EA045319B1 - BORON-CONTAINING PDE4 INHIBITORS - Google Patents

Description

Field of invention

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

Prerequisites for creating the invention

Inflammation is a major component of numerous diseases and individuals with such diseases often demonstrate high levels of inflammatory regulators including, but not limited to, the following cytokines IL-1a, IL-1e, IL-2, IL-3, IL-4, IL- 5, IL-6, IL-7, IL-9, IL-12, IL13, 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 conditions that are directly associated with inflammatory cytokines include atopic dermatitis, in which inflammatory cytokines induce inflammation; psoriasis, in which inflammatory cytokines induce dermatitis; arthritis, in which inflammatory cytokines can damage the synovial membrane and destroy joint cartilage and bone; fibrosis, in which inflammatory cytokines can attack injured tissue; lupus, in which inflammatory cytokines can increase immune deposits and damage; allergies, in which inflammatory cytokines can induce inflammation, IgE production and congestion; fibromyalgia, in which inflammatory cytokines are elevated in patients; and surgical complications in which inflammatory cytokines may prevent 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 depletion 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. Arteriosclerosis, osteoporosis, Parkinson's disease, bacterial infection, viral infection, inflammatory bowel disease including Crohn's disease and ulcerative colitis, and multiple sclerosis (a typical disease associated with autoimmune inflammation) are also associated with inflammation. Current methods available for the treatment of such inflammatory diseases may be unsatisfactory due to lack of sufficient effectiveness and/or the presence of drug-related side effects. Therefore, there is a need for new therapeutic methods that modulate the inflammatory process involved in the diseases, conditions, and disorders disclosed herein.

Specifically, atopic dermatitis (AD) is an inflammatory skin disease that typically appears in early childhood, but may manifest during adolescence or adulthood, and after either chronic or relapsing/remitting disease progression. Patients with AD exhibit pruritus and are susceptible to cutaneous secondary bacterial, viral, and fungal infections. Patients with AD may also demonstrate impaired barrier function, which leads to 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 disease sites. Chemokines that promote 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 anti-inflammatory steroids have been used in the treatment of AD, especially in cases of exacerbations 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, including, but not limited to, skin atrophy, telangiectasia (abnormal dilatation of capillary vessels), 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, have been used to reduce the use of topical steroids.

Topical application of mevalonic acid and niacinamide has been 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 have been used in the treatment of AD. Cyclosporine A (CyA) has been used as an immunosuppressant to inhibit calcineurin phosphatase, thereby leading to decreased IL-2 levels and inhibition of T cell proliferation. Systemic treatments include humanized monoclonal antibodies such as omalizumab, efalizumab and etanercept, dupilumab, which target serum IgE, LFA-1, TNF-α, and IL-4r, respectively [Rahman, Inf. & All. 2011, 10, 486]. Additional eczema, skin diseases and conditions include hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermos bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, chronic physical urticaria, disease VogtaKoyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, and hidradenitis pustules [Eyerich and Eyerich, J. Eur. Ac. Derm. Ven., 32, 692 (2018)].

Psoriasis is an immune-mediated chronic skin disease that exists in several different forms, including plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, and inverse psoriasis. Plaque psoriasis (psoriasis vulgaris) is the most common form of psoriasis and typically appears as areas of raised red skin covered with scaly white accumulation (pustules). Pustular psoriasis appears as raised bumps that are filled with non-infectious pus (pustules). The skin underneath the surrounding ulcers is red and tender. Pustular psoriasis can be localized, typically on the arms and legs, or generalized with widespread patches that occur anywhere on the body. Nail psoriasis causes various changes in the appearance of the fingernails and toenails. These changes include discoloration under the nail plate, pitting of the nails, lines that run along the nails, thickening of the skin under the nail, loosening (onycholysis) and crumbling of the nail. Psoriasis of the flexor surfaces (inverse psoriasis) appears as smooth, inflamed areas of the skin. It occurs in folds of skin, especially around the genitals (between the thighs and groin), armpits, under excess abdominal weight (pannus), and under the breasts (inframammary fold). It is aggravated by friction and sweat, making it vulnerable to fungal infections. Guttate psoriasis is characterized by numerous small oval spots. These psoriasis patches 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 result in 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 peeling of the skin over most of the body. This may be accompanied by severe itching, swelling and pain. This often results from exacerbation of unstable plaque psoriasis, especially after abrupt discontinuation of systemic treatment. Current therapies available for the treatment of psoriasis include topical treatment, phototherapy, and systemic administration. The treatment is either cosmetically undesirable, inconvenient for long-term use, or has limited effectiveness.

