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.02 (dd, J= 2.4, 8.4 Hz, 1H), 6.98 (d, J= 2.4 Hz, 1H), 6, 76-6.73(m, 1H), 4.08(kv, J= 7.2Hz, 2H), 3.88(s, 3H), 1.47(t, J= 7.2Hz, 3H ).

Preparation Example 151 : 4-bromo-1-methoxy-2-propoxybenzene

To a solution of 5-bromo-2-methoxyphenol (40.0 g, 197.0 mmol) and K ₂ CO ₃ (54.5 g, 394 mmol) in DMF (200 ml), 295 mmol) in portions at about 20°C. The mixture was stirred at about 20° C. for about 1 hour. The mixture was poured into ice water (500 ml) and extracted with EtOAc (3×300 ml). The combined EtOAc extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (40:1) to give 4-bromo-1-methoxy-2-propoxybenzene (43.0 g, crude). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.27 (s, 1H), 6.99-7.03 (m, 1H), 6.74 (d, J= 8.4 Hz, 1H), 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).

Preparation Example 152 : 4-bromo-2-isopropoxy-1-methoxybenzene

4-Bromo-2-isopropoxy-1-methoxybenzene (16 g, 95%) was prepared in a manner analogous to Preparation 150 using 2-bromopropane (12.7 g, 103.4 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.00-7.05 (m, 2H), 6.75 (d, J= 8.3 Hz, 1H), 4.50-4.54 (m , 1H), 3.83 (s, 3H), 1.35-1.40 (m, 6H). LCMS m/z =245 [MH] ⁺ .

Production Example 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), PPh ₃ (48.4 g, 185 mmol) in anhydrous DCM (400 ml) at about 0°C add DIAD (37.3 g, 185 mmol) dropwise under N ₂ . The mixture is stirred at about 0° C. for about 2 hours. Additional DIAD (2.53 g, 12.5 mmol) and 2-methylpropan-1-ol (1.03 g, 13.9 mmol) are added and the mixture is stirred at about 10°C for about 5 days, then filtered. The filtrate is concentrated under reduced pressure. MTBE (500 ml) is added and the mixture is stirred at about 10° C. for about 20 minutes. The white precipitate is filtered off. The filtrate is concentrated. The residue is dissolved in water (200 ml) and extracted with MTBE (2×300 ml). The combined MTBE extracts are concentrated and the residue is purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:1 to 90:10) to give 4-bromo-2-isobutoxy-1-methoxybenzene (22 g, 69%). ¹ H NMR (CDCl ₃ , 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= 6.5Hz, 6H).

Preparation Example 154 : 4-bromo-2-cyclopropoxy-1-methoxybenzene

4-Bromo-2-cyclopropoxy-1-methoxybenzene (6.15 g, 64%) was prepared in a similar manner to Preparation 150 using bromocyclopropane (8.0 g, 39 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.36 (d, J= 2.5 Hz, 1H), 7.05 (dd, J= 2.5, 8.5 Hz, 1H), 6, 74 (d, J= 8.5 Hz, 1H), 3.84 (s, 3H), 3.70-3.77 (m, 1H), 0.80-0.90 (m, 4H).

Production Example 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), PPh ₃ (3.10 g, 11.8 mmol) in anhydrous DCM (20 ml) at about 0°C add DIAD (2.39 g, 11.8 mmol) dropwise under N ₂ . The mixture is stirred at about 0° C. for about 2 hours. The mixture is stirred for about 3 days. The mixture is filtered and the filtrate is concentrated. MTBE (50 ml) was added to the residue and stirred at about 10° C. for about 20 minutes. The white precipitate is filtered off. The filtrate is again concentrated. The residue is dissolved in water (20 ml) and extracted with MTBE (2×30 ml). The combined MTBE extracts are concentrated and the residue is purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:1 to 90:10) to give 3-(5-bromo-2-methoxyphenoxy)tetrahydrothiophene (2.0 g, 88%). ¹ H NMR (CDCl ₃ , 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).

Preparation Example 156 : 4-(5-bromo-2-methoxyphenoxy)tetrahydro-2H-thiopyran

4-(5-Bromo-2-methoxyphenoxy)tetrahydro-2H-thiopyran (5.1 g, 68%) was prepared in a similar manner to Preparation 155 using tetrahydro-2H-thiopyran-4-ol (3.2 g, 27.1 mmol). ¹ H NMR (CDCl ₃ , 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).

Production Example 157 : (2-(5-bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane

(2-(5-Bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane (60 g, 86%) was prepared in a similar manner to Preparation 155 using 2-((tert-butyldimethylsilyl)oxy)ethane-1 -ola (34 g, 190 mmol). ¹ H NMR (CDCl ₃ , 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).

Production Example 158 : (3-(5-bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane

(3-(5-Bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane (19.8 g, 86%) was prepared in a similar manner to Preparation 155 using 3-((tert-butyldimethylsilyl)oxy)propane -1-ol (Preparation Example 236, 12.5 g, 61.6 mmol). ¹ H NMR (CDCl ₃ , 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).

Production Example 159 : 4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene

4-Bromo-2-(2-fluoroethoxy)-1-methoxybenzene (12 g, 98%) was prepared in a manner analogous to Preparation 155 using 2-fluoroethan-1-ol (3.79 g, 59 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.08 (dd, J= 2.5, 8.8 Hz, 1H), 7.03 (d, J= 2.5 Hz, 1H), 6, 75-6.79 (m, 1H), 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).

Production Example 160 : 4-bromo-2-(3-fluoropropoxy)-1-methoxybenzene

4-Bromo-2-(3-fluoropropoxy)-1-methoxybenzene (10 g, 100%) was prepared in a similar manner to Preparation 155 using 3-fluoropropan-1-ol (3.69 g, 47.3 mmol) . ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.03-7.07 (m, 1H), 7.01-7.03 (m, 1H), 6.75 (d, J= 8.3 Hz , 1H), 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).

Preparation Example 161 : 1-bromo-2-fluoro-3,4-dimethoxybenzene

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 N ₂ . The reaction mixture was quenched with water (300 ml) and extracted with DCM (2×300 ml). The combined DCM extracts were washed with brine (2×100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 1-bromo-2-fluoro-3,4-dimethoxybenzene (35.0 g, 66%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.17-7.21 (m, 1H), 6.60-6.63 (m, 1H), 3.93 (s, 3H), 3.87 (s, 3H).

Preparation Example 162 : 6-bromo-2,3-dimethoxybenzonitrile

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde oxime (Preparation Example 163, 30.0 g, 115 mmol) in DCM (500 ml) was added TFAA (24.0 ml, 173 mmol) and Et ₃ N (48.0 ml, 346.0 mmol). The mixture was stirred at about 20° C. for about 2 hours. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1 to 3:1) to give 6-bromo-2,3-dimethoxybenzonitrile (25.0 g, 90%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.34-7.29 (m, 1H), 6.99 (d, J= 8.8 Hz, 1H), 4.04-4.01 (m , 3H), 3.90-3.88 (m, 3H).

Production Example 163 : 6-bromo-2,3-dimethoxybenzaldehyde oxime

NaHCO ₃ (7.7 g, 91.8 mmol) and NH ₂ OH ∙HCl (6.4 g, 91.8 mmol). The mixture was stirred at about 20° C. for about 2 hours. The mixture was quenched by adding water (300 ml) at about 0° C. and extracted with EtOAc (200 ml). The EtOAc layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 6-bromo-2,3-dimethoxybenzaldehyde oxime (15.0 g) which was used in Preparation 162. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 164 : 6-bromo-2,3-dimethoxybenzaldehyde

6-Bromo-2,3-dimethoxybenzaldehyde (35.0 g, 82.5%) was prepared in a manner analogous to Preparation 172 using 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Preparation 165, 40 g, 173 .1 mmol) and iodomethane (36.8 g, 259.7 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 165 : 6-bromo-2-hydroxy-3-methoxybenzaldehyde

To a solution of 3-bromo-2-formyl-6-methoxyphenyl acetate (Production Example 166, 40.0 g, 146.5 mmol) in MeOH (400 ml) and water (50 ml) was added NaHCO ₃ 161.1 mmol) and LiOH (12.3 g, 293.0 mmol). The mixture is stirred at about 20° C. for about 12 hours. The reaction mixture is adjusted to pH 5-6 and extracted with DCM. The DCM layer was concentrated to give 6-bromo-2-hydroxy-3-methoxybenzaldehyde (40.0 g) which was used in Preparation 164. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 166 : 3-bromo-2-formyl-6-methoxyphenyl acetate

To a solution of 2-formyl-6-methoxyphenyl acetate (Production Example 167, 50.0 g, 257.5 mmol) in water (500 ml) were added Br ₂ (53.5 g, 334.7 mmol) and KBr (46, 0 g, 386.2 mmol). The mixture is stirred at about 20° C. for about 10 hours. The precipitate is filtered off, washed with ethyl acetate and recrystallized with EtOAc/pet. ether to give 3-bromo-2-formyl-6-methoxyphenyl acetate (40.0 g, 57%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.28 (s, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 3.87 (s, 3H), 2.40 (s, 3H).

Production Example 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 Ac ₂ O (33.5 g, 329 mmol), DMAP (4.0 g, 32.8 mmol) and Et ₃ N (33.2 g, 329 mmol). The mixture was stirred at about 20° C. for about 2 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with DCM (2×100 ml). The combined DCM extracts were washed with HCl (100 ml, 1 M), brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 2-formyl-6-methoxyphenyl acetate (60.0 g, 94%) . ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 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 (Production Example 169, 4.64 g, 17.9 mmol) in DCM (20 ml) at about -20°C. The reaction mixture is heated to about 25°C for 0.5 h and then at about 25°C for _about 15 h. 100 ml). The combined DCM extracts are concentrated and the residue is purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 97:3) to give 1-bromo-2-(difluoromethyl)-3-ethoxy-4-methoxybenzene (4.77 g, 95%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.31 (d, J =8.8 Hz, 1H), 7.10 (t, J =54.0 Hz, 1H), 6.87 (d, J =8.8Hz, 1H), 4.11(kv, J =7.0Hz, 2H), 3.87(s, 3H), 1.40(t, J =7.0Hz, 3H) .

Production Example 169 : 6-bromo-2-ethoxy-3-methoxybenzaldehyde

To a mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Production Example 165.5 g, 21.64 mmol) and K ₂ CO ₃ (5.98 g, 43.3 mmol) in MeCN (100 ml) was added iodoethane (16.9 g, 108 mmol). The mixture is heated to 60° C. and stirred for 4 h, then heated to 100° C. for 19 h. The mixture is cooled to rt. and condense under reduced pressure. The residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to give 6-bromo-2-ethoxy-3-methoxybenzaldehyde (5.1 g, 92%) as a light yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 170a : 1-bromo-3-ethoxy-2-fluoro-4-methoxybenzene

1-Bromo-3-ethoxy-2-fluoro-4-methoxybenzene (25 g, 58%) was prepared in a similar manner to Preparation 155 using 3-bromo-2-fluoro-6-methoxyphenol (38 g, 170 mmol) and iodoethane (40.2 g, 258 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 170b : 1-bromo-2-fluoro-4-methoxy-3-propoxybenzene

1-bromo-2-fluoro-4-methoxy-3-propoxybenzene (10.2 g, 57%) was prepared in a manner analogous to Preparation 155 using 3-bromo-2-fluoro-6-methoxyphenol (15 g, 68. 2 mmol) and 1-bromopropane (10.8 g, 88.6 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 171 : 6-bromo-3-methoxy-2-propoxybenzonitrile

6-Bromo-3-methoxy-2-propoxybenzonitrile (10.9 g, 92%) was prepared in a similar manner to Preparation 155 using 6-bromo-2-hydroxy-3-methoxybenzonitrile (10 g, 44 mmol) and 1-bromopropane (7 g, 57 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

Production Example 172 : 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene

K ₂ CO ₃ (2.07 g, 15 mmol). The mixture is heated to about 50° C. and stirred for about 5 hours. The mixture is cooled to about 20° C. and filtered. The filtrate was concentrated and the residue was triturated with MTBE (20 ml) for about 20 minutes. The mixture is filtered and the filtrate is concentrated to give 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene (1.85 g, 74%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.88-6.91 (m, 1H), 6.82-6.83 (m, 1H), 4.07 (q, J =7.0 Hz , 2H), 3.90 (d, J = 0.7 Hz, 3H), 1.46 (t, J = 7.0 Hz, 3H).

Production Example 173 : 5-bromo-3-fluoro-2-methoxyphenol

To a mixture of 5-bromo-3-fluoro-2-methoxyphenyl formate (Production Example 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 is stirred at about 25° C. for about 16 hours. The mixture is concentrated. The resulting aqueous phase is diluted with water and NaHCO ₃ added to pH 8. The aqueous phase is washed with MTBE (2×30 ml) and the combined MTBE extracts are concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to give 5-bromo-3-fluoro-2-methoxyphenol (2.4 g, 54% over 2 steps). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 174 : 5-bromo-3-fluoro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-fluoro-2-methoxybenzaldehyde (Production Example 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 hours. The reaction mixture was concentrated to give 2-(5-bromo-3-fluoro-2-methoxyphenyl)acetaldehyde (3.74 g), which was used in Preparation 173.

Production Example 175 : 5-bromo-3-fluoro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (Production Example 176, 18.6 g, 85.0 mmol) in MeCN (150 ml) was added K ₂ CO ₃ (17.6 g, 128.0 mmol) and iodomethane (24.1 g, 170.0 mmol). The mixture is heated to about 50° C. for about 16 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue was triturated in MTBE (50 ml) and the resulting solid was filtered to give 5-bromo-3-fluoro-2-methoxybenzaldehyde (4.9 g, 25%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.33 (s, 1H), 7.73-7.74 (m, 1H), 7.47-7.51 (m, 1H), 4.10 (d, J =3.0 Hz, 3H).

Production Example 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 is heated at about 90°C for about 16 hours the Mixture is poured into water (800 ml) and get a solid, which is filtered. The cake was washed with water (2×150 ml) and dried to give 5-bromo-3-fluoro-2-hydroxybenzaldehyde (18.9 g, 82%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.90 (s, 1H), 9.88 (d, J =2.0 Hz, 1H), 7.49-7.53 (m, 2H).

Production Example 177 : 5-bromo-1-chloro-3-ethoxy-2-methoxybenzene

5-bromo-1-chloro-3-ethoxy-2-methoxybenzene (1.25 g, 86%) was prepared in a similar manner to Preparation 172 using 5-bromo-3-chloro-2-methoxyphenol (Preparation 178 , 1.3 g, 5.47 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 178 : 5-bromo-3-chloro-2-methoxyphenol

LiOH (4.93 g, 118 .0 mmol) in portions. The mixture was stirred at about 25° C. for about 16 hours. The mixture was concentrated and the resulting aqueous phase was diluted with aqueous NaHCO ₃ (50 ml). The solution is extracted with MTBE (2×30 ml) and the combined MTBE extracts are dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to give 5-bromo-3-chloro-2-methoxyphenol (1.3 g, 7% over 2 steps). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.07 (d, J =2.3 Hz, 1H), 7.05 (d, J =2.3 Hz, 1H), 5.79 (s, 1H), 3.92 (s, 3H).

Production Example 179 : 5-bromo-3-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-chloro-2-methoxybenzaldehyde (Production Example 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 hours. The white solid was filtered and the filtrate was concentrated to give 5-bromo-3-chloro-2-methoxyphenyl formate (15.0 g, 70%), which was used in Preparation Example. 178. LCMS m/z =266 [MH] ⁺ .

Preparation Example 180 : 5-bromo-3-chloro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (Production Example 181, 10 g, 42.5 mmol) was dissolved in MeCN (150 ml), iodomethane (24.1 g, 170 mmol) and K ₂ CO ₃ ( 11.7 g, 84.9 mmol). The mixture is heated to about 50° C. and stirred for about 24 hours. The mixture is cooled to about 20° C., filtered. The filtrate was concentrated and the residue was triturated with MTBE (30 ml) for about 20 minutes, then filtered. The filtrate is concentrated and the residue is diluted with water (20 ml) and extracted with EtOAc (2×100 ml). The combined EtOAc extracts were concentrated to give 5-bromo-3-chloro-2-methoxybenzaldehyde (8.9 g, 84%), which was used in Preparation 179. ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.30 ( s, 1H), 7.87 (d, J =2.5 Hz, 1H), 7.77 (d, J =2.5 Hz, 1H), 4.01 (s, 3H).

Production Example 181 : 5-bromo-3-chloro-2-hydroxybenzaldehyde

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 hours. The mixture was poured into water (800 ml) to give a precipitate. The precipitate is filtered, washed with water (2×150 ml) and dried to give 5-bromo-3-chloro-2-hydroxybenzaldehyde (22.7 g) which is used in Preparation 180. ¹ H NMR (CDCl ₃ , 400 MHz) : δ 11.40 (brs, 1H), 9.86 (s, 1H), 7.75 (d, J =2.3Hz, 1H), 7.63 (d, J =2.3Hz, 1H).

Production Example 182 : 1-bromo-5-ethoxy-2-fluoro-4-methoxybenzene

1-Bromo-5-ethoxy-2-fluoro-4-methoxybenzene (7.1 g, 90%) was prepared in a manner analogous to Preparation 172 using 5-bromo-4-fluoro-2-methoxyphenol (Preparation 192, 7.0 g, 32.0 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 183 : 1-bromo-2-chloro-5-ethoxy-4-methoxybenzene

1-bromo-2-chloro-5-ethoxy-4-methoxybenzene (5.7 g, 98%) was prepared in a manner analogous to Preparation 172 using 5-bromo-4-chloro-2-methoxyphenol (Preparation 184, 5.2 g, 21.9 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 184 : 5-bromo-4-chloro-2-methoxyphenol

NaOH (0.72 g, 18 .1 mmol). The mixture is stirred at about 20° C. for about 1 hour. The mixture is acidified using 1N HCl to pH 3. The mixture is concentrated and the remaining aqueous phase is extracted with EtOAc (3×100 ml). The combined EtOAc extracts were washed with brine (200 ml), dried with anhydrous Na ₂ SO 4 , filtered and concentrated to give 5-bromo-4-chloro-2-methoxyphenol (2.8 g, 98%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.16 (s, 1H), 6.93 (s, 1H), 5.58 (s, 1H), 3.28 (s, 3H).

Production Example 185 : 5-bromo-4-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-4-chloro-2-methoxybenzaldehyde (Production Example 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 hours. The mixture was partitioned between DCM (400 ml) and saturated sodium metabisulphite solution (200 ml). The separated DCM layer was washed with water (400 ml), brine (400 ml), dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 5-bromo-4-chloro-2-methoxyphenyl formate (3.2 g, 25%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.22 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 3.85 (s, 3H).

Preparation Example 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 is stirred at about 80°C for about 12 hours. The mixture is poured into water (1000 ml) and stirred at about 20°C for about 1 hour, with the formation of a precipitate. The precipitate is filtered, dissolved in EtOAc (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 5-bromo-4-chloro-2-methoxybenzaldehyde (6.7 g, 40%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.33 (s, 1H), 8.03 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H).