Inflammatory bowel disease (IBD) describes a group of intestinal disorders involving 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, which can invade adjacent tissues. Patients with IBD may have diarrhea, abdominal pain, fatigue and weight loss, and these conditions can be severe and debilitating. Since symptoms vary depending on the level and duration of inflammation, an agent that modulates said inflammation will be useful for 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 level of cyclic nucleotides in cells and maintain cyclic nucleotide homeostasis by hydrolyzing such cyclic mononucleotides, resulting in the cessation of their signaling function. 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 splice variants of each PDE4 isoform were detected. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5'monophosphate (AMP).

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Regulation of cAMP activity is important in many biological processes, including inflammation.

The compounds of the present invention inhibit phosphodiesterases, including PDE4, and modulate the levels of inflammatory cytokines and are therefore useful in the treatment of inflammatory disorders 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.

The essence of the invention

The present invention provides compounds of formula (IA) or formula (IB) that inhibit PDE4 and are useful for the treatment or prevention of disorders that are normalized by PDE4 inhibition in humans

or pharmaceutically acceptable salts thereof, in which

B represents boron;

A ₁ and A2 are independently O or S;

R1, R2 and R5 are independently H, deuterium, (C1-C6)alkoxy, ( _C1 - _C6 )alkoxy- _d1-13 , (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl- d ₁ . ₁₃ , cyano, halogen or halogen(C1- _C6 )alkyl;

R3 and R4 are independently (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl- _d1 . ₁₃ , (C ₃ -C ₈ )cycloalkyl, halogen(C1-C ₆ )alkyl, or hydroxy(C1-C ₆ )alkyl;

_R6 , _R7 and R9 are independently, H, deuterium, (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl- _6-13 or halogen(C1- _C6 )alkyl; and p represents 0.

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

In another embodiment, the present invention provides the use of a compound of formula (IA) or formula (IB), or pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment of a disorder selected from the group consisting of atopic dermatitis, hand dermatitis, contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrhea eczema, pemphigus , vulvovaginite, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, diseases of Vogta-Koyanagi-harada, nevus of Satton/nevus, pasteal hypopigmentation, senile leukeoderma, chemical leukeoderma, skin red lupus, discord lupus wolf, discord lupus. Donis-landing pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa and psoriasis.

Brief description of drawings

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

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

Fig. 3 is the X-ray structure (ORTEP graphic) of crystalline (8)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5).

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

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

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

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

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

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

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

Fig. 11 is a powder X-ray diffraction analysis of crystalline

3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine.

Fig. 12 is a powder X-ray 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

The present invention provides compounds of formula (IA) or formula (IB) that inhibit PDE4 and are useful for the treatment or prevention of disorders that are normalized by PDE4 inhibition in humans

Formula (IA) Formula (IB) or pharmaceutically acceptable salts thereof, in which

B represents boron;

A1 and A2 are independently O or S;

R1, R2 and R5 independently represent H, deuterium, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy-d _1-13 , (C ₁ -C ₆ )vlkyl, (C ₁ -C ₆ )alkyl-d _1-13 , cyano, halogen or halogen (C1-C ₆ )alkyl;

R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 , (C ₃ -C8)cycloalkyl, halogen(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl;

R6, R7 and R9 are independently, H, deuterium, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 or halogen(C ₁ -C ₆ )alkyl; and p represents 0.

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

Formula (IA) or a pharmaceutically acceptable salt thereof, wherein

B represents boron;

A1 and A2 are independently O or S;

R1, R2 and R5 are 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 halogen (C1-C ₆ )alkyl,

R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 , (C ₃ -C8)cycloalkyl, halogen(C ₁ -C ₆ )alkyl, or hydroxy( C ₁ -C ₆ )alkyl;

R6, R7 and R9 are independently, H, deuterium, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 or halogen(C ₁ -C ₆ )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IA), or pharmaceutically acceptable salts thereof, wherein B is boron; A1 and A2 represent O; R1, R2 and R5 are independently H, cyano, halogen, or halogen(C ₁ -C ₆ )alkyl; R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₃ -C8)cycloalkyl, halogen(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R6, R7 and R9 are independently H, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IA), or pharmaceutically acceptable salts thereof, wherein B is boron; A1 and A2 represent O; R1, R2 and R5 represent H; R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₃ -C 8 )cycloalkyl, halogen(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R7 and R9 represent H or (C ₁ -C ₃ )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IA), or pharmaceutically acceptable salts thereof, wherein B is boron; A1 and A2 represent O; R1, R2 and R5 represent H; R3 and R4 independently represent

- 4 045319 (C1-C ₃ )alkyl; R ₆ , R ₇ , and R9 represent H or (C1-C ₃ )alkyl; and p represents 0.

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

Formula (IB) or pharmaceutically acceptable salts thereof, wherein B represents boron; A1 and A2 are independently O or S; R1, R2 and R5 are independently H, deuterium, ( _C1 - _C6 )alkoxy, (C1-C6)alkoxy-0 _1-13 , (C1 _- C6)alkyl, (C1- _C6 )alkyl-0 _1-13 , cyano, halogen or halogen(C ₁ -C ₆ )alkyl; R3 and R4 are independently (C ₁ -C ₃ )alkyl, (C1-C ₆ ) _1-13 alkyl, (C ₃ -C ₈ )cycloalkyl, halogen(C1-C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R9 are independently H, deuterium, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-b _1-13 or halogen(C1-C ₆ )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IB), or pharmaceutically acceptable salts thereof, wherein B is boron; A ₁ and A ₂ represent O; R1, R2 and R5 are independently H, cyano, halogen or halogen(C ₁ -C ₆ )alkyl; R3 and _R4 are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halogen(C ₁ -C ₆ )alkyl, or hydroxy(C ₁ -C ₆ )alkyl; R6, _R7 and R9 are independently H( _C1 - _C6 )alkyl or halogen( _C1 - _C6 )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IB), or pharmaceutically acceptable salts thereof, wherein B is boron; A ₁ and A ₂ represent O; R1, R2 and R5 represent H; R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halogen(C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ , and R9 represent H or (C ₁ -C ₆ )alkyl; and p represents 0.

In another embodiment, the present invention provides compounds of formula (IB), or pharmaceutically acceptable salts thereof, wherein B is boron; A ₁ and A ₂ represent O; R1, R2 and R5 represent H; R3 and R4 are independently (C ₁ -C6)alkyl; R ₆ , R ₇ , and R9 represent H or (C ₁ -C ₆ )alkyl; and p represents 0.

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

- 5 045319 (R) 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3,4dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-isopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-isopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(2-hydroxyethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(2-hydroxyethoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-(3-hydroxypropoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-(3-hydroxypropoxy)-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-chloro-5-ethoxy-4methoxyphenyl)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)-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-(difluoromethoxy)-3propoxyphenyl)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]-5yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2oxaborolan-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;

- 6 045319 (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-(3ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol; 4-(5-(4-methoxy-3propoxyphenyl)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-(4methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (R) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol; 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol; (R) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol; (R) 4-(hydroxymethyl)-4(5-(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'-(3fluoropropoxy)-4'-methoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-(3fluoropropoxy)-4'-methoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 3'-(2-hydroxy1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile; (S) 3'-(2hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile; (R) 3'-(2-hydroxy-2,5-dihyde rho-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,T-biphenyl]-2carbonitrile; (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-3yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; (R) 4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(hydroxymethyl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(3-ethoxy-4methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(3-ethoxy-4methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (2R)-2-(5-(4-MeTOKcn-3propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1- ol; (28)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2dioxaborinan-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'-bipyridin]-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-3propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S)4-(4-(hydroxymethyl)-6-(4-

- 7 045319 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-(thiethan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4methoxy-3-(thiethan-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;

methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;

methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;

methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;

(S) (R) (S)

4-(5-(5-ethoxy-44-(5-(3-ethoxy-44-(5-(3-ethoxy-4(R) methoxyphenyl)pyridin-3-yl)-1,2-oxaborolane-2 -ol;

(S)

4-(5-(3-ethoxy-2-fluoro-44-(5-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(3'-isopropoxy-4'-methoxy-[1,Tbiphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-isopropoxy-4'-methoxy- [1, 1'-biphenyl]-3yl)-1,2-oxaborolan-2-ol;