Production Example 187 : 1-bromo-5-ethoxy-4-methoxy-2-methylbenzene

1-Bromo-5-ethoxy-4-methoxy-2-methylbenzene (8.0 g, 99%) was prepared in a manner analogous to Preparation 172 using 5-bromo-2-methoxy-4-methylphenol (Preparation 189, 7.16 g, 33.0 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 188 : 1-bromo-2-fluoro-4-methoxy-5-propoxybenzene

1-bromo-2-fluoro-4-methoxy-5-propoxybenzene (13.5 g, 95%) was prepared in a similar manner to Preparation 172 using 5-bromo-4-fluoro-2-methoxyphenol (Preparation 192, 12 g, 109 mmol) and 1-iodopropane (18.5 g, 109 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.98 (d, J= 6.8 Hz, 1H), 6.70 (d, J= 9.8 Hz, 1H), 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).

Production Example 189 : 5-bromo-2-methoxy-4-methylphenol

NaOH (4.72 g, 118 .1 mmol). The mixture is stirred at about 20° C. for about 1 hour. The mixture is acidified using 1N HCl to pH 3. The mixture is concentrated and the remaining aqueous phase is extracted with EtOAc (3×150 ml). The combined EtOAc extracts are dried, filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to give 5-bromo-2-methoxy-4-methylphenol (10.25 g, 60% over 2 steps). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.10 (s, 1H), 6.72 (s, 1H), 5.46 (br, 1H), 3.87 (s, 3H), 2, 33 (s, 3H).

Production Example 190 : 5-bromo-2-methoxy-4-methylphenyl formate

To a mixture of 5-bromo-2-methoxy-4-methylbenzaldehyde (Production Example 191, 18.0 g, 78.58 mmol) in DCM (200 ml) was added m- CPBA (33.9 g, 157.0 mmol). The mixture is stirred at about 18° C. for about 16 hours. The mixture is filtered and the filtrate is concentrated. The residue was washed with aqueous sodium metabisulphite (1N, 200 ml), aqueous Na ₂ CO ₃ (1N, 100 ml) and water. The residue gave 5-bromo-2-methoxy-4-methylphenyl formate (19.3 g) which was used in Preparation 189.

Production Example 191 : 5-bromo-2-methoxy-4-methylbenzaldehyde

To a mixture of 1-bromo-4-methoxy-2-methylbenzene (25.1 g, 125.0 mmol) in TFA (120 ml) was added HMTA (26.3 g, 188 mmol) in portions. The mixture is stirred at about 80° C. for about 12 hours. The mixture is poured into water (500 ml) and stirred at about 20° C. for about 2 hours, with the formation of a precipitate. The precipitate is filtered, suspended in water at about 60°C for about 20 minutes, cooled to about 20°C and filtered. The precipitate was dissolved in EtOAc (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-2-methoxy-4-methylbenzaldehyde (18.0 g, 63%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.34 (s, 1H), 7.95 (s, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 2, 45 (s, 3H).

Production Example 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 Br ₂ (6.18 g, 38.7 mmol ) in DCM (20 ml). The solution is stirred for about 16 hours at about 20°C. The mixture was washed with water (3×200 ml) and NaOH (1N). The DCM layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 5-bromo-4-fluoro-2-methoxyphenol (6.0 g, 77%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.07 (d, J= 6.8 Hz, 1H), 6.68 (d, J= 9.6 Hz, 1H), 5.47 (s, 1H), 3.87 (s, 3H).

Production Example 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 (Production Example 194, 24.5 g, 172.0 mmol) in MeCN (100 ml) was added K ₂ CO ₃ (9.52 g, 68.9 mmol). The mixture is heated to about 60° C. and stirred for about 5 hours. The mixture is cooled to about 20° C., filtered and concentrated. The residue is dissolved in EtOAc (200 ml). The EtOAc layer was washed with water (80 ml), brine (50 ml), dried over MgSO4, filtered and concentrated to give 2-ethoxy-1,5-difluoro-3-methoxybenzene (5.0 g, 77%) which used in Preparation Example 137. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 194 : 2-ethoxy-3,5-difluorophenol

To a mixture of 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 195, 13.0 g, 45.76 mmol) in THF (100 ml) add H ₂ O ₂ (30%, 7.78 g, 68.6 mmol) and aqueous NaOH (1M, 48.0 ml, 48.0 mmol) at about 0°C. The mixture is heated to about 25° C. for about 2 hours. The mixture is acidified with 1N HCl to pH 5. Saturated salt solution (100 ml) is added and the mixture is extracted with EtOAc (2×200 ml). The combined EtOAc extracts are dried over NaSO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 2-ethoxy-3,5-difluorophenol (6.0 g, 75%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 195 : 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Combined 1-bromo-2-ethoxy-3,5-difluorobenzene mixture (Preparation Example 196, 11.0 g, 46.4 mmol), Pin ₂ B ₂ (6.53 g, 51.0 mmol) Pd(dppf) Cl ₂ (1.7 g, 2.32 mmol) and KOAc (9.11 g, 92.8 mmol) in anhydrous 1,4-dioxane (200 ml) are degassed, heated and stirred at about 80°C for about 24 h under N ₂ . The suspension is filtered and the filtrate is concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 70:30) to give 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.0 g , 99%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.14-7.17 (m, 1H), 6.90-6.95 (m, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1Hz, 3H), 1.37 (s, 12H). LCMS m/z =285 [MH] ⁺ .

Preparation Example 196 : 1-bromo-2-ethoxy-3,5-difluorobenzene

K ₂ CO ₃ (13.2 g, 95.7 mmol). The mixture is heated to about 60° C. and stirred for about 16 hours. The mixture is cooled to about 20° C., filtered and the filtrate is concentrated. The residue is dissolved in EtOAc (200 ml). The EtOAc layer was washed with water (80 ml), brine (50 ml), dried over MgSO ₄ , filtered and concentrated to give 1-bromo-2-ethoxy-3,5-difluorobenzene (11.0 g, 97%), which is used in Preparation Example 195. ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 197 : 4-bromo-1,2-diethoxybenzene

4-Bromo-1,2-diethoxybenzene (6.3 g, 97%) was prepared in a manner analogous to Preparation 172 using 4-bromobenzene-1,2-diol (5.0 g, 26 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 198 : 4-bromo-1-ethoxy-2-methoxybenzene

4-Bromo-1-ethoxy-2-methoxybenzene (5.1 g, 98%) was prepared in a similar manner to Preparation 172 using 4-bromo-2-methoxyphenol (4.57 g, 22.5 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.99-7.03 (m, 1H), 6.97-6.99 (m, 1H), 6.74 (d, J= 8.8 Hz , 1H), 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] ⁺ .

Production Example 199 : 1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene

1-Bromo-4-ethoxy-2-fluoro-3-methoxybenzene was obtained as a yellow oil (6.3 g, 99%) in a manner analogous to Preparation 172 using 3-bromo-6-ethoxy-2-fluorophenol ( Preparation Example 200, 6 g, 25.5 mmol) and iodomethane (10.9 g, 76.6 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 200 : 3-bromo-6-ethoxy-2-fluorophenol

To a solution of 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation Example 201, 15.2 g, 44.1 mmol) in THF (150 ml) add H ₂ O ₂ (30%, 7.49 g, 66.1 mmol) and aqueous NaOH (1M, 46.3 ml, 46.3 mmol) at about 0°C. The mixture is heated to about 25° C. for about 1.5 hours. The mixture is acidified with 1N HCl to pH 5. Saturated salt solution (150 ml) is added and the mixture is extracted with EtOAc (2×200 ml). The combined EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give 3-bromo-6-ethoxy-2-fluorophenol (10.0 g, 97%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.99 (dd, J= 7.0, 9.0 Hz, 1H), 6.53-6.62 (m, 1H), 4.07-4 .20 (m, 3H), 1.46 (t, J = 7.0 Hz, 3H).

Production Example 201 : 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1-bromo-4-ethoxy-2-fluorobenzene (Production Example 202, 11.0 g, 50.2 mmol) in THF (250 ml) was added dropwise a DAL solution (37.7 ml, 2 M in THF) at about -78°C. The solution is stirred at about -78°C for about 1 hour, PinBO-Pr (14.0 g, 75.3 mmol) is added dropwise. After stirring at about -78°C for about 2 h, the solution is quenched with aqueous NH ₄ Cl (1 M, 100 ml) and extracted with MTBE (3×300 ml). The combined MTBE extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.2 g, 88 %). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.43 (t, J= 8.6 Hz, 1H), 6.51 (d, J= 8.8 Hz, 1H), 3.99 (q, J= 6.9 Hz, 2H), 1.35-1.45 (m, 16H).

Production Example 202 : 1-bromo-4-ethoxy-2-fluorobenzene

1-Bromo-4-ethoxy-2-fluorobenzene (11 g, 96%) was prepared in a similar manner to Preparation 172 using 4-bromo-2-methoxyphenol (10 g, 52 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.33-7.45 (m, 1H), 6.69 (dd, J= 2.9, 10.8 Hz, 1H), 6.60 (dd , J= 1.0, 2.9, 8.8 Hz, 1H), 4.00 (kv, J= 7.2 Hz, 2H), 1.42 (t, J= 6.9 Hz, 3H) .

Preparation Example 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 slowly added 4-bromo-2-methoxybenzamine (50 g, 247.46 mmol). The mixture is stirred at about 70° C. for about 3 hours. The reaction mixture is concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give (4-bromo-2-methoxyphenyl)(methyl)sulfane (50 g, 87%). ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

Production Example 204 : (4-bromo-2-ethoxyphenyl)(methyl)sulfane

(4-Bromo-2-ethoxyphenyl)(methyl)sulfane (35.0 g, 83%) was prepared in a manner analogous to Preparation 172 using 5-bromo-2-(methylthio)phenol (Production Example 20, 16 g, 73 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Production Example 205 : (4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane

(4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane (6.0 g, 92%) was prepared in a manner analogous to Preparation 153 using 5-bromo-2-(methylthio)phenol (5 g, 22 .8 mmol) and cyclopentanol (2.36 g, 27.4 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 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 BBr ₃ (179 ml, 179 mmol, 1 M in DCM) dropwise under N ₂ atmosphere. The reaction mixture is heated to about 20° C. and stirred for about 2 hours. The mixture is 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 give 5-bromo-2-(methylthio)phenol (16.3 g, 91%). ¹ H NMR (CDCl ₃ , 400 MHz): 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, 1H), 2.32 (s, 3H).

Preparation Example 207 : 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile

A mixture of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (Preparation Example 208, 7 g, 22.3 mmol), TFAA (7.16 g, 33.45 mmol) and Et ₃ N (6.76 g , 66.9 mmol) in DCM (100 ml) was stirred at about 20° C. for about 16 hours. Water (200 ml) was added to the mixture and extracted with DCM (2×200 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 give 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile (1.6 g, 24%). ¹ H NMR (CDCl ₃ , 400 MHz): 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 ).

Production Example 208 : 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime

To a solution of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (Production Example 209, 6.8 g, 22.7 mmol) in EtOH (100 ml) was added NaHCO ₃ (3.8 g, 45.4 mmol) and NH ₂ OH∙HCl (2.35 g, 34 mmol). The mixture was stirred at about 20°C for about 2 hours. The reaction mixture was concentrated to give 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (7 g), which was used in Preparation 207.

Production Example 209 : 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde

6-Bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (6.8 g, 90%) was prepared in a manner analogous to Preparation 172 using 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Production Example 165, 6 g , 30 mmol) and bromocyclopentane (4.26 g, 28.6 mmol) at about 60° C. for about 3 hours. ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.31-10.38 (m, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 4.95-5.01 (m, 1H), 3, 87 (s, 3H), 1.70-1.93 (m, 7H), 1.62 (d, J= 5.4 Hz, 2H). LCMS m/z =323 [M+Na] ⁺ .

Preparation Example 210 : 1-bromo-2,4-dimethoxy-3-propoxybenzene

1-Bromo-2,4-dimethoxy-3-propoxybenzene (10 g, 85%) was prepared in a similar manner to Preparation 172 using 3-bromo-2,6-dimethoxyphenol (Preparation 211, 10 g, 43 mmol ) and 1-iodopropane (14.6 g, 86 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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), 1.01-1.07 (m, 4H). LCMS m/z =276 [MH] ⁺ .

Preparation Example 211 : 3-bromo-2,6-dimethoxyphenol

To a stirred solution of 2,6-dimethoxyphenol (1 g, 6.5 mmol) in CCI ₄ (35 ml) at about -10°C, add Br ₂ (1.04 g, 6.5 mmol) and stir for about 2 h. The reaction mixture was diluted with CCl ₄ (20 ml), washed with water (3×60 ml) and the CCl ₄ layer was washed with saturated salt solution, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to give 3-bromo-2,6-dimethoxyphenol (1.46 g, 97%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 212 : 6-iodo-3-methoxy-2-propoxypyridine

6-iodo-3-methoxy-2-propoxypyridine (11 g, 95%) was prepared in a similar manner to Preparation 172 using 6-iodo-2-propoxypyridin-3-ol (Preparation 213, 11 g, 39 mmol ) and 1-iodomethane (57 g, 402 mmol) at about 15° C. for about 6 hours. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.24 (d, J= 8.0 Hz, 1H) , 6.91 (d, J= 8.0 Hz, 1H), 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] ⁺ .

Preparation Example 213 : 6-iodo-2-propoxypyridin-3-ol

Sodium p-propan-1-olate (21.8 g, 265 mmol) was added to 2-bromo-6-iodopyridin-3-ol (Preparation Example 214, 26.5 g, 88.4 mmol) in DMF (200 ml), and the reaction mixture is stirred for about 16 h at about 110°C under N ₂ . After cooling to about 20°C, the reaction mixture is divided between saturated salt solution (200 ml) and EtOAc (250 ml). The aqueous layer was extracted with EtOAc (200 ml). The combined EtOAc extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 80:20) to give 6-iodo-2-propoxypyridin-3-ol (11.2 g, 45%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.17 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.0 Hz, 1H), 5.47 (s, 1H), 4.31 (dt, J= 0.9, 6.7 Hz, 2H), 1.74-1.86 (m, 2H), 0.98-1.05 (m, 3H).

Preparation Example 214 : 2-bromo-6-iodopyridin-3-ol

K 2 CO 3 ( _31.8 g, 230 mmol) and I ₂ (29.2 g _, 115 mmol). The mixture is stirred at about 20° C. for about 5 hours. The mixture is cooled to 0° C. and treated with concentrated HCl. The precipitate is filtered to give 2-bromo-6-iodopyridin-3-ol (30 g, 87%). ¹ H NMR (DMSO- d ₆ , 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] ⁺ .

Preparation Example 215 : 5-bromo-2-methoxy-3-propoxypyridine

To a solution of 2-methoxy-3-propoxypyridine (Preparation Example 216, 5.68 g, 34 mmol) was dissolved in DCM (60 ml), HOAc (2.04 g, 34 mmol) was added. To the mixture was added NBS (6.35 g, 35.7 mmol) in portions with stirring. The mixture is stirred at about 12° C. for about 16 hours. The mixture is concentrated. The residue was diluted with water (200 ml) and extracted with EtOAc (2×100 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 give a mixture of 6-bromo-2-methoxy-3-propoxypyridine and 5-bromo-2-methoxy-3-propoxypyridine. The mixture is cooled to about -10°C during the night. A precipitate is obtained which is separated from the oil by centrifugation (3×5 min @ 3000 rpm) to give 5-bromo-2-methoxy-3-propoxypyridine (3 g, 53%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 216 : 2-methoxy-3-propoxypyridine

2-methoxy-3-propoxypyridine (5.7 g, 85%) was prepared in a similar manner to Preparation 172 using 2-methoxypyridin-3-ol (5 g, 40 mmol) and 1-iodopropane (13.6 g , 80 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.73 (dd, J= 1.5, 4.9 Hz, 1H), 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).

Preparation Example 217 : 2-bromo-5-methoxy-4-propoxypyridine

To a solution of 2-bromo-4-iodo-5-methoxypyridine (Production Example 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 is heated to about 60° C. for about 1 hour. The solution is quenched with aqueous NH ₄ Cl (1 M, 30 ml) and extracted with EtOAc (3×100 ml). The combined EtOAc extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 89:11) to give 2-bromo-5-methoxy-4-propoxypyridine (2 g, 64%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.84 (s, 1H), 6.91 (s, 1H), 4.00 (t, J= 6.9 Hz, 2H), 3.90 ( s, 3H), 1.83-1.92 (m, 2H), 1.05 (t, J= 7.3 Hz, 3H). LCMS m/z =247.8 [MH] ⁺ .

Preparation Example 218 : 2-bromo-4-iodo-5-methoxypyridine

Sodium hydride (1.27 g, 31.8 mmol, 60%) is 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-4-iodopyridine (Production Example 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 hour. The solution was quenched with aqueous NH ₄ Cl (1 M, 60 ml) and extracted with MBTE (3×200 ml). The combined MTBE extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 2-bromo-4-iodo-5-methoxypyridine (4 g, 48.1%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.88 (s, 1H), 7.85 (s, 1H), 3.97 (s, 3H).

Preparation Example 219 : 2-bromo-5-fluoro-4-iodopyridine

A solution of 2-bromo-5-fluoropyridine (24.6 g, 140 mmol) in THF (300 ml) is cooled to about -78°C. DAL (2 M in THF, 90.9 mL, 182 mmol) is added dropwise and the mixture is stirred for about 20 minutes. A solution of iodine (49.7 g, 196 mmol) in THF (100 ml) was added dropwise to the mixture. The reaction mixture is warmed to about 0° C. and stirred for about 30 minutes. The reaction mixture was quenched with 10% aq. Na ₂ S ₂ O ₃ solution and extracted with EtOAc (3×500 ml). The combined EtOAc extracts were washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1) to give 2-bromo-5-fluoro-4-iodopyridine (50 g, 67% pure). The product was further purified by preparative HPLC (Column: Phenomenex Synergi Max-RP 150 mm x 50 mm, 10 µ; Mobile phase: [water (0.225% HCO ₂ H)-ACN]; B%: 30%-60%, 25 min. Flow rate 120 ml/min) to give 2-bromo-5-fluoro-4-iodopyridine (16.8 g, 40%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.15 (s, 1H), 7.92 (s, 1H). LCMS m/z =303 [MH] ⁺ .

Preparation Example 220 : 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine

Ag 2 SO ₄ (7.07 g _, 22.7 mmol) was added to a solution of 5-fluoro-3-methoxy-2-propoxypyridine (Production Example 221, 2.80 g, 15.1 mmol) in EtOH (50 ml) and I ₂ (5.76 g, 22.7 mmol). The reaction mixture was stirred at about 10° C. for about 16 hours. The mixture and solution were partitioned between EtOAc (3×100 ml) and water (100 ml). The EtOAc extracts were dried with Na ₂ SO ₄ , filtered and concentrated to give 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine (4.38 g, 93%). ¹ H NMR (CDCl ₃ , 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] ⁺ .

Preparation Example 221 : 5-fluoro-3-methoxy-2-propoxypyridine

tBuXPhos-Pd-G3 mixture (CAS 14447963-75-8, 443 mg, 0.557 mmol), PrOH (803 mg, 13.4 mmol), 2-chloro-5-fluoro-3-methoxypyridine (Production Example 222, 1800 mg , 11.14 mmol) and Cs ₂ CO ₃ (7260 mg, 22.3 mmol) are dissolved in PrOH (40 ml) under N ₂ . The mixture is heated at about 90° C. for about 16 hours. The mixture is dried and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 5-fluoro-3-methoxy-2-propoxypyridine (1280 mg, 77%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.57 (d, J= 2.5 Hz, 1H), 6.87 (dd, J= 2.7, 9.3 Hz, 1H), 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] ⁺ .