(R)

4-(3'-ethoxy-4'-methoxy-[1,T-biphenyl]-3-yl)-1,2oxaborolan-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-3yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; ^)-4-(6-((5)-1-hydroxyethyl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R)-4-(6-((R)-1-rnflpoKCH3Tnn)-2-(4methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;

(S)-4-(6-((S)-1hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S)

4-(6-((R)-1-hydroxyethyl)-2-(4-methoxy-3-πpoπocyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol (R) 4-(5-(4 -methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2oxaborolan-2-ol; (R) 6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2propoxybenzonitrile; (S) 6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy2-propoxybenzonitrile; (R) 4-(4'-methoxy-3'-propoxy-[1,T-biphenyl]-3-yl)-1,2oxaborolan-2-ol; (S) 4-(4'-methoxy-3'-propoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborolan-2ol; (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-(3ethoxy-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-(3,4diethoxyphenyl)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)-4-8 045319 (methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;

(R) 4-(2-(4-methoxy-3propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-(4methoxy-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-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(2-fluoro-3,4dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2-fluoro-3,4dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(4'-methoxy-3'-(pentyloxy)[1,T-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;

methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;

oxaborolan-4-yl)-4,5-dimethoxy-[1,1'-biphenyl]-3-carbonitrile;

oxaborolan-4-yl)-4,5-dimethoxy-[1,1'-biphenyl]-3-carbonitrile;

(S) 4-(2'-fluoro-4'3'-(2-hydroxy-1,23'-(2-hydroxy-1,23-ethoxy-5-(5-(2(R) ( S) (R) hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile; (S) 3-ethoxy-5-(5-(2hydroxy-1,2-oxaborolan-4 -yl)pyridin-3-yl)-2-methoxybenzonitrile; 4-(3-(6-ethoxy-5methoxypyridin-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-methoxypyridin2-yl)phenyl)- 1,2-oxaborolan-2-ol; (R) 4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2oxaborolan-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-(4methoxy-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)-5fluoropyridin-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)-4methoxyphenyl)-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-4yl)acetate; (S) ethyl 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)acetate; (R) 2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetic acid; (S) 2-(6-(2-hydroxy-1,2oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetic acid; (R)

- 9 045319

4-(5-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S) 4-(5fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(6-(4methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(4-(difluoromethyl)-5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(4-(difluoromethyl)-5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)-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-(3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-propoxyphenyl)pyridin3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)1,2-oxaborolan-2-ol; (S) 4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2oxaborolan-2-ol; (R) 4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; (S) 4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol; (R) 4-(2'-fluoro-4',5'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2ol; (S) 4-(2'-fluoro-4',5'-dimethoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) 2-ethoxy6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile; (S) 2-ethoxy6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile; (R) 4-(3-(5,6dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5,6-dimethoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol; (R) 6-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3yl)-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-5propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; 4-(3-(5methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R) 4-(3-(5-methoxy-6propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5-methoxy-6propoxypyridin-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)-1,2oxaborolan-2-ol; (R) 4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2oxaborolan-2-ol; (S) 4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2oxaborolan-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-(5,6dimethoxypyridin-3-yl)phenyl)-1,2-oxaborolan-2-ol; (S) 4-(3-(5,6-dimethoxypyridin-Zyl)phenyl)-1,2-oxaborolan-2-ol; (R) 4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol; (S) 4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2ol; (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

- 10 045319 (3'-(cyclopropylmethoxy)-4'-methoxy-[1,T-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'(cyclopropyl methoxy)-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-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(2,4-dimethoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4-methoxy-3-((tetrahydro2H-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-ethoxy4-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)pyridin3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-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-2ol; (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-4propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol; (R) 4-(2-(hydroxymethyl)-6-(4methoxy-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-(3cyclopropoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(3cyclopropoxy-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,T-biphenyl]3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3'-isobutoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol; (R) 4-(3'-cyclobutoxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan2-ol: (S) 4-(3'-cyclobutoxy-4 '-methoxy-[1,T-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-(3ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-(4ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(5-(4-ethoxy-3methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R) 3-ethoxy-3'-(2-hydroxy-1,2oxaborolan-4-yl)-4-methoxy-[1,1'-biphenyl]-2-carbonitrile; (S) 3-ethoxy-3'-(2-hydroxy1,2-oxaborolan-4-yl)-4-methoxy-[1,1'-biphenyl]-2-carbonitrile; (R) 4-(6-(2hydroxyethoxy)-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)-1,2-11 045319 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;

methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol;