Preparation Example 222 : 2-chloro-5-fluoro-3-methoxypyridine

2-Chloro-5-fluoro-3-methoxypyridine (1.8 g, 72%) was prepared in a similar manner to Preparation 153 using 2-chloro-5-fluoro-pyridin-3-ol (2.3 g, 16 mmol) and methanol (5 g, 156 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.89 (d, J= 2.70 Hz, 1H), 7.00 (dd, J= 2.5, 9.1 Hz, 1H), 3, 93 (s, 3H).

Production Example 223 : 4-bromo-1-(difluoromethoxy)-2-propoxybenzene

Powdered KOH (1.34 g, 23.8 mmol) is added to a stirred solution of 4-bromo-2-propoxyphenol (Production Example 224, 5.5 g, 23.8 mmol) in NMP (150 ml) at about 15°C under N ₂ . The mixture is heated at about 50°C for about 45 minutes, then cooled to about 15°C. Difluorochloromethane is bubbled through the reaction mixture (approximately 20 minutes) until saturated and the mixture is stirred for another 20 minutes. Potassium hydroxide (2.68 g in 3 ml of water) is added dropwise, keeping the temperature below 33°C. The mixture is stirred for another 40 minutes. Additional potassium hydroxide (1.34 g, in 3 ml water) was added dropwise and the mixture was stirred for 1 hour. N ₂ was bubbled through the reaction mixture and water was added. The pH of the resulting mixture was adjusted to 8 with potassium hydroxide (aqueous) and the mixture was extracted using MTBE (2×100 ml). The combined MBTE extracts were washed with water (50 ml), brine (3×100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 4-bromo-1-(difluoromethoxy)-2-propoxybenzene (4.8 g, 72%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.09 (d, J= 1.3 Hz, 1H), 7.03-7.06 (m, 2H), 6.33-6.74 (m , 1H), 3.93-4.01 (m, 2H), 1.80-1.92 (m, 2H), 1.06 (t, J= 7.4 Hz, 3H).

Production Example 224 : 4-bromo-2-propoxyphenol

To a solution of 4-bromo-2-propoxyphenyl formate (Preparation Example 225, 10.9 g, 42 mmol) in MeOH (75 ml) and water (75 ml) was added NaOH (4200 mg, 105 mmol). The mixture is stirred at about 10° C. for about 1 hour. The mixture is allowed to stand overnight. The mixture is acidified with HCl (1N) to pH 3. The mixture is concentrated and filtered. The filter cake is washed with water (20 ml). The cake is dissolved in MTBE (200 ml) and EtOAc (50 ml). The combined MTBE and EtOAc extracts are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 75:25) to give 4-bromo-2-propoxyphenol (6.11 g, 63%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.94-7.06 (m, 2H), 6.81 (d, J= 8.5 Hz, 1H), 3.99 (t, J= 6 .8 Hz, 2H), 1.79-1.95 (m, 2H), 1.06 (t, J= 7.5 Hz, 3H).

Production example of 225 : 4-bromo-2-propoxyphenyl formate

To a solution of 4-bromo-2-propoxybenzaldehyde (Preparation Example 226, 10.2 g, 42 mmol) was dissolved in DCM (150 ml) m- CPBA (18.1 g, 84 mmol) was added. The mixture is stirred at about 18°C for about 16 hours, then stand over the weekend. The mixture is filtered and concentrated to give 4-bromo-2-propoxyphenyl formate (10.9 g) which is used in Preparation 224. LCMS m/z =248 [MH] ⁺ .

Preparation Example 226 : 4-bromo-2-propoxybenzaldehyde

4-bromo-2-propoxybenzaldehyde (11.5 g, 95%) was prepared in a similar manner to Preparation 172 using 4-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol) and 1-iodopropane (11 g, 65 mmol). ¹ H NMR (CDCl ₃ , 400 MHz): 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 ).

Production Example 227 : ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane

Five reactions are carried out in parallel. TBS- Cl (140 g, 0.93 mol) in portions at about 30°C. The mixture is then stirred at about 35° C. for 1 hour. The mixture is poured into water (5.0 L). The combined mixtures are extracted with MTBE (3 x 2.5 L). The organic layer was washed with brine (2.0 L), dried over Na ₂ SO ₄ and concentrated to give ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane (1250 g, 92%). ¹ H NMR (CDCl ₃ , 400 MHz): 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).

Preparation Example 228 : 2-bromoprop-2-en-1-ol

Five reactions are carried out in parallel: To a solution of 2,3-dibromoprop-1-ene (300 g, 1.50 mol) in DMF (900 ml) is 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 hours. A solution of LiOH (126 g, 3.01 mol) in MeOH (900 ml) and H ₂ O (300 ml) was added dropwise to the above mixture with stirring at about 20 °C. The mixture is stirred at about 20° C. for about 1 hour. The mixture is concentrated and poured into ice water (2.0 L). The mixture is extracted with EtOAc (3×1.5 L). The EtOAc extracts were washed with brine (1.0 L), dried over Na ₂ SO ₄ and concentrated to give 2-bromoprop-2-en-1-ol (750 g, 72%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.87-6.02 (m, 1H), 5.45-5.62 (m, 1H), 4.17 (s, 2H), 3.70 (ws, 1H).

Production Example 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-Cl (9.98 g, 66.2 mmol). The mixture was stirred at about 18° C. for about 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2×200 ml). The combined EtOAc extracts are washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate is concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether to give ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (16.0 g, 91%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.64 (s, 1H), 5.46 (d, J =1.6 Hz, 1H), 3.80 (t, J =6.4 Hz, 2H), 2.63 (t, J =6.2 Hz, 2H), 0.90 (s, 9H), -0.08 (s, 6H).

Production Example 230 : 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine

TBS- Cl (3.24 g, 22.4 mol) in portions at about 0°C. The mixture was stirred at about 0° C. for about 2 hours. The mixture was poured into ice water (50 ml) and extracted with EtOAc (3×50 ml). The combined EtOAc extracts were washed with brine (2×30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine (3.1 g, 54%). ¹ H NMR (CDCl ₃ , 400 MHz): 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] ⁺ .

Production Example 231 : 2,6-dichloropyrimidin-4-yl)methanol

2,6-Dichloropyrimidine-4-carbonyl chloride (Preparation Example 232, 10 g, 47.3 mmol) was dissolved in a mixture of MeCN (60 ml) and THF (70 ml). The mixture is cooled to about -78°C and treated with a solution of NaBH ₄ (3.58 g, 94.6 mmol) in DMF (30 ml) dropwise. The mixture was stirred at about -78°C for about 2 h and diluted with aqueous HCl (1 M, 10 ml). The mixture was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (2×100 ml). The combined EtOAc extracts were dried over MgSO ₄ , filtered and concentrated to give 2,6-dichloropyrimidin-4-yl)methanol (8 g, 95%), which was used in Preparation 230. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.51 (s, 1H), 4.78 (s, 2H).

Preparation Example 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 PCl ₅ (220 g, 1.06 mol) in POCl ₃ (250 ml) is heated to reflux (120° C.) for about 16 hours. The resulting mixture was concentrated and distilled under reduced pressure (120° C., 10 mmHg) to give 2,6-dichloropyrimidine-4-carbonyl chloride (21 g , 31%), which is used in Preparation Example 231.

Preparation Example 233 : 4-methoxy-3-propoxybenzimidamide

Ethyl 4-methoxy-3-propoxybenzimidate (Preparation Example 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 hours. After concentration, MTBE (150 ml) was poured onto the residue, stirred for 1 hour and filtered and concentrated to give 4-methoxy-3-propoxybenzimidamide (33.8 g, 100%). ¹ H NMR (CD ₃ OD, 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] ⁺ .

Production Example 234 : Ethyl 4-methoxy-3-propoxybenzimidate

Acetyl chloride (69.0 g, 879 mmol) was added dropwise to a solution of 4-methoxy-3-propoxybenzonitrile (Production Example 235, 21.0 g, 110 mmol) in dry EtOH (60.7 g, 1320 mmol), then stirred at about 30° C. for about 12 hours. The mixture is concentrated and MTBE (150 ml) is added to the residue. The mixture was stirred for about 1 hour and filtered to give ethyl 4-methoxy-3-propoxybenzimidate (26.1 g, 100%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 12.28 (br, 1H), 11.56 (br, 1H), 8.01 (d, J= 2.2 Hz, 1H), 7.98 ( dd, J= 2.2, 8.6 Hz, 1H), 7.0 (d, J= 8.6 Hz, 1H), 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] ⁺ .

Preparation Example 235 : 4-methoxy-3-propoxybenzonitrile

4-Methoxy-3-propoxybenzonitrile (32.10 g, 100%) was prepared in a similar manner to Preparation 172 using 3-hydroxy-4-methoxybenzonitrile (25 g, 170 mmol) and 1-iodopropane (57 g, 335 mmol ). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.25-7.29 (m, 1H), 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), 1.03-1 .09 (m, 3H). LCMS m/z =191 [MH] ⁺ .

Production Example 236 : 3-((t-butyldimethylsilyl)oxy)propan-1-ol

Propan-1,3-diol (20 g, 260 mmol), tert-butylchlorodimethylsilane (47.5 g, 315 mmol), Et ₃ N (76.0 ml, 526 mmol) and DMAP (1.610 g, 13.1 mmol ) is suspended in DCM (300 ml). The mixture is stirred at about 18°C overnight. The reaction mixture is partitioned between DCM (3×300 ml) and water (300 ml). The combined DCM extracts are concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 97:3) to give 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (50 g, 100%), which is used in Preparation 158.

Production Example 237 : 1-(6-bromopyridin-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) is heated to about 70°C. Bromine (1.4 ml, 27.5 mmol) is added dropwise over 30 minutes. The solution is stirred at about 70° C. for about 19 hours. The solution is cooled with EtOAc (50 ml) and hexane (50 ml) is added. The precipitate is filtered and washed with heptane (2×50 ml). The combined filtrates were washed with brine (30 ml), dried over MgSO ₄ , filtered and concentrated to give 2-bromo-1-(6-bromopyridin-2-yl)ethan-1-one (6.85 g) which was used immediately to the next stage.

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 hours. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The aqueous layers are extracted with EtOAc. The combined EtOAc extracts were washed with brine (20 ml), dried with MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with heptane/EtOAc (90:10 to 70:30) to give 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one (977 mg) which was used in Preparation 88. ¹ H NMR (CDCl ₃ , 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) further purified by preparative SLC (Prep SLC Method A) to give 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (233 mg, 46%). ¹ H NMR ( DMSO- d ₆ , 400 MHz): δ 8.72 (d, J =2.8 Hz, 2H), 8.43 (d, J =2.0 Hz, 1H), 7.95 ( t, J= 2.0 Hz, 1H), 7.25-7.29 (m, 1H), 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, 1H), 1.12-1.18 (m, 1H). LCMS m/z =300 [MH] ⁺ ; RT [Analytical SLC Method A] = 5.20 min.

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 preparative SLC (Prep SLC Method B). The solids are recrystallized with EtOAc (442 mg in 2 ml) to give 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (253 mg, 11%) as a crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (d, J= 2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J= 1.6 Hz, 1H), 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 (kv, 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 SLC Method B] = 6.59 min. [α] ²⁰ _D +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 of the preparative SLC column (Prep SLC Method B) described in Example 2 gave enantiomer 2 which was recrystallized from EtOAc to give (R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl) -1,2-oxaborolan-2-ol (610 mg, 27%) as a crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (d, J= 2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J= 1.6 Hz, 1H), 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 (kv, 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 SLC Method B] = 7.07 min. [α] ²⁰ _D -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-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (Production Example 6, 55 g, 120 mmol) in IPA (247 ml) add 5 M hydrogen chloride in IPA (37 ml, 185 mmol) at about 20°C. The mixture is stirred for about 3 hours and concentrated. The residue was diluted with EtOAc (500 ml) and 1N HCl (500 ml) was added. The layers are separated and the EtOAc layer is extracted with 0.5 N HCl (2×200 ml). The aqueous extracts are combined with the separated acidic aqueous layer and washed with EtOAc (3×250 ml). The combined acidic aqueous layers are treated with K ₃ PO ₄ to pH 5-6. The mixture is extracted with EtOAc (1×500 ml, 2×200 ml). The combined EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolane -2-ol (34.5 g, 88%). The resulting mixture was further purified by preparative SLC (Prep SLC Method C) to give 29 g as a crude product. The crude product was dissolved in methanol (250 ml) and water (50 ml) and stirred at 20° C. for about 30 minutes, then concentrated. The concentrated solution is divided between brine and EtOAc. The aqueous layer is separated and extracted with EtOAc. The EtOAc extracts are combined with the separated EtOAc layer and washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in degassed EtOAc (200 ml) and degassed heptane (100 ml) was added slowly. Heptane is added until a precipitate appears and the resulting mixture is stirred overnight under N ₂ . The solid is filtered to give 8.08 g of product. The filtrate was concentrated and the residue was taken up in EtOAc (50 ml). Heptane (25 ml) is added slowly and the mixture is stirred overnight in the open air. The solid is filtered to obtain a second batch (6.16 g). The workup is repeated a second time to give 3.0 g. The filtrate is stirred overnight to give additional batches (2.09 g and 3.1 g), respectively. Solid lots are combined to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (22.3 g, 57%) as crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 7.4 Hz, 3H). LCMS m/z =328 [MH] ⁺ ; RT [Analytical SLC Method B] = 7.30 min. [α] ²⁰ _D -23.7 ( c =0.9, EtOH). Elemental analysis, calculated (%) for C ₁₈ H ₂₂ BNO ₄ : 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 (Example 50, 3.0 g, 7.25 mmol), [Ir(COD)Cl] ₂ (CAS 12112-67-3, 36.9 mg, 0.054 mmol) and (S)[(S _p )-2- (diphenylphosphino)phenocenyl]-4-isopropyloxazoline (CAS 163169-29-7, 52.4 mg, 0.109 mmol). Additional THF (6.0 ml) was added to the mixture, which was heated to about 50° C. for about 5 minutes. Catecholborane (10.9 ml, 1.0 M in THF) is added to the mixture and stirred at about 50°C for about 1 hour. The mixture is cooled to about 20°C and treated with HCl (12.2 M, 1.51 ml ) more than 1 min. The mixture is stored at about 20° C. for about 1 hour, after which a precipitate forms. The mixture is 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 give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl) hydrochloride monohydrate -1,2-oxaborolan-2-ol (3.98 g, 91%) as a crystalline solid. ¹ H NMR (CD ₃ OD, 400 MHz): δ8.98 (d, J= 1.5 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J= 1.3 Hz, 1H), 7.37-7.43 (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)pyridin-3-yl)-1,2-oxaborolan-2-ol hydrochloride monohydrate (2.0 g, 5.24 mmol) in water (60 ml) add EtOAc (20 ml). NaOH (1N) was added dropwise to the stirred mixture to adjust the pH of the aqueous layer to 7-8. The mixture is stirred at about 20° C. for about 5 minutes. The layers are separated and the aqueous layer is extracted with EtOAc (2×10 ml). The combined EtOAc extracts are concentrated. The residue was dissolved in THF/MTBE (1:3, 22 ml) and stirred at about 20° C. overnight. The precipitate is filtered and dried under vacuum to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.17 g, 68% ) as a crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 7.4 Hz, 3H). LCMS m/z =328 [MH] ⁺ .

Method C:

To a solution of (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (Production Example 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 hours. The mixture was concentrated. The mixture was diluted with 1 M HCl and extracted with EtOAc (3×100 ml). The combined EtOAc extracts were washed with 1 M HCl (3 x 50 ml). The combined aqueous extracts were neutralized with K ₃ PO ₄ to pH 7-8 and extracted with EtOAc (3×100 ml). The combined EtOAc extracts are dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ( 19.0 g, 92%). It was further purified by preparative SLC (Prep SLC Method C) to give 18 g of crude product. The crude product was dissolved in MeOH (100 ml) and water (50 ml). The mixture is partitioned between brine and EtOAc. The layers are separated and the aqueous layer is extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 15 g of product. The residue was dissolved in EtOAc (60 ml) and heptane (30 ml) was added slowly over about 3 hours. The mixture was stirred at about 20° C. overnight. The precipitate is filtered and dried to give (8.08 g). This process is repeated 2 more times to obtain additional batches (2.01 g and 1.03 g), respectively. Three batches are combined in heptane (100 ml), cooled to about -78°C over about 10 min, filtered and dried to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3- yl)-1,2-oxaborolan-2-ol (10.4 g, 51%) as a crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 7.4 Hz, 3H). LCMS m/z =328 [MH] ⁺ .

Example 5 : (S)-4-(5-(4-Methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

[ Ir(COD)Cl] ₂ (CAS 12112-67-3, 1.22 g, 1.81 mmol), (R, R)-[2-(4'-i-propyloxazolin-2-yl)phenocenyl]diphenylphosphine (CAS 541540-70-9, 1.75 g, 3.63 mmol) and THF (240 ml) are cooled in an ice bath for about 30 minutes. A solution of catecholborane (109 ml, 109 mmol, 1.0 M in THF) was added slowly over about 20 minutes, then the mixture was stirred at about 20° C. for about 3 hours. The reaction mixture was quenched with MeOH (30 ml). The mixture is concentrated and dried overnight. The residue is treated with 3 M aqueous HCl/THF (1:1, v/v) for about 2 h and washed with EtOAc. The aqueous layer is separated and neutralized to pH 7-8 and extracted with EtOAc. The EtOAc extract is dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in THF/MTBE (1:1, 180 ml) and mixed with Biotage MP-TMT resin (28 g, Biotage P/N 801470) at about 20° C., under N ₂ , overnight. The mixture is filtered and the resin is washed with THF (2×50 ml). The combined THF/MTBE filtrates are concentrated to give (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (23.5 g, 71% ). This was further purified via SLC purification (Prep SLC Method C) to give 12 g of crude product. The crude product was dissolved in MeOH (35 ml) and water (15 ml). The mixture is partitioned between brine and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAC. The combined EtOAc extracts are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in EtOAc (30 ml) and heptane was added until cloudy. The mixture is stirred overnight. The precipitate is filtered and dried to give (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (5.39 g, 45%) in form of a crystalline solid. ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 7.4 Hz, 3H). LCMS m/z =328 [MH] ⁺ ; RT [Analytical SLC Method B] = 6.35 min. [α] ²⁰ _D +27.3 ( c =0.6, EtOH). Elemental analysis, calculated (%) for C ₁₈ H ₂₂ BNO ₄ : 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 preparative SLC (Prep SLC Method D) then preparative HPLC (Method A) to give 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (17 mg, 19% ). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.92 (t, J= 2.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.07 (d, J= 8.0 Hz, 1H), 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 [MH] ⁺ . RT [Analytical SLC 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 preparative SLC (Prep SLC Method E) to give 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (205 mg, 41%) . ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69-8.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H), 7.28 (dd, J= 2.4, 8.3 Hz, 1H), 7.07 (d , J= 8.8 Hz, 1H), 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 SLC Method D] = 5.736 min.

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 preparative SLC (Prep SLC Method F) to give 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (261 mg , 27%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 4.25-4.30 (m, 1H), 4.09 (t, J= 5, 0 Hz, 2H), 3.86 (t, J= 9.0 Hz, 1H), 3.81 (s, 3H), 3.75 (kv, 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+H ₂ O] ⁺ ; RT [Analytical SLC Method D] = 3.357 min. [α] ²⁰ _D -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 preparative SLC (Prep SLC Method G) to give 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (639 mg , 35%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68-8.72 (m, 2H), 8.43 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.29 (d, J= 2.0 Hz, 1H), 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, 1H), 3.80 (s, 3H), 3.58 (kv, 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 SLC Method F] = 1.060 min. [α] ²⁰ _D -19.5 ( c =0.02, EtOH).

Example 10 : (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 41, 800 mg, 2.20 mmol) further purified preparative SLC (Prep SLC Method H) to give 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ( 308 mg, 39%). The product is recrystallized from EtOAc/heptane (1:1, v/v) to give a crystalline solid, ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 1.25-1.38 (m, 4H), 1 .00-1.12 (m, 1H). LCMS m/z =364 [MH] ⁺ ; RT [Analytical SLC Method E] = 3.640 min. [α] ²³ _D -27.5 ( c= 0.2, EtOH).

Example 11 : (+) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

Additional elution of the preparative SLC column (Prep SLC Method H) described in Example 10 gives 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2 (259 mg, 32%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, 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 SLC Method E] = 4.050 min. [α] ²³ _D +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 preparative SLC (Prep LC Method I) to give 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (18 mg, 30 %). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J= 1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd, J= 2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.21 (kv, 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+H ₂ O] ⁺ ; RT [Analytical SLC 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) further purified by preparative SLC (Prep LC Method J) to give 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (411.3 mg , 37%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 8.02 (t, J= 2.2 Hz, 1H), 7.42 (d, J= 2.0 Hz, 1H), 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 =348 [MH] ⁺ ; RT [Analytical SLC 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 preparative SLC (Prep LC Method K) to give 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (122 mg, 32 %). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H). LCMS m/z =332 [MH] ⁺ ; RT [Analytical SLC 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 preparative SLC (Prep SLC Method L) to give 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (550 mg , 34%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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(kv, J =7.0Hz, 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 SLC Method G] = 4.089 min. [α] ²⁰ _D -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 ) further purified by preparative SLC (Prep SLC Method M) to give 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2 -ol, enantiomer 1 (298 mg, 39%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.49-3.57 (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 SLC Method D] = 4.347 min. [α] ²⁰ _D -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 preparative SLC (Prep SLC Method N) to give 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (165 mg, 33%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.74 (d, J =2.1Hz, 1H), 8.72 (s, 1H), 8.49 (d, J =2.0Hz, 1H), 8.00 (t, J = 2.0Hz, 1H), 7.45 (d, J = 1.6Hz, 1H), 7.28-7.31 (m, 2H), 7.09 ( t, 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+H ₂ O] ⁺ ; RT [Analytical SLC Method E] = 3.402 min. [α] ²⁰ _D -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

4-(6'-Methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol (Example 51, 1.1 g, 3.4 mmol) further purified by preparative SLC (Prep SLC Method O) to give 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (411 mg, 37%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.76 (d, J= 2.2 Hz, 1H), 8.72 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 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+H ₂ O] ⁺ ; RT [Analytical SLC Method G] = 4.231 min. [α] ²⁰ _D -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

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 preparative SLC (Prep LC Method P) to give 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1, (66 mg, 36%. The product is recrystallized with EtOAc/heptane to give a crystalline solid, ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67 (s, 1H), 8.33 (d, J= 2.0 Hz , 1H), 7.47 (d, J= 2.0 Hz, 1H), 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 (kv, 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 SLC Method H] = 1.768 min. [α] ²⁰ _D -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

Additional elution of the preparative SLC column (Prep SLC Method P) described in Example 19 gives 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol , enantiomer 2, (69 mg, 40%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67 (s, 1H), 8.33 (d, J= 2.0 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 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 (kv, 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 SLC 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 preparative SLC ( Prep LC Method I) to give 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (12.5 mg, 28 %). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 SLC 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 preparative SLC (Prep LC Method Q) to give 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (68 mg, 22 %). ¹ H NMR (CD ₃ OD, 400 MHz): 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 (brs, 1H), 4.07 (t, J= 6.5 Hz, 2H), 4 .00 (brs, 1H), 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, 1H), 1.09 (t, J= 7.3 Hz, 3H). LCMS m/z =343 [MH] ⁺ ; RT [Analytical SLC Method J] = 3.148 min. [α] ²⁰ _D -23.2 ( c =0.1, EtOH).

Example 23 : (-) 4-(2-(4-Methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-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) further purified preparative SLC (Prep SLC Method M) to give 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ( 100 mg, 18%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 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= 7.4 Hz, 3H). LCMS m/z =397 [MH] ⁺ ; RT [Analytical SLC Method E] = 4.765 min. [α] ²⁰ _D -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 preparative SLC (Prep SLC Method R) to give 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (6.4 mg, 34%). LCMS m/z =315 [MH] ⁺ . RT [Analytical SLC 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-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl) -5-(4-Methoxy-3-propoxyphenyl)pyridine (Production Example 8, 1.30 g, 2.41 mmol) in AcOH (10 ml) and water (5 ml) was stirred at about 50° C. for about 1 h. The mixture is concentrated and add EtOH (10 ml). The mixture is stirred at about 0° C. for about 15 minutes and filtered. The solid was washed with water (15 ml) and dried to give 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol (560 mg, 68 %). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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-2-yl)-6-(4 -methoxy-3-propoxyphenyl)pyridine (Preparation Example 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 give 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol (60 mg, 70%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 1.92-2.00 (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

4-(6-(4-Methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol mixture (Example 28, 50 mg, 0.15 mmol) and Adam's catalyst (10.0 mg, 0.044 mmol) in EtOAc (1.5 mL) were hydrogenated at 20 psi. surf at about 40° C. for about 2 hours. The reaction mixture is filtered through a pad of Celite® and the filtrate is 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 give 4-(6-(4-methoxy-3-propoxyphenyl)pyridine -2-yl)-3-methyl-1,2-oxaborolan-2-ol (40 mg, 80%). ¹ H NMR (CDCl ₃ .400 MHz): δ 7.73 (br, 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 (brs, 1H), 1.87 -1.96 (m, 2H), 1.70-1.80 (m, 1H), 1.08 (t, J= 7.4 Hz, 3H), 0.80 (d, J= 7.0 Hz, 3H). LCMS m/z =342 [MH] ⁺ .

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%) is obtained by a method similar to that described in Example 25 using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-ene -2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Preparation Example 32, 370 mg, 0.668 mmol). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 7.86-7.91 (m, 2H), 7.75 (d, J= 2.0 Hz, 1H ), 7.67 (dd, J= 2.0, 8.6 Hz, 1H), 7.36-7.44 (m, 1H), 7.07 (d, J= 8.6 Hz, 1H) , 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 = 7.4 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)propanoate (Preparation Example 33, 134 mg, 0.277 mmol) in THF (3.0 mL) at about 20°C, add LiBH ₄ (6.0 mg, 0.28 mmol) followed by water (0.10 mL ). The reaction mixture is stirred at about 20°C for about 3 hours Add another portion of LiBH ₄ (25 mg, 1.15 mmol) and water (0.2 ml). The mixture is stirred at about 20° C. for about 5 minutes. Add another portion of LiBH ₄ (25 mg, 1.15 mmol) and water (0.3 ml) and stir at about 20° C. for about 10 minutes. The mixture is diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine and dried over Na ₂ SO ₄ . The mixture is filtered, concentrated and dissolved in THF (3 ml) and water (1 ml). The solution is treated with excess LiBH ₄ at about 20° C. for about 3 hours. The mixture is diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep HPLC (Prep HPLC Method C) to give 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol (46.1 mg, 49%). ¹ H NMR (CD ₃ OD, 500 MHz): δ 7.80 (br, 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] ⁺ .

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-1,3,2-dioxaborolan-2-yl)butan-2-yl)-3-( 4-Methoxy-3-propoxyphenyl)pyridazine (Preparation Example 34, 160 mg, 0.29 mmol) in AcOH (6 ml) and water (1 ml) was stirred at about 70° C. for about 21 hours. The mixture was concentrated, dissolved in MeCN (15 ml) and concentrated again. The mixture was purified by preparative HPLC (Prep HPLC Method D) to give 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol (10.6 mg, 11%). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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, J= 6.0 Hz, 3H), 1.01 ( t, J= 7.0 Hz, 6H), 0.77 (d, J= 7.0 Hz, 1H). LCMS m/z =343 [MH] ⁺ .

Example 31 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-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 N ₂ for about 30 min to give a mixture that was used immediately in following method (Reagent A). To a solution of 3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (Preparation Example 77, 120 mg, 0. 25 mmol) in THF (0.50 ml) under N ₂ add Reagent A. The mixture is stirred at about 20° C. for about 1 hour. Trimethyl borate (0.33 ml, 2.98 mmol) is added and stirred at about 20° C under N ₂ for about 1 hour. The cooled mixture is treated with HCl in IPA (5.5 M, 0.45 ml, 2.48 mmol) for about 1 hour. The mixture is diluted with 1 M HCl and washed with EtOAc. The EtOAc layer was extracted with 1 M HCl (2×5 ml). The combined aqueous extracts are neutralized to pH 6-7 with K ₃ PO ₄ . The aqueous extract is extracted with EtOAc (3×10 ml). The combined EtOAc extracts are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative SLC (Prep SLC Method S) to give 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (38 mg, 43%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (d, J= 2.0 Hz, 1H), 8.63 (s, 1H), 8.37 (d, J= 2.0 Hz, 1H), 7.75(m, 1H), 7.19-7.28(m, 2H), 7.08(d, J= 8.6Hz, 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, 1H), 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-dioxaborolan-2-yl)propan-2-yl)-5-( 3,4-dimethoxyphenyl)pyridine (Preparation Example 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 preparative HPLC (Prep HPLC Method E) to give 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (98 mg, 17 %). ¹ H NMR ( DMSO- d ₆ , 400 MHz): δ 8.72 (d, J =2.8 Hz, 2H), 8.43 (d, J =2.0 Hz, 1H), 7.95 ( t, J= 2.0 Hz, 1H), 7.25-7.29 (m, 1H), 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, 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-dioxaborolan-2-yl)propan-2-yl)-5-( 3-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 3, 3.80 g, 7.20 mmol) in AcOH (60 mL) and water (10 mL) was stirred at about 50° C. for about 1 hour. The mixture was concentrated and the residue was purified by prep HPLC (Prep HPLC Method F) to give 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (810 mg, 34%) . ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (d, J= 2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J= 1.6 Hz, 1H), 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 (kv, 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] ⁺ .

Example 34 4-(5-(4-methoxy-3-propoxyphenyl)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-dioxaborolan-2-yl)propan-2-yl)-5-( 4-Methoxy-3-propoxyphenyl)pyridine (Preparation Example 5, 3.44 g, 6.35 mmol) in AcOH (60 mL) and water (10 mL) was stirred at about 50° C. for about 1 hour. The mixture was concentrated and the residue was purified by prep HPLC (Prep HPLC Method G) to give 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.04 g, 49 %), 1H NMR (DMSO- d ₆ , 400 MHz): 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= 7.4 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 a manner similar to that described in 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 -4-methoxyphenyl)pyridine (Preparation Example 9, 400 mg, 0.74 mmol) and purified by preparative HPLC (Prep HPLC Method H). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.92 (t, J= 2.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.07 (d, J= 8.0 Hz, 1H), 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 [MH] ⁺ .

Example 36 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-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 a manner similar to that described in 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 -4-methoxyphenyl)pyridine (Preparation Example 10, 750 mg, 1.39 mmol) and purified by preparative HPLC (Prep HPLC Method I). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69-8.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H), 7.28 (dd, J= 2.4, 8.3 Hz, 1H), 7.07 (d , J= 8.8 Hz, 1H), 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] ⁺ .

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%) is obtained by a method similar to that described in 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-(2-((t-Butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine (Preparation Example 11, 4.0 g, 6.1 mmol) and purified by prep HPLC (Prep HPLC Method J). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 4.25-4.30 (m, 1H), 4.09 (t, J= 5, 0 Hz, 2H), 3.86 (t, J= 9.0 Hz, 1H), 3.81 (s, 3H), 3.75 (kv, 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 =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%) is obtained by a method similar to that described in 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-(3-((t-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Preparation Example 12, 12 g, 18.0 mmol) and purified by prep HPLC (Prep HPLC Method K). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68-8.72 (m, 2H), 8.43 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.29 (d, J= 2.0 Hz, 1H), 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, 1H), 3.80 (s, 3H), 3.58 (kv, 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] ⁺ .

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 obtained by a method similar to that described in 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-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (Preparation Example 13, 700 mg, 1.28 mmol) and purified by preparative HPLC (Prep HPLC Method L). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, J= 8.0 Hz, 1H), 4.81-4.87 (m, 1H) , 4.70-4.75(m, 1H), 4.38-4.43(m, 1H), 4.30-4.34(m, 1H), 4.27(d, J= 8, 5 Hz, 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 obtained by a method similar to that described in 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 (Production Example 14) ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.50 (br s, 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, J =5.9 Hz, 1H), 4 .57 (t, J = 5.9 Hz, 1H), 4.26 (t, J = 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-2-ol

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol is obtained (80 mg, 42%) by a method similar to that described in 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-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 15, 300 mg, 0.519 mmol) and purified by preparative HPLC (Prep HPLC Method M). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, 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]-2-carbonitrile

To a solution of 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile (Example 43 , 500 mg, 1.43 mmol) in EtOAc (15 ml) was added with PtO ₂ (16 mg, 72 μmol) under N ₂ . The mixture was stirred under H ₂ (15 psi) at about 0° C. for about 2 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (Prep HPLC Method N) to give 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2- carbonitrile (284 mg, 55%), ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.45 (d, J= 8.8 Hz, 2H), 7.41 (d, J= 7.2 Hz, 1H), 7.34 (t, J= 7.2 Hz, 2H), 7.26 (d, J= 8.8 Hz, 1H), 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), 1.69-1.78 (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-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)acrylate (Preparation Example 30, 13.6 g, 28.5 mmol) in THF (150 ml) and MeOH (5 ml) NaBH ₄ (754 mg, 19.9 mmol) was added slowly at about 0°C. The mixture was stirred at about 20° C. for about 1 hour. Water (150 ml) was added and the mixture was extracted with EtOAc (2×150 ml). The combined EtOAc extracts were washed with brine (150 ml), dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (10:1), then recrystallized from EtOH (30 ml) at about 0°C to give 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4 -methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile (2.60 g, 26%). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 7.70 (s, 1H), 7.64-7.65 (m, 1H), 7.53 (d , J= 4.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 1H), 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] ⁺ .

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 a manner similar to that described in 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-ethoxy-5-fluoro-4-methoxyphenyl)pyridine (Preparation Example 16, 600 mg, 1.1 mmol) and purified by preparative HPLC (Prep HPLC Method O). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J= 1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd, J= 2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.21 (kv, 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 obtained by a method similar to that described in 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-chloro-5-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 17, 800 mg, 1.42 mmol) and purified by preparative HPLC (Prep HPLC Method P). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 8.02 (t, J= 2.2 Hz, 1H), 7.42 (d, J= 2.0 Hz, 1H), 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 a manner similar to that described in Example 33 , using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5 -(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (Preparation Example 18, 2.0 g, 3.67 mmol) and purified by preparative HPLC (Prep HPLC Method Q). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H). 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%) is obtained by a method similar to that described in 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-chloro-5-ethoxy-4-methoxyphenyl)pyridine (Preparation Example 19, 4.1 g, 7.30 mmol) and purified by preparative HPLC (Prep HPLC Method R). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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(kv, J =7.0Hz, 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%) is obtained according to the method, similar to that described in Example 33, using 5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan- 2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (Preparation Example 22, 4.02 g, 7.14 mmol) and purified by preparative HPLC (Prep HPLC Method S). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.49-3.57 (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] ⁺ .

Example 49 : 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2-Fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.2 g, 49%) is obtained by a method similar to that described in 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-5-propoxyphenyl)pyridine (Preparation Example 20, 4.0 g, 7.1 mmol) and purified by preparative HPLC (Prep HPLC Method T). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.89 (s, 1H), 8.74 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8, 09 (s, 1H), 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), 1.75-1.80 (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 by a method similar to that described in Example 33 , using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5 -(4-(difluoromethoxy)-3-propoxyphenyl)pyridine (Preparation Example 21, 2.6 g, 4.50 mmol) and purified by preparative HPLC (Prep HPLC Method U). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.74 (d, J =2.1Hz, 1H), 8.72 (s, 1H), 8.49 (d, J =2.0Hz, 1H), 8.00 (t, J = 2.0Hz, 1H), 7.45 (d, J = 1.6Hz, 1H), 7.28-7.31 (m, 2H), 7.09 ( t, 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 =382 [MH+H ₂ O] ⁺ .

Example 51 : 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol

4-(6'-Methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol is obtained (720 mg, 25%) by a method similar to that described in 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 (Preparation Example 23, 1.034 g, 1.9 mmol) and purified by preparative HPLC (Prep HPLC Method V). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.76 (d, J= 2.2 Hz, 1H), 8.72 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 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 =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 obtained by a method similar to that described in Example 33, using 5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3- (3-ethoxy-4-methoxyphenyl)-2-methylpyridine (Preparation Example 24, 700 mg, 1.29 mmol) and purified by preparative HPLC (Prep HPLC Method W). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67 (s, 1H), 8.33 (d, J= 2.0 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 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 (kv, 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] ⁺ .

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 a manner similar to that described in 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-ethoxy-4-methoxyphenyl)-4-methylpyridine (Preparation Example 35, 0.28 g, 0.51 mmol) and purified by preparative HPLC (Prep HPLC Method X). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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] ⁺ .

Example 54 : 4-(2-(4-Methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol

4-(2-(4-Methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol (314 mg, 95%) was obtained by a method similar to that described in Example 33, using ethyl 2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl )-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (Preparation Example 28, 500 mg, 0.96 mmol) and purified by preparative HPLC (Prep HPLC Method Y). ¹ H NMR (CD ₃ OD, 400 MHz): 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 (brs, 1H), 4.07 (t, J= 6.5 Hz, 2H), 4 .00 (brs, 1H), 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, 1H), 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)-1,2-oxaborolan-2-ol

4-(2-(4-Methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (582 mg, 36%) is obtained by a method similar to that described in Example 33 using 4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl) -2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (Preparation Example 25, 2.5 g, 4.09 mmol) and purified by preparative HPLC (Prep HPLC Method Z). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 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= 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 a manner similar to that described in Example 33 using 2 -(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(3- ethoxy-4-methoxyphenyl)pyrazine (Preparation Example 26, 720 mg, 1.36 mmol) and purified by preparative HPLC (Prep HPLC Method AA). ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, 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)-1,2-oxaborolan-2-ol

4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (0.2 g, 38.4%) was obtained according to the method , similar to that described in Example 33, using 4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan- 2-yl)-6-(((t-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (Preparation Example 29, 1.0 g, 1.5 mmol) and purified by preparative HPLC (Prep HPLC Method BA). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.00 (dd, J= 2.0, 8.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.27-7.31 (m, 1H), 7.06 (d, J= 8.5 Hz, 1H), 5.60 -5.66 (m, 1H), 4.59 (d, J= 6.0 Hz, 2H), 4.31 (dd, J= 7.0, 9.0 Hz, 1H), 3.96- 4.04 (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] ⁺ .