(S)propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol;

(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;

(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;

(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;

(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;

(R) (S) (R) (S) (R)methoxyphenyl)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol;

methoxyphenyl)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol;

(S) (R) (R) 4-(1-(44- (1 - (4- methoxy-34-(5-(3-methoxy-44-(5-(3-methoxy-44-(6- (3-ethoxy-44-(6-(3-ethoxy-44-(5-(3-ethoxy-44-(5-(3-ethoxy-44-(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)-1,2oxaborolan-2-ol; (R) 4-(2'-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2ol; (S) 4-(2'-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R) (cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;

(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;

(S) (R)

4-(2-(34-(2-(34-(2-(4methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; (S) 4-(2-( 4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;

propoxyphene yl)pyridin-2-yl)-1,2-oxaborolan-2-ol;

propoxyphene yl)pyridin-2-yl)-1,2-oxaborolan-2-ol;

propoxyphene yl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;

propoxyphene yl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;

methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;

(R) (S) (R) (S) (R) (S)

4- (6- (2-fluoro-4-methoxy-34-(6-(2-fluoro-4-methoxy-34-(6-(2-fluoro-4-methoxy-34- (6- (2- fluoro-4-methoxy-34-(5-(4-ethoxy-2-fluoro-34-(5-(4-ethoxy-2-fluoro-3methoxyphenyl)pyridin-3-yl)-1,2-oxaborolane-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-(trifluoromethyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; propoxyphene yl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol; propoxyphene yl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;

4-(6-(3-ethoxy-4-methoxyphenyl)(R) (S) (R) (S) (R)

4-(6-ethoxy-2-(3-ethoxy-44-(6-ethoxy-2-(3-ethoxy-44- (6-methoxy-2- (4-methoxy-34-(6-methoxy-2 -(4-methoxy-32-(cyclopentyloxy)-6-(6-(2hydroxy-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)-3methoxybenzonitrile; 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-(4methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S)

4-(3-fluoro-6-(4methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R) 4-(5-methoxy-2'-methyl6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol;

propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol;

(S) (R)

4-(5-methoxy-2'-methyl-64-(3',4'-d imethoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S) 4-(3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol; (R) 4-(6-(3-ethoxy-4-methoxyphenyl) pyridin-2-yl)-1,2-oxaborolan-2ol; and (S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;

- 12 045319 or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a pharmaceutical composition containing a compound of formula (IA), formula (IB), 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 (IA), formula (IB), or a pharmaceutically acceptable salt thereof.

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 (IA), formula (IB), 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 atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IA), formula (IB), or a pharmaceutical thereof acceptable salt.

In another embodiment, the present invention provides a method for treating or preventing atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nommoid dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis follicularis, seborrheic eczema, pemphigus, vulvovaginitis, acne, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis , pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising locally administering to a human in need of such treatment a therapeutically effective amount connections formula (IA), formula (IB) 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 resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of formula (IA), formula (IB) 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 resulting from surgical complications in a human, comprising locally administering to a human in need of such treatment a therapeutically effective amount of a compound formula (IA), formula (IB) 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 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 (IA), formula (IB) or a pharmaceutically acceptable compound thereof salt.

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

- 13 045319

In another embodiment, the present invention provides the use of a compound of formula (IA), formula (IB), 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, noimmular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, se boreal eczema, pemphigus , vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus , palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface 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 (IA), formula (IB), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in humans.

In another embodiment, the present invention provides the use of a compound of formula (IA), formula (IB), or a pharmaceutically acceptable salt thereof, 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)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 from 3 to 10 diffraction peaks, listed in table. 7.

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 given in table. 7.

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, as shown in Fig. 5.

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

In another embodiment, the present invention provides a method for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, red

- 14 045319 lichen sclerosus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi disease - Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis , flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis 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 the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising locally 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 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, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline ( R)-4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising locally 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 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-2ol.

In another embodiment, the present invention provides for 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 the treatment of inflammatory disease in humans.