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 a manner similar to that described in Example 33, with 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 (Preparation Example 36, 1.42 g, 2.66 mmol) and purified by preparative HPLC (Prep HPLC Method CA). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (br s, 1H), 7.42-7.46 (m, 2H), 7.30 (s, 1H), 7.05 (d , J =8.3Hz, 1H), 4.24-4.28(m, 1H), 4.09(kv, J =7.0Hz, 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 [MH] ⁺ .

Example 59: (2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl )propan-1-ol

To hexylene glycol (1.0 g, 8.46 mmol) was added (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4, 0.051 g, 0.16 mmol) at about 20°C. The mixture is stirred until homogeneous to obtain (2R)-2-(5-(4-methoxy-3-propoxyphenyl)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 diastereoisomers (ratio 1:1). ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.64 (d, J =2.2 Hz, 1H), 8.32 (d, J =1.9 Hz, 1H), 7.77 ( t, J = 2.2 Hz, 1H), 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, 1H). LCMS m/z =428 [MH] ⁺ .

The following compounds, Example 60-, receive similarly, using the methods described above. Examples containing an asterisk (*) denote one enantiomer obtained by chiral purification methods. For these HPLC retention time (RT) HPLC examples, analytical HPLC methods are described.

Example No. Structure and name Analytical data 60

4-(5-метокси-6-пропокси-[2,3'-бипиридин]-5'-ил)-1,2-оксаборолан-2-ол

4-(5-methoxy-6-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 9.04 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.22 (t, J= 2.2 Hz, 1H), 7.61 (d, J= 7.8 Hz, 1H), 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, 1H), 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] ⁺ . Example 61

4-(5-methoxy-6-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d _6, 400 MHz): δ 9.04 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.22 (t, J= 2.2 Hz, 1H), 7.61 (d, J= 7.8 Hz, 1H), 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, 1H), 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 SLC Method I] = 4.57 min. 62

4-(5-methoxy-6-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d _6, 400 MHz): δ 9.04 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.22 (t, J= 2.2 Hz, 1H), 7.61 (d, J= 7.8 Hz, 1H), 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, 1H), 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 SLC Method I] = 4.98 min. 63

4-(3'-(2-fluoroethoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.51 (br s, 1H), 7.46 (d, J =7.8 Hz, 1H), 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), 4.69 -4.71(m, 1H), 4.36-4.38(m, 1H), 4.24-4.30(m, 2H), 3.79-3.83(m, 4H), 3 .42-3.51 (m, 1H), 1.26-1.32 (m, 1H), 1.05-1.12 (m, 1H). LCMS m/z =331 [MH] ⁺ . 64

4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.59 (br s, 1H), 7.69 (d, J= 2.0 Hz, 1H), 7.57-7.66 (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= 7.5Hz, 3H). LCMS m/z =376 [MH+H ₂ O] ⁺ . 65

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 4.90 (t, J= 5.9 Hz, 1H) , 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+H ₂ O] ⁺ . 66

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 LCMS m/z =354 [MH] ⁺ . RT [Analytical SLC Method V] = 3.60 min. 67

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2 LCMS m/z =354 [M+H] ⁺ . RT [Analytical SLC Method V] = 3.93 min. 68

4-(5-(4-methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.92 (t, J= 2.0 Hz, 1H), 7.31 (dd, J= 2.3, 8.3 Hz, 1H), 7.22 (d, J= 2 .5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 5.44-5.53 (m, 1H), 4.27 (t, J= 8.3 Hz, 1H ), 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

4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (MeOD- d ₃ , 400 MHz): δ 8.40 (d, J= 2.0 Hz, 1H), 8.31 (d, J= 2.5 Hz, 1H), 7.69 ( t, J= 2.0 Hz, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 4.06 (kv, 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

4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (br s, 1H), 8.31-8.49 (m, 2H), 7.66 (br s, 1H), 6.91 (br , 1H), 6.81(brs, 1H), 4.27(brs, 1H), 4.01(d, J= 5.9Hz, 2H), 3.73-3.90(m, 4H) , 3.49(brs, 1H), 2.18(brs, 3H), 1.30(brs, 3H), 0.99-1.16(m, 2H). LCMS m/z =346 [MH+H ₂ O] ⁺ . RT [Analytical SLC Method L] = 2.67 min. 71

4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (br s, 1H), 8.31-8.49 (m, 2H), 7.66 (br s, 1H), 6.91 (br , 1H), 6.81(brs, 1H), 4.27(brs, 1H), 4.01(d, J= 5.9Hz, 2H), 3.73-3.90(m, 4H) , 3.49(brs, 1H), 2.18(brs, 3H), 1.30(brs, 3H), 0.99-1.16(m, 2H). LCMS m/z =327 [MH] ⁺ . RT [Analytical SLC Method L] = 2.91 min. 72

4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 1.23-1.43 (m, 5H). LCMS m/z= 321.1 [MH] ⁺ . 73

4-(5-(3-ethoxy-2-fluoro-4-
methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 7, 81 (d, J= 1.5 Hz, 1H), 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

4-(5-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 7, 81 (d, J= 1.5 Hz, 1H), 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 SLC Method GA] = 6.58 min. 75

4-(3'-isopropoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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] ⁺ . 76

(-) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl) pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.00 (dd, J= 2.0, 8.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.27-7.31 (m, 1H), 7.06 (d, J= 8.5 Hz, 1H), 5.60 -5.66 (m, 1H), 4.59 (d, J= 6.0 Hz, 2H), 4.31 (dd, J= 7.0, 9.0 Hz, 1H), 3.96- 4.04 (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] ²⁰ _D -10.0 ( c =0.1, EtOH). 77

4-(3'-ethoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, 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

4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (brw, 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, 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] ⁺ . 79

4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, diastereomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (brw, 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, 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 SLC Method EA] = 3.30 min. 80

4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, diastereomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (brw, 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, 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 =372.1 [MH] ⁺ . RT [Analytical SLC Method EA] = 4.18 min. 81

4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.54 (t, J= 2.0 Hz, 1H), 8.48 (d, J= 2.0 Hz, 1H), 7.82 (d, J= 1.5 Hz, 1H), 7.26 (t, J= 8.7 Hz, 1H), 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] ⁺ . 82

4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.54 (t, J= 2.0 Hz, 1H), 8.48 (d, J= 2.0 Hz, 1H), 7.82 (d, J= 1.5 Hz, 1H), 7.26 (t, J= 8.7 Hz, 1H), 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 SLC Method E] = 4.76 min. 83

4-(6-(1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, diastereomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68 (s, 1H), 8.00 (dd, J= 2.0, 8.3 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J= 8.3 Hz, 1H), 5.57 (d, J= 4.9 Hz, 1H), 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+H ₂ O] ⁺ . RT [Analytical SLC Method E] = 4.07 min. 84

4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J= 7 .8 Hz, 1H), 6.90 (d, J= 2.0 Hz, 1H), 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, 1H), 0.97 (t, J= 7.3 Hz, 3H). LCMS m/z =342 [MH] ⁺ . 85

(+) 4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J= 7 .8 Hz, 1H), 6.90 (d, J= 2.0 Hz, 1H), 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, 1H), 0.97 (t, J= 7.3 Hz, 3H). LCMS m/z =342 [MH] ⁺ . [α] ²⁰ _D +14.7( c =0.1, EtOH). 86

6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J= 7.7 Hz, 1H), 7.60 (d, J= 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.44-7.49 (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), 1.70-1 .79 (m, 2H), 1.20-1.37 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). LCMS m/z =353 [MH] ⁺ . 87

6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J= 7.7 Hz, 1H), 7.60 (d, J= 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.44-7.49 (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), 1.70-1 .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 SLC Method M] = 5.79 min. 88

4-(4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol 1H NMR (DMSO- d ₆ , 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, 1H), 4.26 (t, J =8.0 Hz, 1H), 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] ⁺ . 89

4-(4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 1H NMR (DMSO- d ₆ , 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, 1H), 4.26 (t, J =8.0 Hz, 1H), 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 SLC Method N] = 3.76 min. 90

4-(4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 1H NMR (DMSO- d ₆ , 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, 1H), 4.26 (t, J =8.0 Hz, 1H), 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 SLC Method N] = 3.97 min. 91

4-(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, J= 6.9 Hz, 2H), 3.93 (dd, J= 7.5, 9.0 Hz, 1H), 3.83 (s, 3H), 3.57-3.66 (m, 1H), 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] ⁺ . 92

(-) 4-(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, J= 6.9 Hz, 2H), 3.93 (dd, J= 7.5, 9.0 Hz, 1H), 3.83 (s, 3H), 3.57-3.66 (m, 1H), 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 SLC Method O] = 4.13 min. [α] ²⁰ _D -37.9 ( c =0.1, EtOH). 93

4-(3-(4-(cyclopentyloxy)-5-methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67 (br s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 8.10-8.15 (m , 1H), 7.39-7.45 (m, 1H), 7.34-7.38 (m, 1H), 5.56-5.63 (m, 1H), 4.26-4.32 (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

4-(5-(3-ethoxy-4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 1H), 4.19-4.34 (m, 1H), 4.09 (td, J= 3.1, 9.9 Hz, 2H), 3.87-3.95 (m, 3H), 3.72-3.83(m, 1H), 3.46-3.55(m, 1H), 1.26-1.37(m, 4H), 1.00-1.13(m, 1H ). LCMS m/z =382 [MH] ⁺ . 95

4-(5-(3-ethoxy-4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 1H), 4.19-4.34 (m, 1H), 4.09 (td, J= 3.1, 9.9 Hz, 2H), 3.87-3.95 (m, 3H), 3.72-3.83(m, 1H), 3.46-3.55(m, 1H), 1.26-1.37(m, 4H), 1.00-1.13(m, 1H ). LCMS m/z =382 [MH] ⁺ . RT [Analytical SLC Method E] = 3.14 min. 96

4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68-8.75 (m, 2H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (s, 1H ), 7.27 (d, J= 2.0 Hz, 1H), 7.23 (dd, J= 1.8, 8.3 Hz, 1H), 7.04 (d, J= 8.5 Hz , 1H), 4.27 (t, J= 8.3 Hz, 1H), 4.13 (kv, J= 6.9 Hz, 2H), 4.06 (kv, J= 7.0 Hz, 2H ), 3.86 (t, J= 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J= 10.5, 16.1 Hz, 1H). LCMS m/z =328 [MH] ⁺ . 97

4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68-8.75 (m, 2H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (s, 1H ), 7.27 (d, J= 2.0 Hz, 1H), 7.23 (dd, J= 1.8, 8.3 Hz, 1H), 7.04 (d, J= 8.5 Hz , 1H), 4.27 (t, J= 8.3 Hz, 1H), 4.13 (kv, J= 6.9 Hz, 2H), 4.06 (kv, J= 7.0 Hz, 2H ), 3.86 (t, J= 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J= 10.5, 16.1 Hz, 1H). LCMS m/z = 345 [MH+H ₂ O] ⁺ . RT [Analytical SLC Method D] = 5.73 min. 98

4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68-8.75 (m, 2H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (s, 1H ), 7.27 (d, J= 2.0 Hz, 1H), 7.23 (dd, J= 1.8, 8.3 Hz, 1H), 7.04 (d, J= 8.5 Hz , 1H), 4.27 (t, J= 8.3 Hz, 1H), 4.13 (kv, J= 6.9 Hz, 2H), 4.06 (kv, J= 7.0 Hz, 2H ), 3.86 (t, J= 8.8 Hz, 1H), 3.45-3.54 (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 SLC Method D] = 5.37 min. 99

4-(5-(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 7.19-7.24 (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= 4.5Hz, 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

4-(5-(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 7.19-7.24 (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= 4.5Hz, 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+H ₂ O] ⁺ . RT [Analytical SLC Method P] = 3.83 min. 101

4-(5-(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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), 7.19-7.24 (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= 4.5Hz, 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+H ₂ O] ⁺ . RT [Analytical SLC Method P] = 4.17 min. 102

4-(2-(4-methoxy-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (brs, 1H), 7.99 (dd, J= 1.9, 8.4 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 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), 1.24-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.96- 1.06 (m, 3H). LCMS m/z =391 [MH+H ₂ O] ⁺ . 103

(-) 4-(2-(4-Methoxy-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (brs, 1H), 7.99 (dd, J= 1.9, 8.4 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 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), 1.24-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.96- 1.06 (m, 3H). LCMS m/z =391 [MH+H ₂ O] ⁺ . RT [Analytical SLC Method Q] = 3.25 min. [α] ²⁰ _D -38.3 ( c =0.1, EtOH). 104

4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J= 1.5 Hz, 1H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (t, J= 2.0 Hz, 1H), 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, 1H), 4.00-4.11 (m, 4H), 3 .86 (t, J= 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.70-1.80 (m, 3H), 1.27-1.37 (m , 3H), 1.10-1.19 (m, 1H), 1.00 (t, J= 7.5 Hz, 3H). LCMS m/z =342 [MH] ⁺ . 105

4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J= 1.5 Hz, 1H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (t, J= 2.0 Hz, 1H), 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, 1H), 4.00-4.11 (m, 4H), 3 .86 (t, J= 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.70-1.80 (m, 3H), 1.27-1.37 (m , 3H), 1.10-1.19 (m, 1H), 1.00 (t, J= 7.5 Hz, 3H). LCMS m/z = 342 [MH] ⁺ . RT [Analytical SLC Method R] = 3.48 min. 106

4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J= 1.5 Hz, 1H), 8.42 (d, J= 1.5 Hz, 1H), 7.93 (t, J= 2.0 Hz, 1H), 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, 1H), 4.00-4.11 (m, 4H), 3 .86 (t, J= 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.70-1.80 (m, 3H), 1.27-1.37 (m , 3H), 1.10-1.19 (m, 1H), 1.00 (t, J= 7.5 Hz, 3H). LCMS m/z =342 [MH] ⁺ . RT [Analytical SLC Method R] = 2.25 min. 107

4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.56 (dd, J= 2.0, 8.8 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.25-7.29 (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

4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 LCMS m/z = 332 [MH+H ₂ O] ⁺ . RT [Analytical SLC Method S] = 5.28 min. 109

4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 LCMS m/z= 318 [MH] ⁺ . RT [Analytical SLC Method S] = 5.35 min. 110

4-(4'-methoxy-3'-(pentyloxy)-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol LCMS m/z = 355 [MH] ⁺ . 111

(-) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.89 (s, 1H), 8.74 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8, 09 (s, 1H), 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), 1.75-1.80 (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 = 346 [MH] ⁺ . [ɑ] ²⁰ _D -17.7( c =0.15, EtOH). 112

4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.74 (d, J= 2.5 Hz, 1H), 8.73 (s, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.98 (t, J= 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.26 (d, J= 1.5 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 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 .27-1.36 (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, J= 7.5 Hz, 3H). LCMS m/z =344 [MH] ⁺ . 113

4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.74 (d, J= 2.5 Hz, 1H), 8.73 (s, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.98 (t, J= 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.26 (d, J= 1.5 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 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 .27-1.36 (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. 114

4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.74 (d, J= 2.5 Hz, 1H), 8.73 (s, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.98 (t, J= 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.26 (d, J= 1.5 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 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 .27-1.36 (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

4-(6-(4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 9.06 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.73 (br, 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

4-(2'-fluoro-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _{6 ,} 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) , 1.65-1.71(m, 2H), 1.26-1.28(m, 1H), 1.02-1.08(m, 1H), 0.98(t, J =8, 0 Hz, 3H). LCMS m/z =343 [MH] ^- . 117

3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1'-biphenyl]-3-carbonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.47 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 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 =324 [MH] ⁺ . 118

3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.47 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 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

3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.47 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 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 = 339.1 [MH] ⁺ .RT [Analytical FLC Method T] = 4.71 min. 120

4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.02 (d, J= 7.6 Hz, 1H), 7, 60 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.35 ( d, J= 8.0 Hz, 1H), 6.27 (s, 1H), 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] ⁺ . 121

4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.65 (s, 1H), 7.88 (s, 1H), 7.83 (d, J =7.6 Hz, 1H), 7, 49 (d, J = 8.0 Hz, 1H), 7.32-7.36 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 4.44 (q, J =7.2Hz, 2H), 4.27(t, J =8.0Hz, 1H), 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

4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (w dd, J = 8, 4, 16.2 Hz, 1H), 1.04 (w dd, J= 9.6, 16.1 Hz, 1H). LCMS m/z =317 [MH] ⁺ . 123

4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol, enantiomer 1 RT [Analytical SLC Method U] = 1.64 min. 124

(+) 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 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= 7.4 Hz, 3H). LCMS m/z =397 [MH+H ₂ O] ⁺ .[α] ²⁰ _D +19.4( c =0.1, EtOH). 125

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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] ⁺ . 126

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 SLC Method C] = 7.2 min. 127

4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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

(-) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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 =328 [MH] ⁺ . [α] ²⁰ _D -39.5 ( c= 3.8, EtOH). 129

4-(3'-(cyclopentyloxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborol-2(5H)-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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

4-(3'-(cyclopentyloxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.48 (s, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.21 (d, J= 7.6 Hz, 1H), 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= 8.0Hz, 1H), 1.05-1.11(m, 1H). LCMS m/z =353 [MH] ⁺ . 131

4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.61 (s, 1H), 7.68 (dd, J= 8.3, 11.8 Hz, 1H), 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, 1H), 3.97 (dd, J= 7.3, 8.8 Hz , 1H), 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 (br, 2H), 1.23-1.31 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z =344 [MH] ⁺ . 132

4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 1, 94 (d, J= 6.5 Hz, 2H), 1.68-1.82 (m, 4H), 1.59 (brs, 2H), 1.20-1.29 (m, 1H), 1 .09-1.18 (m, 1H). LCMS m/z =385 [MH] ⁺ . 133

ethyl 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl) pyrimidin-4-yl)acetate ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J= 2.0, 8.3 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 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) , 3.54-3.62 (m, 1H), 1.73-1.81 (m, 2H), 1.25-1.33 (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+H ₂ O] ⁺ . 134

2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetic acid ¹ H NMR (CD ₃ OD, 400 MHz): 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= 6.5Hz, 2H), 3.96-4.02(m, 1H), 3.90(s, 3H), 3, 70 (s, 2H), 3.40-3.46 (m, 1H), 1.81-1.90 (m, 2H), 1.15-1.31 (m, 2H), 1.08 ( t, J= 7.3 Hz, 3H). LCMS m/z =387 [MH] ⁺ . 135

4-(5-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.61 (s, 1H), 7.68 (dd, J= 8.8, 11.7 Hz, 1H), 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 , 1H), 4.27 (dd, J= 7.3, 8.8 Hz, 1H), 3.92-4.01 (m, 3H), 3.82 (s, 3H), 3.58- 3.65 (m, 1H), 1.71-1.80 (m, 2H), 1.23-1.31 (m, 1H), 1.11-1.19 (m, 1H), 0. 99 (t, J= 7.3 Hz, 3H). LCMS m/z =346 [MH] ⁺ . 136

4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 LCMS m/z =342.3 [MH] ⁺ . RT [Analytical SLC Method V] = 6.90 min. 137

4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 LCMS m/z = 342.3 [MH+H ₂ O] ⁺ .RT [Analytical SLC Method V] = 7.90 min. 138

4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol LCMS m/z =364.4 [MH] ⁺ . RT [Prep HPLC Method C] = 2.30 min. 139

4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72-8.92 (m, 1H), 8.50 (br, 1H), 6.95-7.01 (m, 1H), 6.86 (dd, J= 2.3, 8.2 Hz, 1H), 6.51-6.83 (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, 1H). LCMS m/z =364 [MH] ⁺ . RT [Analytical SLC Method W] = 3.95 min. 140

4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72-8.92 (m, 1H), 8.50 (br, 1H), 6.95-7.01 (m, 1H), 6.86 (dd, J= 2.3, 8.2 Hz, 1H), 6.51-6.83 (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, 1H). LCMS m/z =364 [MH] ⁺ . RT [Analytical SLC Method W] = 3.95 min. 141

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (CD ₃ OD, 400 MHz): 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, 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

(-) 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.02 (d, J= 11 .5 Hz, 1H), 6.86 (d, J= 7.5 Hz, 1H), 4.26 (t, J= 8.3 Hz, 1H), 4.00 (kv, J= 7.0 Hz, 2H), 3.93(brs, 1H), 3.82(s, 3H), 3.64-3.72(m, 1H), 2.14(s, 3H), 1.27-1 .38 (m, 4H), 0.98-1.12 (m, 1H). LCMS m/z = 346 [MH] ⁺ .[ɑ] ²⁰ _D -8.83 ( c = 0.1, EtOH). 143

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.02 (d, J= 11 .5 Hz, 1H), 6.86 (d, J= 7.5 Hz, 1H), 4.26 (t, J= 8.3 Hz, 1H), 4.00 (kv, J= 7.0 Hz, 2H), 3.93(brs, 1H), 3.82(s, 3H), 3.64-3.72(m, 1H), 2.14(s, 3H), 1.27-1 .38 (m, 4H), 0.98-1.12 (m, 1H). LCMS m/z = 346.2 [MH] ⁺ .RT [Analytical FLC Method X] = 3.52 min. 144

4-(5-(3-ethoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (s, 1H), 7.54 (s, 1H), 7.49 (d, J= 7.6 Hz, 1H), 7, 37 (t, J= 7.6 Hz, 1H), 7.26 (brs, 1H), 7.18-7.25 (m, 2H), 7.18 (s, 1H), 4.26 (t , J= 8.2 Hz, 1H), 4.19 (kv, J= 7.1 Hz, 2H), 3.81 (t, J= 8.9 Hz, 1H), 3.43-3.52 (m, 1H), 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

4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67-8.79 (m, 2H), 8.48 (d, J= 2.0 Hz, 1H), 7.99 (s, 1H ), 7.37-7.46 (m, 1H), 7.24-7.33 (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), 3.45-3.60 ( m, 1H), 1.69-1.86 (m, 2H), 1.25-1.38 (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] ⁺ . 146

(-) 4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.67-8.79 (m, 2H), 8.48 (d, J= 2.0 Hz, 1H), 7.99 (s, 1H ), 7.37-7.46 (m, 1H), 7.24-7.33 (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), 3.45-3.60 ( m, 1H), 1.69-1.86 (m, 2H), 1.25-1.38 (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] ⁺ . [α] ²⁰ _D -25.7 ( c =0.1, EtOH). 147

4-(5-(4-Methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (br s, 1H), 7.56-7.64 (m, 1H), 7.47 (d, J= 2.2 Hz, 1H ), 7.12 (d, J= 8.3 Hz, 1H), 4.29-4.35 (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, 1H), 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

(-) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.70 (br s, 1H), 7.56-7.64 (m, 1H), 7.47 (d, J= 2.2 Hz, 1H ), 7.12 (d, J= 8.3 Hz, 1H), 4.29-4.35 (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, 1H), 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] ⁺ .
[ɑ] ²⁰ _D -10.3 ( c =0.1, EtOH). 149

4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.65-8.74 (m, 2H), 8.43 (d, J= 1.7 Hz, 1H), 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 , 1H), 4.27 (t, J= 8.3 Hz, 1H), 3.86 (t, J= 9.0 Hz, 1H), 3.79 (s, 3H), 3.41-3 .59(m, 1H), 1.90(d, J= 6.4Hz, 2H), 1.66-1.80(m, 4H), 1.58(brs, 2H), 1.29( d, J= 8.3 Hz, 1H), 1.14 (dd, J= 10.4, 16.3 Hz, 1H). LCMS m/z =354 [MH] ⁺ . 150

4-(2'-fluoro-4',5'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 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

2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J= 7.7 Hz, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.50 (m, 1H), 7.33 (d, J= 7.8 Hz, 1H), 4.25 -4.31(m, 1H), 4.20(kv, J= 7.1Hz, 2H), 4.09(t, J= 8.7Hz, 1H), 3.91(s, 3H) , 3.60-3.68 (m, 1H), 1.21-1.38 (m, 5H). LCMS m/z =339 [MH] ⁺ . 152

4-(3-(5,6-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (s, 1H), 7.91 (s, 1H), 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, 1H), 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

6-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2,3-dimethoxybenzonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.57 (d, J= 2.0 Hz, 1H), 8.55 (d, J= 1.7 Hz, 1H), 7.93 (s, 1H), 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] ⁺ . 154

(-) 4-(2-(2-fluoro-4-methoxy-5-propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (s, 1H), 7.57 (d, J= 7.8 Hz, 1H), 7.34 (s, 1H), 6, 95 (d, J= 12.7 Hz, 1H), 5.62 (t, J= 5.6 Hz, 1H), 4.57 (d, J= 5.9 Hz, 2H), 4.26- 4.33 (m, 1H), 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] ⁺ . [ɑ] ²⁰ _D -11.9 ( c =0.1, EtOH). 155

4-(3-(5-Methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J= 7.2 Hz, 1H), 7, 60 (d, J= 8.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.36 ( d, J= 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s, 2H), 4.37 (t, J= 6.8 Hz, 2H), 3.83 ( s, 3H), 1.80 (kv, J= 6.8 Hz, 2H), 1.00 (t, J= 6.8 Hz, 3H). LCMS m/z =326 [MH] ⁺ . 156

4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J= 7.2 Hz, 1H), 7, 60 (d, J= 8.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.36 ( d, J= 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s, 2H), 4.37 (t, J= 6.8 Hz, 2H), 3.83 ( s, 3H), 1.80 (kv, J= 6.8 Hz, 2H), 1.00 (t, J= 6.8 Hz, 3H). LCMS m/z =328 [MH] ⁺ . 157

4-(3',4',5-trimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.84 (s, 3H), 3.79 (d, J= 8.0Hz, 7H), 3.40-3.50(m, 1H), 1.19-1.33(m, 1H), 1.08(dd, J= 10.0, 16.1Hz , 1H), 1.01-1.13 (m, 1H). LCMS m/z =329 [MH] ⁺ . 158

4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.80 (s, 3H), 3.49-3.57(m, 1H), 2.34(s, 3H), 1.72-1.80(m, 2H), 1.20-1.28(m, 1H), 1, 13-1.20 (m, 1H), 1.00 (t, J= 7.3 Hz, 3H). LCMS m/z =342 [MH] ⁺ . 159

4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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

4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 LCMS m/z =319.9 [MH] ⁺ . RT [Analytical SLC Method Y] = 5.76 min. 161

4-(3-(5,6-dimethoxypyridin-3-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 4.26 (t, J= 8.0 Hz, 1H), 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] ⁺ . 162

4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 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

4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 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

(-) 4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 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 =318 [MH] ⁺ . [ɑ] ²⁰ _D -20.6 ( c =0.22, EtOH). 165

4-(3'-(cyclopropylmethoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol 166

4-(3'-ethoxy-2'-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.36-7.39 (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 (kv, 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

4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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

(-) 4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 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] ⁺ .[ɑ] ²⁰ _D -18.8 ( c= 0.1, EtOH). 169

4-(5-(4-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.69 (br, 1H), 8.42 (br, 1H), 7.90 (br, 1H), 7.34 (s, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.09 (d, J= 8.3 Hz, 1H), 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

4-(5-(4-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.69 (br, 1H), 8.42 (br, 1H), 7.90 (br, 1H), 7.34 (s, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.09 (d, J= 8.3 Hz, 1H), 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 FLC Method Z] = 5.20 min. 171

4-(5-(3-ethoxy-4-methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 4.24 (t, J= 8.3 Hz, 1H), 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] ⁺ . 172

4-(3'-ethoxy-4'-(methylthio)-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (s, 1H), 7.54 (s, 1H), 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 (kv, J= 7.1 Hz, 2H), 3.81 (t, J= 8.9 Hz, 1H), 3.43-3.52 (m , 1H), 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

4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (d, J= 2.0 Hz, 1H), 8.02 (t, J= 2.2 Hz, 1H), 7.42 (d, J= 2.0 Hz, 1H), 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 = 348 [MH] ⁺ .RT [Analytical FLC Method E] = 5.33 min 174

4-(3-(4,5-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 7.29 (d, J= 7.2 Hz, 1H), 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(kv, J= 8.0Hz, 1H), 1.08(kv, J= 10.0Hz, 1H). LCMS m/z =300 [MH] ⁺ . 175

4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (ws, 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), 3.55-3.63 (m, 14.2 Hz, 1H), 1.93 (d, J= 5.5 Hz, 2H), 1.72(brs, 4H), 1.58(brs, 2H), 1.22-1.36(m, 2H). LCMS m/z =385 [MH] ⁺ . 176

4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (ws, 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), 3.55-3.63 (m, 14.2 Hz, 1H), 1.93 (d, J= 5.5Hz, 2H), 1.72(brs, 4H), 1.58(brs, 2H), 1.22-1.36(m, 2H). LCMS m/z = 385 [MH] ⁺ .RT [Analytical FLC Method Z] = 2.79 min. 177

3'-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4-dimethoxy-[1,1'-biphenyl]-2-carbonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.19-7.53 (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

4-(5-methoxy-4-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (brs, 1H), 3.39 (brs, 1H), 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] ⁺ . 179

4-(5-methoxy-4-propoxy-[2,3'-bipyridine]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (brs, 1H), 3.39 (brs, 1H), 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 SLC Method G] = 4.36 min. 180

4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl) pyridin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.81 (s, 3H), 3.46-3.54 (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 FLC Method L] = 3.58 min. 181

(-) 4-(5-(3-cyclopropoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (s, 1H), 7.78 (d, J= 2.2 Hz, 1H), 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, 1H), 4.12 (dd, J= 6 .6, 9.0 Hz, 1H), 3.97-3.99 (m, 1H), 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] ⁺ .[ɑ] ²⁰ _D -12.7 ( c = 0.1, EtOH). 182

4-(4'-ethoxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.50 (br, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz , 1H), 7.14-7.22 (m, 3H), 7.01 (d, J = 8.2 Hz, 1H), 4.26 (t, J = 7.8 Hz, 1H), 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] ⁺ . 183

4-(3'-isobutoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.44-7.56 (m, 2H), 7.32-7.39 (m, 1H), 7.15-7.24 (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+H ₂ O] ⁺ . 184

4-(3'-cyclobutoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 6.99-7.05 (m, 2H) , 4.75-4.83 (m, 1H), 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

4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO-d ₆ , 400 MHz): 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 (kv, 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, 1H), 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

(-) 4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO-d ₆ , 400 MHz): 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 (kv, 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, 1H), 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] ⁺ . [ɑ] ²⁰ _D -37.4 ( c =0.1, EtOH). 187

4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 8.3Hz, 1H), 4.05(kv, J= 7.2Hz, 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

4-(5-(4-ethoxy-3-methoxyphenyl) pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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= 8.3Hz, 1H), 4.05(kv, J= 7.2Hz, 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 FLC Method AA] = 3.61 min. 189

4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 FLC Method E] = 5.71 min. 190

4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.92 (t, J= 2.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.07 (d, J= 8.0 Hz, 1H), 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 [MH] ⁺ .RT [Analytical FLC Method BA] = 5.69 min. 191

3-ethoxy-3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1'-biphenyl]-2-carbonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.31-7.46 (m, 3H), 7.33-7.36 (m, 2H), 7.27 (d, J= 8, 8 Hz, 1H), 4.18-4.28 (m, 3H), 3.90 (s, 3H), 3.81 (t, J= 8.8 Hz, 1H), 3.45-3, 52 (m, 1H), 1.26-1.34 (m, 4H), 1.08-1.11 (m, 1H). LCMS m/z =338 [MH] ⁺ . 192

3-ethoxy-3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1'-biphenyl]-2-carbonitrile, enantiomer 2 RT [Analytical SLC Method CA] = 3.14 min. 193

4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69-8.72 (m, 2H), 8.44 (d, J = 2.0 Hz, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H), 7.28 (dd, J= 2.4, 8.3 Hz, 1H), 7.07 (d , J= 8.8 Hz, 1H), 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 FLC Method D] = 5.38 min. 194

(-) 4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.66 (br s, 1H), 7.42-7.46 (m, 2H), 7.30 (s, 1H), 7.05 (d , J =8.3Hz, 1H), 4.24-4.28(m, 1H), 4.09(kv, J =7.0Hz, 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 [MH] ⁺ .RT [Analytical FLC Method DA] = 4.47 min. [ɑ] ²⁰ _D -17.4 ( c = 0.1, EtOH). 195

4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 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, 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+H ₂ O] ⁺ . 196

(-) 4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl) pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 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, 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+H ₂ O] ⁺ .[ɑ] ²⁰ _D -38.9 ( c =0.1, EtOH) 197

4-(6-(3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 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), 3.57-3.60 (m, 1H), 1.15-1.29 (m, 2H) . LCMS m/z =298 [MH] ^- . 198

4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 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 (brs, 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

4-(6-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.60 (br s, 1H), 7.75-7.82 (m, 1H), 7.67 (t, J= 8.8 Hz, 1H ), 7.55 (d, J= 6.4 Hz, 1H), 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= 7.0Hz, 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

4-(1-(4-methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.61 (s, 1H), 8.30 (d, J= 2.0 Hz, 1H), 7.33 (d, J= 2.5 Hz, 1H), 7.25 (dd, J= 2.5, 8.5 Hz, 1H), 7.01 (d, J= 9.0 Hz, 1H), 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), 1.71-1.80 (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

4-(5-(3-methoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.60 (br s, 1H), 7.75-7.82 (m, 1H), 7.67 (t, J= 8.8 Hz, 1H ), 7.55 (d, J= 6.4 Hz, 1H), 7.25 (d, J= 7.6 Hz, 1H), 7.02 (d, J= 8.1 Hz, 1H), 4.25-4.32(m, 1H), 4.06(kv, J= 7.0Hz, 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] ⁺ . 202

4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.74 (s, 1H), 7.61-7.69 (m, 3H), 7.26 (s, 1H), 7.03 (d , J= 8.3 Hz, 1H), 5.40 (t, J= 5.6 Hz, 1H), 4.58 (d, J= 5.9 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 4.00 (t, J= 6.4 Hz, 2H), 3.82-3.89 (m, 1H), 3.81 (s, 3H), 3.47 -3.56 (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

4-(6-(3-ethoxy-4-(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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

4-(6-(3-ethoxy-4-(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 RT [Analytical SLC Method Y] = 7.70 min. 205

(+) 4-(5-(3-ethoxy-4-methoxyphenyl)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.70 (d, J= 2.0 Hz, 1H), 8.31 (s, 1H), 7.03 (d, J= 7.8 Hz, 1H), 6.72 (dd, J= 2.0, 3.9 Hz, 1H), 6.65 (dd, 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] ⁺ .[ɑ] ²⁰ _D +9.6 ( c = 0.1, EtOH). 206

4-(3'-methoxy-4'-(methylthio)-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.65 (s, 1H), 7.56 (s, 1H), 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

4-(3',4'-dimethoxy-5-methyl-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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

(+) 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 3.49-3.57 (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] ⁺ .[ɑ] ²⁰ _D +20.4 ( c = 0.1, EtOH). 209

4-(2'-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.66 (br, 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] ⁺ . 210

4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 1H), 7.03 (d, J= 8.3 Hz, 1H), 4.87-4.94 (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

4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 , 1H), 7.03 (d, J= 8.3 Hz, 1H), 4.87-4.94 (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 SLC Method EA] = 4.27 min. 212

4-(2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.71 (d, J= 5.1 Hz, 1H), 8.69 (s, 1H), 8.00 (dd, J= 1.8 , 8.4 Hz, 1H), 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] ⁺ . 213

4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.61 (s, 1H), 7.75-7.80 (m, 1H), 7.66 (t, J= 8.8 Hz, 1H ), 7.55 (dd, J= 1.8, 7.7 Hz, 1H), 7.24 (d, J= 7.6 Hz, 1H), 6.99-7.04 (m, 1H) , 4.27 (dd, J= 7.8, 8.6 Hz, 1H), 3.92-4.02 (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

4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.75 (d, J= 2.0 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J= 1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd, J= 2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.21 (kv, 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+H ₂ O] ⁺ . RT [Analytical SLC Method D] = 4.59 min. 215

4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.81 (d, J= 2.4 Hz, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7, 67 (t, J= 8.8 Hz, 1H), 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), 3.67-3.75 (m, 1H), 1.64-1.73 (m, 2H), 1.27-1, 36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t, J= 7.3 Hz, 3H). LCMS m/z =347 [MH] ⁺ . 216

4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.81 (d, J= 2.4 Hz, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7, 67 (t, J= 8.8 Hz, 1H), 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), 3.67-3.75 (m, 1H), 1.64-1.73 (m, 2H), 1.27-1, 36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t, J= 7.3 Hz, 3H). LCMS m/z =347 [MH] ⁺ . RT [Analytical SLC Method C] = 4.40 min. 217

4-(5-(4-ethoxy-2-fluoro-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d _6, 400 MHz): δ 8.72 (s, 1H), 8.54 (t, J= 2.0 Hz, 1H), 8.48 (d, J= 2.5 Hz, 1H), 7.82 (d, J= 1.5 Hz, 1H), 7.24 (t, J= 8.8 Hz, 1H), 6.98-7.02 (m, 1H), 4.25-4.31(m, 1H), 4.14(q, J= 6.9Hz, 2H), 3.81-3.87(m, 4H), 3.46-3.56( m, 1H), 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

4-(6'-methoxy-2-methyl-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO-d ₆ , 400 MHz): 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), 1.72-1, 77 (m, 2H), 1.26-1.30 (m, 1H), 1.07-1.11 (m, 1H), 0.96-1.00 (m, 3H). LCMS m/z =343 [MH] ⁺ . 219

(-) 4-(6'-methoxy-2-methyl-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO-d ₆ , 400 MHz): 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), 1.72-1, 77 (m, 2H), 1.26-1.30 (m, 1H), 1.07-1.11 (m, 1H), 0.96-1.00 (m, 3H). LCMS m/z = 343 [MH] ⁺ .RT [Analytical FLC Method Z] = 2.28 min. [ɑ] ²⁰ _D -16.2 ( c =0.1, EtOH). 220

4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR (MeOD- d ₃ , 400 MHz): δ 7.85 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.67 (dd, J= 2.0 , 8.3 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J= 8.8 Hz, 1H), 4.17 (kv, J= 7.2 Hz, 3H), 4.02(brs, 1H), 3.89(s, 3H), 3.57(brs, 1H), 1.45(t, J= 7.1Hz, 3H), 1.33-1.41 (m, 1H), 1.24-1.32 (m, 1H). LCMS m/z 382 [MH] ⁺ . 221

4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (d, J =2.8 Hz, 2H), 8.43 (d, J =2.0 Hz, 1H), 7.95 ( t, J= 2.0 Hz, 1H), 7.25-7.29 (m, 1H), 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, 1H), 1.12-1.18 (m, 1H). LCMS m/z =300 [MH] ⁺ . RT [Analytical SLC Method FA] = 6.04 min. 222

4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, J= 6.9 Hz, 2H), 4.25 (t, J= 8.0 Hz, 1H), 4.09 (kv, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48 (br, 1H), 1.36 (t, J= 7, 0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m, 1H). LCMS m/z [Analytical SLC Method FA] = 359 [MH] ⁺ . 223

4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): 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 (kv, J= 6.9 Hz, 2H), 4.25 (t, J= 8.0 Hz, 1H), 4.09 (kv, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48 (br, 1H), 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 SLC Method D] = 2.97 min. 224

4-(6-Methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J= 2.0, 8.5 Hz, 1H), 7.94-7.97 (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] ⁺ . 225

(-) 4-(6-methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J= 2.0, 8.5 Hz, 1H), 7.94-7.97 (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] ⁺ . [ɑ] ²⁰ _D -16.9 ( c = 0.1, EtOH). 226

2-(cyclopentyloxy)-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile ¹ H NMR (DMSO- d ₆ , 400 MHz): 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, 1H), 7.32 (d, J= 7.6 Hz, 1H), 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) , 3.59-3.68 (m, 1H), 1.79-1.93 (m, 4H), 1.68-1.76 (m, 2H), 1.54-1.63 (m, 2H), 1.28-1.36(m, 1H), 1.21-1.28(m, 1H). LCMS m/z =379 [MH] ⁺ . 227

4-(2-(3,4-dimethoxyphenyl)pyridin-4-yl)-1,2-oxaborol-2(5H)-ol ¹ H NMR (DMSO- d _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, 1H), 7.06 (d, J= 4.8 Hz, 1H), 6.58 (s, 1H), 5.00 (d, J= 1.6 Hz, 1H), 3.86 (m, 3H), 3.82 (s, 3H). LCMS m/z =298 [MH] ⁺ . 228

(+) 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 1H NMR (CD ₃ OD, 400 MHz): δ 8.60 (br, 1H), 8.37 (br, 1H), 7.93 (s, 1H), 7.22-7.30 (m, 2H ), 7.10 (d, J=8.3 Hz, 1H), 4.16 (t, J=4.6 Hz, 2H), 4.08 (br, 1H), 3.83-3.95 (m, 6H), 3.34-3.42 (m, 1H), 1.25-1.39 (m, 2H). LCMS m/z =330 [MH] ⁺ . [ɑ] ²⁰ _D +31.9 ( c =0.1, EtOH). 229

4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.85 (d, J= 2.0 Hz, 1H), 8.77 (s, 1H), 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 (kv, J= 6.8 Hz, 2H), 3.81 (s, 3H), 1.36 (kv, J= 6.8 Hz, 3H ).LCMS m/z =312 [MH] ⁺ . 230

4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 8.64 (br, 1H), 7.84 (dd, J= 3.4, 8.8 Hz, 1H), 7.67 (t, J = 4.6 Hz, 2H), 7.60 (dd, J= 1.5, 8.3 Hz, 1H), 7.03 (d, J= 8.8 Hz, 1H), 4.27 (t , J= 7.8 Hz, 1H), 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 SLC Method G] = 3.25 min. 231

(-) 4-(5-methoxy-2'-methyl-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO-d ₆ , 400 MHz): 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), 1.70-1.78 (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] ⁺ . [ɑ] ²⁰ _D -20.1 ( c =0.1, EtOH). 232

4-(3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.51 (s, 1H), 7.45 (bd, J= 7.6 Hz, 1H), 7.34-7.35 (m, 1H ), 7.16-7.23 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 4.22-4.28 (m, 1H), 3.84 (s, 3H), 3.81 (s, 1H), 3.79 (s, 3H), 3.42-3.51 (m, 1H), 1.25-1.31 (m, 1H), 1.05 -1.12 (m, 1H). LCMS m/z =299 [MH] ⁺ . Example 233

4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol ¹ H NMR ( DMSO- d _6, 400 MHz): δ 8.57 (s, 1H), 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. Single crystal X-ray diffraction data collection is carried out on a Bruker D8 Quest diffractometer at room temperature. Data collection consists of omega and phi scans. Structure is resolved via internal phasing using the SHELX software package in a Monoclinic class space group P2 ₁ . The structure is then refined by the least squares method in the full matrix approximation. All non-hydrogen atoms were found and refined using birefringent substitution parameters. Hydrogen atoms located on oxygen were found from the difference Fourier map and refined with fixed distances. The remaining hydrogen atoms were placed in the calculated positions and allowed to contact their carrier atoms. The final refinement includes isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using probabilistic methods (Hooft 2008) is performed using PLATON (Spek 2010). The Hooft parameter is indicated as 0.02 with HSD 0.003 and the Pearson parameter is indicated as 0.02 with HSD 0.003. The final R-index is 4.5%. The finite Fourier difference did not reveal the absence or shift of the electron density.

Figure 1 shows the resulting X-ray structure (ORTEP image) of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3). Crystal structure data are summarized in Table 1.

Table 1

Crystal Data and Structure Refinement for Example 3

Empirical formula C ₁₇ H ₂₀ BNO ₄ formula mass 313.15 Temperature 296(2) K Wavelength 1.54178 Å Crystal system monoclinic space group P2 ₁ Lattice constants a=11.0798(5) Å α= 90° b=13.1083(6) Å β= 99.346(2)° c=11.2398(6) Å γ = 90° Volume 1610.77(13) Å ³ Z 4 Density (calculated) 1.291 Mg/ ^m3 Absorption coefficient 0.738 mm ^-1 F(000) 664 Crystal size 0.360×0.220×0.140 mm ³ Theta interval for data collection 3.986 to 70.310° Index intervals -13<=h<=13, -16<=k<=15, -13<=l<=12 Collected Reflections 29459 Independent Reflections 6084 [R(int) = 0.0304] Completeness to theta=67.679° 99.9% Absorption correction empirical Refinement method The method of least squares in full-matrix approximation on F ² Data/Restrictions/Parameters 6084/3/426 Adequacy criterion on F ² 1.132 End R indices [I>2sigma(I)] R1=0.0446, wR2=0.1005 R indices (all data) R1=0.0452, wR2=0.1013 Absolute Structure Parameter 0.02(3) extinction coefficient 0.125(4) The largest peak and trough of the diff. 0.307 and -0.371 e.Å ^-3

Single crystal X-ray analysis of crystalline (R) 4-(5-(4-methoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4)

The crystal structure of Example 4 was determined by single crystal X-ray diffraction. Single crystal X-ray diffraction data collection is carried out on a Bruker D8 Venture diffractometer at -150°C. Data collection consists of omega and phi scans. Structure is resolved via internal phasing using the SHELX software package in a Monoclinic class space group P2 ₁ . The structure is then refined by the least squares method in the full matrix approximation. All non-hydrogen atoms were found and refined using birefringent substitution parameters. Hydrogen atoms located on oxygen were found from the difference Fourier map and refined with fixed distances. The remaining hydrogen atoms were placed in the calculated positions and allowed to contact their carrier atoms. The final refinement includes isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using probabilistic methods (Hooft 2008) is performed using PLATON (Spek 2010). The Hooft parameter is listed as 0.08 s HSD 0.003 and the Pearson parameter is listed as 0.15 s HSD 0.003. The final R-index is 4.6%. The finite Fourier difference did not reveal the absence or shift of the electron density.

Figure 2 shows the resulting X-ray structure (ORTEP image) of crystalline (R) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4). Crystal structure data are summarized in Table 2.

table 2

Crystal Data and Structure Refinement for Example 4

Empirical formula C ₁₈ H ₂₂ BNO ₄ formula mass 327.17 Temperature 123(2) K Wavelength 1.54178 Å Crystal system monoclinic space group P2 ₁ Lattice constants a=10.7077(14) Å α= 90° b=13.4140(17) Å β= 110.396(5)° c=13.0151(16) Å γ = 90° Volume 1752.2(4) Å ³ Z 4 Density (calculated) 1.240 Mg/ ^m3 Absorption coefficient 0.699 mm ^-1 F(000) 696 Crystal size 0.240×0.160×0.120 mm ³ Theta interval for data collection 3.623 to 72.240° Index intervals -12<=h<=13, -16<=k<=16, -16<=l<=16 Collected Reflections 63647 Independent Reflections 6737 [R(int) = 0.0312] Completeness to theta=67.679° 98.8% Absorption correction empirical Refinement method The method of least squares in full-matrix approximation on F ² Data/Restrictions/Parameters 6737/3/443 Adequacy criterion on F ² 1.044 End R indices [I>2sigma(I)] R1=0.0457, wR2=0.1282 R indices (all data) R1=0.0477, wR2=0.1311 Absolute Structure Parameter 0.08(3) extinction coefficient n/a The largest peak and trough of the diff. 0.279 and -0.203 e.Å ^-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 is also determined by single crystal X-ray diffraction. Single crystal X-ray diffraction data collection is carried out on a Bruker D8 Quest diffractometer at room temperature. Data collection consists of omega and phi scans. Structure is resolved via internal phasing using the SHELX software package in a Monoclinic class space group P2 ₁ . The structure is then refined by the least squares method in the full matrix approximation. All non-hydrogen atoms were found and refined using birefringent substitution parameters. Hydrogen atoms located on oxygen were found from the difference Fourier map and refined with fixed distances. The remaining hydrogen atoms were placed in the calculated positions and allowed to contact their carrier atoms. The final refinement includes isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using probabilistic methods (Hooft 2008) is performed using PLATON (Spek 2010). The Hooft parameter is indicated as 0.01 with HSD 0.007 and the Pearson parameter is indicated as 0.01 with HSD 0.006. The final R-index is 4.8%. The finite Fourier difference did not reveal the absence or shift of the electron density.

Figure 3 shows the resulting X-ray structure (ORTEP image) of crystalline (S)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5). Crystal structure data are summarized in Table 3.

Table 3

Crystal Data and Structure Refinement for Example 5

Empirical formula C ₁₈ H ₂₂ BNO ₄ formula mass 327.17 Temperature 296(2) K Wavelength 1.54178 Å Crystal system monoclinic space group P2 ₁ Lattice constants a=10.6918(4) Å α= 90° b=13.4115(6) Å β= 110.311(2)° c=13.0161(6) Å γ = 90° Volume 1750.37(10) Å ³ Z 4 Density (calculated) 1.242 Mg/ ^m3 Absorption coefficient 0.700 mm ^-1 F(000) 696 Crystal size 0.260×0.220×0.140 mm ³ Theta interval for data collection 3.621 to 70.234° Index intervals -12<=h<=13, -16<=k<=16, -15<=l<=15 Collected Reflections 16854 Independent Reflections 6536 [R(int) = 0.0328] Completeness to theta=67.679° 99.3% Absorption correction empirical Refinement method The method of least squares in full-matrix approximation on F ² Data/Restrictions/Parameters 6536/3/446 Adequacy criterion on F ² 1.065 End R indices [I>2sigma(I)] R1=0.0478, wR2=0.1176 R indices (all data) R1=0.0512, wR2=0.1220 Absolute Structure Parameter 0.01(7) extinction coefficient 0.0385(19) The largest peak and trough of the diff. 0.236 and -0.273 e.Å ^-3

Single crystal X-ray analysis of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19)

The crystal structure of Example 19 was also determined by single crystal X-ray diffraction. Single crystal X-ray diffraction data collection is carried out on a Bruker D8 Quest diffractometer at room temperature. Data collection consists of omega and phi scans. Structure is resolved via internal phasing using the SHELX software package in a Monoclinic class space group P2 ₁ . The structure is then refined by the least squares method in the full matrix approximation. All non-hydrogen atoms were found and refined using birefringent substitution parameters. Hydrogen atoms located on oxygen were found from the difference Fourier map and refined with fixed distances. The remaining hydrogen atoms were placed in the calculated positions and allowed to contact their carrier atoms. The final refinement includes isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using probabilistic methods (Hooft 2008) is performed using PLATON (Spek 2010). The Hooft parameter is indicated as 0.06 with HSD 0.003 and the Pearson parameter is indicated as 0.06 with HSD 0.003. The final R-index is 4.0%. The finite Fourier difference did not reveal the absence or shift of the electron density.

Figure 4 shows the resulting X-ray structure (ORTEP image) of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19). Crystal structure data are summarized in Table 4.

Table 4

Crystal Data and Structure Refinement for Example 19

Empirical formula C ₃₆ H ₄₄ B ₂ N ₂ O ₈ formula mass 654.35 Temperature 296(2) K Wavelength 1.54178 Å Crystal system monoclinic space group P2 ₁ Lattice constants a=11.2655(18) Å α= 90° b=12.903(2) Å β= 111.269(5)° c=12.959(2) Å γ = 90° Volume 1755.4(5) Å ³ Z 2 Density (calculated) 1.238 Mg/ ^m3 Absorption coefficient 0.698 mm ^-1 F(000) 696 Crystal size 0.420×0.360×0.120 mm ³ Theta interval for data collection 3.660 to 72.747° Index intervals -13<=h<=13, -15<=k<=15, -15<=l<=16 Collected Reflections 53020 Independent Reflections 6907 [R(int) = 0.0361] Completeness to theta=67.679° 100.0% Absorption correction empirical Refinement method The method of least squares in full-matrix approximation on F ² Data/Restrictions/Parameters 6907/3/446 Adequacy criterion on F ² 1.055 End R indices [I>2sigma(I)] R1=0.0396, wR2=0.1023 R indices (all data) R1=0.0414, wR2=0.1043 Absolute Structure Parameter 0.06(4) extinction coefficient 0.0261(13) The largest peak and trough of the diff. 0.230 and -0.298 e.Å ^-3

X-ray powder diffraction

The crystal structures of examples 3, 4, 5, 10 and 19 are analyzed using X-ray powder diffraction ("XRD").

For Example 4, X-ray powder diffraction was performed using a Bruker AXS D8 ADVANCE diffractometer equipped with a Cu (K-α average) radiation source. The system is equipped with 2.5 Soller axial slots on the primary circuit. On the secondary circuit, 2.5 axial Soller slots and motor slots are used. Diffracted radiation is detected by the Lynx Eye XE sensor. The voltage and current of the X-ray tube are set to 40 kV and 40 mA, respectively. Data is collected on a Theta-Theta goniometer at a Cu wavelength of 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 are obtained by placing them in a low background holder (Bruker part number: C79298A3244B261) and rotating during collection. Data is collected using the Bruker DIFFRAC Plus software. The analysis is carried out in the EVA diffract plus program. The TX data file is not processed until the peak is detected. Using the peak search algorithm in the EVA program, the peaks selected with a threshold value of 1 and a width of 0.3 are used to perform a preliminary peak determination. To ensure reliability, adjustments are made manually; the output of the automatic determinations is visually checked and the peak positions are adjusted to the maximum peak. Usually choose peaks with a relative intensity ≥3%. Peaks that are not resolved or correspond to noise are not selected. The typical error associated with the position of the peak from the XRD is specified in the USP up to +/-0.2° 2-Theta (USP-941).

For examples 3, 5, 10 and 19, X-ray powder diffraction was performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu (K-α average) radiation source. The system is equipped with 2.5 Soller axial slots on the primary circuit. On the secondary circuit, 2.5 axial Soller slots and motor slots are used. Diffracted radiation is detected by the Lynx Eye XE sensor. The voltage and current of the X-ray tube are set to 40 kV and 40 mA, respectively. Data is collected with a Theta-2Theta goniometer at a Cu wavelength of 3.0 to 43.0 degrees 2-Theta using a step size of 0.020 degrees and a step time of 3 seconds per step. Samples are obtained by placing them in a low background holder (Bruker part number: C79298A3244B261) and rotating during collection. Data is collected using the Bruker DIFFRAC Plus software. The analysis is carried out in the EVA diffract plus program. The TX data file is not processed until the peak is detected. Using the peak search algorithm in the EVA program, the peaks selected with a threshold value of 1 and a width of 0.3 are used to perform a preliminary peak determination. To ensure reliability, adjustments are made manually; visually check the output of automatic determinations, and the positions of the peaks are adjusted to the maximum peak. Usually choose peaks with a relative intensity ≥3%. Peaks that are not resolved or correspond to noise are not selected. The typical error associated with the position of the peak from the XRD is specified in the USP up to +/-0.2° 2-Theta (USP-941).

As one skilled in the art of crystallography will appreciate, the relative intensities of the various peaks presented in the tables and figures below may vary due to a number of factors such as the degree of orientation of the 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 largely as defined. One skilled in the art of crystallography will also appreciate that measurements using a different wavelength will result in different shifts according to the Bragg equation -nλ=2d sin θ. Such additional samples of the XRP crystalline materials of the present invention, as such, are included in the scope of this information.

Figure 5 shows the X-ray powder diffraction profile for crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3) and in Table 5 lists the PRD peaks.

Table 5

DRP Data for Example 3

Angle 2-Theta (degrees) Rel. intensity % 10.5 87.7 12.3 19.2 13.5 10.1 15.8 10.6 16.0 15.9 16.2 6.0 17.3 2.8 18.3 71.9 20.4 3.8 21.0 7.9 21.1 7.0 21.5 63.0 22.9 27.1 23.8 6.4 24.4 67.2 24.9 100.0 25.4 23.3 25.6 14.4 26.5 10.8 27.8 17.4 28.4 6.2 29.2 3.3 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 shows the X-ray powder diffraction profile for crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4) and in Table 6 lists the peaks of the PRD.

Table 6

DRP Data for Example 4

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 shows the X-ray powder diffraction profile for crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5) and in Table 7 lists the PRD peaks.

Table 7

DRP Data for Example 5

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 shows the X-ray powder diffraction profile for crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ( Example 10) and Table 8 lists the PRD peaks.

Table 8

DRP data for Example 10

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 shows the X-ray powder diffraction profile for crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19 ) and Table 9 lists the PRD peaks.

Table 9

DRP data for Example 11

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 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

Composition examples

In one embodiment, the present invention provides a topical pharmaceutical composition comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% (wt. /mass.) to about 15% (wt./mass.) solvent and (c) the base for the ointment. In one embodiment, the present invention provides a topical pharmaceutical composition comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% (w/w) ./mass.) to about 15% (wt./mass.) solvent and (c) petrolatum. In one embodiment, the present invention provides a topical pharmaceutical composition comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% (w/w) ./wt.) to about 15% (wt./wt.) solvent, (c) ointment, (d) antioxidant, (e) stabilizer, (f) emulsifying agent and (g) filler that increases the stiffness of the mixture. In one embodiment, the present invention provides a topical pharmaceutical composition comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% (w/w) ./wt.) to about 15% (wt./wt.) solvent, (c) ointment, (d) antioxidant, (e) emulsifying agent and (f) filler that increases the stiffness of the mixture. In one embodiment, the present invention provides a topical pharmaceutical composition comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% (w/w) ./mass.) to about 15% (wt./mass.) solvent, (c) petrolatum, (d) antioxidant, (e) emulsifying agent and (f) filler that increases the stiffness of the mixture. In one embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 8% (w/w) ./wt.) to about 10% (wt./wt.) propylene or hexylene glycol, (c) from about 75% (wt./wt.) to about 80% (wt./wt.) medical petrolatum, ( d) about 8% (w/w) to about 10% glyceride mixture, (e) about 4% to about 6% paraffin, and (f) about 0.05% to 0.5% butylated hydroxytoluene. In one embodiment, the present invention provides a topical pharmaceutical formulation comprising: (a) an active agent of the invention that treats an inflammation-related condition, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 8% (w/w) ./wt.) to about 10% (wt./wt.) hexylene glycol, (c) from about 75% (wt./wt.) to about 80% (wt./wt.) medical petrolatum, (d) from about 8% (w/w) to about 10% glyceride mixture, (e) about 4% to about 6% paraffin, and (f) about 0.05% to 0.5% butylated hydroxytoluene.

In one embodiment, the present invention provides a topical pharmaceutical composition containing an active agent, where the "active agent" is a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate 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 salt, hydrate or solvate 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 salt, hydrate or solvate 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 salt, hydrate or solvate 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 salt thereof , hydrate or solvate. In another embodiment, the active agent is (-)-4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or its a pharmaceutically acceptable salt, hydrate or solvate.

In another embodiment, the present invention provides a topical pharmaceutical composition containing an active agent present at a concentration of from about 0.0001% to about 3.0% (w/w). In another embodiment, the active agent is present at a concentration of from about 0.001% to about 2.0% (w/w). In another embodiment, the active agent is present at a concentration of from about 0.01% to about 1.0% (w/w). In another embodiment, the active agent is present at a concentration of from about 0.05% to about 0.5% (w/w).

In another embodiment, the present invention provides an active agent or its salt, hydrate or solvate. In another embodiment, the present invention provides a combination of an active agent and a second active agent, wherein the second active agent is used to treat inflammatory disorders such as atopic dermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, wound healing and inflammation after surgical complications. The combination may consist of a mixture or co-formulation of the two active ingredients. Alternatively, the combination can be packaged in a dispenser where one active agent is in one chamber and the other active ingredient is in a second chamber, but when dosing, the two active agents are simultaneously delivered together so that administration of the combination can occur in a single application. Alternatively, the active agents may be administered separately with another active agent, where the second active agent may be administered orally or topically.

In another embodiment, the present invention provides the active agent described herein, or its salt, hydrate or solvate, in a local composition that contains a solvent. In another embodiment, the solvent is an alkyl glycol or an 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 butylene glycol. In another embodiment, the solvent is present at a concentration of from about 5.0% (w/w) to about 15.0% (w/w). In another embodiment, the solvent is present at a concentration of from about 6.0% (w/w) to about 12.0% (w/w). In another embodiment, the solvent is present at a concentration of from about 7.0% (w/w) to about 11.0% (w/w). In another embodiment, the solvent is present at a concentration of from about 8.0% (w/w) to about 10.0% (w/w).

In another embodiment, the present invention provides the active agent described herein, or a salt, hydrate or solvate thereof, in a topical formulation that contains an ointment base. In another embodiment, the base for the ointment is medical vaseline. In another embodiment, the ointment base is petrolatum, petrolatum, yellow petrolatum, yellow soft paraffin, yellow petrolatum, medical petrolatum, or white soft paraffin. In another embodiment, the base is mineral oil, light mineral oil, paraffin, or lanolin alcohol. The amount of ointment base in a topical pharmaceutical composition will depend on the amounts of the other components. In another embodiment, the ointment base is present in sufficient concentration. In another embodiment, the ointment base is present at a concentration of from about 65% (w/w) to about 85% (w/w). In another embodiment, the base is present at a concentration of from about 70% (w/w) to about 80% (w/w). In another embodiment, the base is present at a concentration of from about 75% (w/w) to about 80% (w/w).

In another embodiment, the present invention provides the active agent described herein, or a salt, hydrate or solvate thereof, in a topical formulation, which further contains an antioxidant. In another embodiment, the antioxidant is butylated hydroxytoluene, ascorbic acid, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butyl hydroquinone, or tocopherol. In another embodiment, the antioxidant is butylated hydroxytoluene. In another embodiment, the antioxidant is present at a concentration of from about 0.01% (w/w) to about 1% (w/w). In another embodiment, the antioxidant is present at a concentration of from about 0.01% (w/w) to about 0.5% (w/w). In another embodiment, the antioxidant is present at a concentration of from about 0.05% (w/w) to about 0.5% (w/w). In another embodiment, the antioxidant is present at a concentration of from 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 mixture. In another embodiment, the emulsifying agent is a glyceride mixture, where the glyceride mixture contains a monoglyceride and a diglyceride. In another embodiment, the emulsifying agent is a glyceride mixture, wherein the glyceride mixture contains a monoglyceride, a diglyceride, and a triglyceride. In another embodiment, the emulsifying agent is a glyceride mixture, wherein the glyceride mixture comprises a monoglyceride and a diglyceride, and wherein from about 40% (w/w) to about 55% (w/w) of the glyceride mixture is monoglyceride. In another embodiment, the emulsifying agent is a glyceride mixture, wherein the glyceride mixture comprises a monoglyceride, a diglyceride, and a triglyceride, and wherein from about 40% (w/w) to about 55% (w/w) of the glyceride mixture is 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 one 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 mixture is present at a concentration of from about 3.0% (w/w) to about 10.0% (w/w). In another embodiment, the glyceride mixture is present at a concentration of from about 5.0% (w/w) to about 10.0% (w/w). In another embodiment, the glyceride mixture is present at a concentration of from about 6.0% (w/w) to about 8.0% (w/w).

In another embodiment, the topical pharmaceutical formulation further comprises an excipient to increase the stiffness of the mixture. In another embodiment, the hardening agent is a wax. In another embodiment, the hardening agent is a wax and the wax is selected from the group consisting of beeswax, paraffin and spermaceti wax. In another embodiment, the filler that increases the hardness of the mixture is paraffin. In another embodiment, the stiffener is present at a concentration of from about 3.0% (w/w) to about 7.0% (w/w). In a preferred embodiment, the stiffener is present at a concentration of from about 4.0% (w/w) to about 6.0% (w/w). In another embodiment, the stiffening agent is present at a concentration of from 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 salt thereof. In another embodiment, the stabilizer is a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid and the salt is a sodium salt or a potassium salt or a calcium salt, or a combination thereof. In another embodiment, the stabilizer is present at a concentration of from about 0.000010% (w/w) to about 0.0450% (w/w).

The composition of topical formulations of the compounds of the present invention includes excipients that provide at least one of the following functionality: solvent; basics; a dispersing agent; emulsifying agent; a filler that increases the rigidity of the mixture; a rheology modifying agent; stabilizing agent; and an antioxidant. For example, suitable topical ointment formulations, for example, include, but are not limited to, those listed in Tables 10, 11, 13, and 14. In addition to the ointment formulations listed in Tables 10 and 11, other formulations for topical use, suitable compounds of the present invention include, but are not limited to, creams, lotions, gels, solutions, suspensions, foams, and sprays.

Table 10

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 Hexylene glycol 2-9 Transcutol 2-9 Diisopropyl adipate 2-20 PEG 400 2-9 propylene carbonate 2-9 Medical Vaseline dk dk dk dk dk dk 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 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

*dk or sufficient quantity means sufficient quantity to obtain full volume=100%

The topical formulations prepared with Example 4, on which the skin permeability and maximum flux of Example 4 are tested, are listed in Table 11.

Table 11

Quantity (% w/w) Example 4 1 0.1 0.01 0 Medical Vaseline, 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, NF 5 5 5 5 Hexylene Glycol, NF/USP 9 9 9 9 Total (%) 100.0 100.0 100.0 100.0

An in vitro skin permeability study or a Franz cell assay is used to demonstrate the ability of the formulations of Table 11 to allow Example 4 to penetrate the stratum corneum barrier and progress through the epidermis and dermis through the flow measurement. The formulations exhibit concentration-dependent flux through the skin (Table 12) and can accommodate a wide range of concentrations of Example 4, providing a range of thermodynamic driving forces for Example 4 to penetrate the skin. Higher driving force can be achieved by including additional penetration enhancers such as oleyl alcohol in formulations.

Table 12

Total Penetrated Amount and Maximum Flow of Example 4

Example 4 Compositions from Table 11 N* 24 hour total, mean (ng) 24 hour total, standard error (ng) Maximum flow, average (ng/ ^cm2 /h) Maximum flow, standard error (ng/cm ² /h) 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 donors=3; Repeats per donor=5.

Table 13

Quantity (% w/w) Example 4 0.001-1 0.001-1 0.001-1 0.001-1 Medium Chain Triglycerides* 2-20 Cromadol GTCC 2-20 Cromadol GMCC 2-20 Triacetin 2-10 Medical Vaseline dk dk dk dk 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 0-5 0-5 0-5 0-5 Total (%) 100.0 100.0 100.0 100.0

* Medium chain triglycerides contain two or three fatty acids having an aliphatic tail of 6-12 carbon atoms.

Table 14

Local compositions of Example 4 in the form of an ointment

Component milligrams/grams (mg/g) milligrams/grams (mg/g) milligrams/grams (mg/g) Example 4 0.100 0.300 0.600 Hexylene glycol 90,000 90,000 90,000 Medical Vaseline 788.900 788.700 788.400 Mono- and diglycerides 70,000 70,000 70,000 Paraffin 50,000 50,000 50,000 Butylated hydroxytoluene (BHT) 1,000 1,000 1,000 Total 1000,000 1000,000 1000,000

Biological analyzes

PDE4 SPA analysis

Phosphodiesterase (PDE) activity is determined by measuring the effect of a test agent on PDE4B enzyme activity in a scintillation proximity assay (SPA). During the assay, approximately 30 µl of PDE4B (aa 152-484, Uniprot ID Q07343) in 50 mM Tris pH 7.5, 1.3 mM MgCl ₂ , 0.004% Brij 35 is added to a 384-well white clear bottom polystyrene plate (Corning ) containing 1 µl of varying concentrations of the test compound. After ~10 minutes at room temperature (RT; ~21°C), the assay is started by adding 20 µl of a mixture of ³ H-labeled (adenosine 3',5'-cyclic phosphate, ammonium salt, [ ^2.8-3 H]; Perkin Elmer) and unlabeled cAMP. Final assay conditions include approximately 81.6 pM PDE4B in 50 mM Tris pH 7.5, 1.3 mM MgCl ₂ , 0.004% Brij 35, 1 μM ³ H-labeled/unlabeled cAMP (1425 r/min/pmol) and the indicated final concentration of the test compound (approximately 10 μM to 9.5 pM at 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 adding approximately 20 μl of an aqueous solution of PDE YSI SPA beads (8 mg/ml in water; Perkin Elmer). The beads are allowed to settle for at least 2 hours and the plate is then read on MicroBeta2 (Perkin Elmer). The concentration and effect values for the test compounds are plotted and the compound concentrations required for 50% effect (IC50) are determined using a four parameter logistic dose-response equation (E-WorkBook, ID Business Solutions Ltd.) and are shown in Table 15.

Cytokine analysis

Cytokine inhibitory activity is determined by measuring the effect of the test agent on the release of cytokines IL-4, IL-13 and IFNγ from human peripheral blood mononuclear cells (PBMC) stimulated with the T-cell mitogen phytohemagglutinin-L (PHA-L). During analysis, human PBMCs (Astarte Biologics) are taken out of cryopreservation, rapidly thawed at 37°C, diluted in assay medium (RPMI medium - Gibco 1640, 10% heat-inactivated fetal bovine serum (HIFBS), 2 mM glutamine and 10 mM HEPES pH 7.4) and then centrifuged at 250 xg for 5 minutes. The resulting pellet is resuspended in assay medium to a concentration of approximately 5×10 ⁶ cells/ml and 50 μl of this cell suspension (approximately 250,000 cells) is added to each well of a 384-well cell culture microtiter plate (Perkin Elmer). Different concentrations of the test compound are then diluted in the assay medium and added to the wells of the assay plate in a volume of 25 µl. After ˜10 minutes at room temperature (˜21° C.), cells are stimulated with 25 μl PHA-L (14 μg/ml; Millipore) and the assay plate is placed in a 37° C. incubator in humidified 5% carbon dioxide. Assay end conditions include approximately 250,000 human PBMC in assay medium containing 3.5 μg/mL PHA-L and the indicated final test compound concentration (approximately 10 μM to 9.5 pM at 4-fold dilution). The final concentration of DMSO in the assay is approximately 0.25%. After 48 hours, the assay plate is removed from the incubator and centrifuged at 250 xg for 5 minutes. A portion of the resulting cell supernatant is then added to determine the amount of IL-4, IL-13 and IFNγ in each well. Cytokine measurements are performed using human IL-4, IL-13 or IFNγ HTRF assay kits (CisBio) according to the manufacturer's assay protocol. The resulting concentrations and actions for test compounds are plotted and the compound concentration required for a 50% effect (IC50) is determined using a four-parameter logistic dose-response equation (E-WorkBook, ID Business Solutions Ltd.) and shown in Table 15.

Table 15

Example number PDE4B2
IC ₅₀ nM IL13
IC ₅₀ nM IL4
IC ₅₀ nM IFNγ
IC ₅₀ 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 eleven 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 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 thirty 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 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 2.84 128 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 0.74 180 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 1.72 232 4.65 583 197.03 17.92 233 8.74 508 103.58 2.94

PDE4B is the main PDE4 isoform in neutrophils and monocytes, and the PDE4B2 variant is the main subtype in these cells associated with inflammation. Interferon gamma (IFNγ), interleukin 4 (IL4) and interleukin 13 (IL13) are cytokines that are primarily produced by T cells in addition to certain innate immune cell populations. The production of these cytokines is associated with inflammatory skin diseases such as atopic dermatitis and other immune and inflammatory diseases. Inhibition of the release of these inflammatory cytokines can modulate the inflammatory response.

It should be understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the 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, derivatives, intermediates, synthesis, compositions, and/or methods of using the invention, may be made without departing from its spirit and scope.

Powder X-ray diffraction analysis for crystalline (4-methoxy-3-propoxyphenyl)boronic acid, 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine and 3-(3-((tert-butyldimethylsilyl)oxy)prop- 1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

X-ray powder diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu (K-α medium) radiation source. The divergence slit is set to 15 mm continuous exposure. Diffracted radiation is measured with a PSD-Lynx Eye sensor where the aperture of the PSD sensor is set to 2.99 degrees. The voltage and current of the X-ray tube are set to 40 kV and 40 mA, respectively. Data is collected on a Theta-Theta protractor at a Cu wavelength of 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1 second. The anti-scattering screen is installed at a fixed distance of 1.5 mm. The samples are rotated at 15 rotations/min during collection. Samples are obtained by placing them in a silicon low background sample holder and rotating during collection. Data is collected using the Bruker DIFFRAC Plus software and analysis is performed on the EVA diffract plus software.

The analysis is carried out in the EVA diffract plus program (version 4,2,1). The TX data file is not processed until the peak is detected. Using the peak search algorithm in the EVA program, the peaks selected with a threshold value of 1 are used to perform a preliminary peak determination. To ensure reliability, adjustments are made manually; visually check the output of automatic determinations, and the positions of the peaks are adjusted to the maximum peak. Usually choose peaks with a relative intensity ≥3%. Peaks that are not resolved or correspond to noise are not selected. The typical error associated with the position of the peak of the crystalline product from the XRD is specified in the USP up to +/-0.2° 2-Theta (USP-941).

Table 16

List of XRD peaks for (4-methoxy-3-propoxyphenyl)boronic acid.

Angle 2-Theta (degrees) Rel. 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 35.8 5.4 38.7 5.6 39.3 7.5

Table 17

List of XRD peaks for 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine.

Angle 2-Theta (degrees) Rel. 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 7.7 39.2 3.8

Table 18

List of XRD peaks for 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

Angle 2-Theta (degrees) Rel. 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 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

Claims (58)

1. Compound of formula (IA) or formula (IB)

or a pharmaceutically acceptable salt thereof, wherein B is boron; A ₁ and A ₂ are independently O or S; R ₁ , R ₂ and R ₅ are each independently H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy-d _1-13 , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 , cyano, halogen or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are each independently (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 , (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are each independently H, deuterium, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 or halo(C ₁ -C ₆ )alkyl; And p is 0. 2. Compound according to claim 1 having formula (IA)

or a pharmaceutically acceptable salt thereof. 3. The compound according to claim. 2 or its pharmaceutically acceptable salt, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; And R ₆ , R ₇ and R ₉ are each independently H, (C ₁ -C ₆ )alkyl or halo(C ₁ -C ₆ )alkyl. 4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H; R ₃ and R ₄ are each independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, or hydroxy(C ₁ -C ₆ )alkyl; And R ₆ , R ₇ and R ₉ are each independently H or (C ₁ -C ₆ )alkyl. 5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H; R ₃ and R ₄ are each independently (C ₁ -C ₃ )alkyl; And R ₆ , R ₇ and R ₉ are each independently H or (C ₁ -C ₃ )alkyl. 6. Compound according to claim 1 having the formula (IB)

or a pharmaceutically acceptable salt thereof. 7. The compound according to claim. 6 or its pharmaceutically acceptable salt, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H, cyano, halo or halo(C ₁ -C ₆ )alkyl; R ₃ and R ₄ are each independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, or hydroxy(C ₁ -C ₆ )alkyl; And R ₆ , R ₇ and R ₉ are each independently H, (C ₁ -C ₆ )alkyl or halo(C ₁ -C ₆ )alkyl. 8. The compound according to claim. 6 or its pharmaceutically acceptable salt, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H; R ₃ and R ₄ are each independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are each independently H or (C ₁ -C ₃ )alkyl. 9. The compound according to claim 6 or its pharmaceutically acceptable salt, where A ₁ and A ₂ are each independently O; R ₁ , R ₂ and R ₅ are each independently H; R ₃ and R ₄ are each independently (C ₁ -C ₃ )alkyl; And R ₆ , R ₇ and R ₉ are each independently H or (C ₁ -C ₃ )alkyl. 10. (R)-4-(5-(4-Methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof. 11. Connection structure

12. Crystalline compound (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern containing diffraction peaks of 11.0 ± 0.2, 22.9 ± 0.2 and 25.1 ± 0.2 degrees two theta. 13. A crystalline compound according to claim 12, having an X-ray powder diffraction pattern containing 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 are two theta. 14. (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof. 15. Connection structure

16. Crystalline compound (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol having an X-ray powder diffraction pattern containing diffraction peaks of 18.7 ± 0.2, 22.8 ± 0.2 and 25.0 ± 0.2 degrees two theta. 17. A crystalline compound according to claim 16, having an X-ray powder diffraction pattern containing 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 theta. 18. Pharmaceutical composition with inhibitory activity against phosphodiesterase 4 (PDE4), containing a compound according to any one of paragraphs. 11, 14 or 15 or a pharmaceutically acceptable salt thereof, a crystalline compound according to any one of paragraphs. 12, 13, 16 or 17 and at least one pharmaceutically acceptable excipient, diluent or carrier. 19. The use of a compound according to any one of paragraphs. 11, 14 or 15 or its pharmaceutically acceptable salt or crystalline compound according to any one of paragraphs. 12, 13, 16 or 17 for the preparation of a medicament for the treatment of atopic dermatitis in humans. 20. Use according to claim 19, wherein the compound is (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof and where the disorder is atopic dermatitis.

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