In another embodiment, the present invention provides for 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 the treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, scleroatrophic lichen, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, psoriasis of flexor surfaces, guttate psoriasis , psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans.

- 15 045319

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

In another embodiment, the present invention provides for 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 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-(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 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 from 3 to 10 diffraction peaks given in table. 8.

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 given in table. 8.

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, as shown in Fig. 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 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-(4methoxy-3-propoxyphenyl)pyridine-3 - yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,

- 16 045319 pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans, including 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 for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising locally 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 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, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline ( R)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising locally 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 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-(4-methoxy -3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides for the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug for the treatment inflammatory disease in humans.

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

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

In another embodiment, the present invention provides for the use of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the production of a medicine for the 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 from 3 to 10 diffraction peaks given in table. 9.

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 given in table. 9.

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, as shown in Fig. 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-(4methoxy-3-propoxyphenyl)pyridine-3- yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis 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 atopic dermatitis, hand dermatitis, contact dermatitis, allergic

- 18 045319 contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, in itiligo, rosacea, epidermosis bullosa, follicular keratosis, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, leukoderma induced chemical/drug, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriasis tic arthritis, erythrodermic psoriasis, or inverse psoriasis in a person, 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-oxaborolane -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 arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline ( S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising locally 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 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 (S)-4-(5-(4-methoxy -3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan2-ol.

In another embodiment, the present invention provides for the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug for the treatment inflammatory disease in humans.

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

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

In another embodiment, the present invention provides for the use of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in the manufacture of a drug for the treatment 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 X-ray powder diffraction pattern containing diffraction peaks 12.8±0.2, 20.4±0.2,

- 19 045319 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 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 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 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 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 X-ray powder diffraction pattern containing from 3 to 10 diffraction peaks shown in table. 10.

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 X-ray powder diffraction pattern containing the diffraction peaks given in table. 10.

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 X-ray powder diffraction pattern as shown in FIG. 8.

In another embodiment, the present invention provides a pharmaceutical composition containing crystalline (-)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolane-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 for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis 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 for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, follicular keratosis, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria willow, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, ps oriaza , plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising locally 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 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, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline ( -) 4-(5-(2(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising locally 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 as 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 for the use of crystalline (-)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in production of a medicinal product for the treatment of an inflammatory disease in humans.

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

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

In another embodiment, the present invention provides for the use of crystalline (-)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol in manufacturing a medicinal product 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 X-ray powder diffraction a pattern containing diffraction peaks of 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 X-ray 21 045319 powder 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 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 X-ray powder 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 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 X-ray powder 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 X-ray powder diffraction a picture containing from 3 to 10 diffraction peaks given in table. eleven.

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 X-ray powder diffraction a picture containing the diffraction peaks given in table. eleven.

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 X-ray powder diffraction picture as shown in Fig. 9.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin3-yl)-1,2-oxaborolan-2-ol and at least 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-(3ethoxy-4-methoxyphenyl)-6-methylpyridinium- 3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method for the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis 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 the treatment or prevention of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, dermatitis eyelids, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Pho disease gta -Koyanagi-Harada, Sutton's nevus/nevoid tumor, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexor surface psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in a human, comprising locally 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 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, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising administering to the human in need of such treatment a therapeutically effective amount of crystalline ( R) 4-(5-(3ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method of treating or preventing arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammation resulting from surgical complications in a human, comprising locally 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 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)-6-methylpyridin-3-yl)-1,2oxaborolan-2-ol.

In another embodiment, the present invention provides for 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 for the treatment of inflammatory disease in humans.

In another embodiment, the present invention provides for 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 for the treatment of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, noimmular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus , lichen sclerosus, alopecia areata, vitiligo, rosacea, epidermosis bullosa, keratosis pilaris, seborrheic eczema, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, nevus/nevoid tumor Sat tones , post-inflammatory hypopigmentation, senile leukoderma, chemical/drug induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis pustules, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis oriasis, psoriasis of the flexor surfaces, guttate psoriasis , psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in humans.

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

In another embodiment, the present invention provides for 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 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 containing 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 diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention for topical use include, but are not limited to: a second compound of formula (I), formula (IA), formula (IB) or formula (IC); a PDE4 inhibitor including, but not limited to, crisaborole, ampremilast, roflumilast, rolipram and piclamilast; a corticosteroid including, but not limited to, fluocinonide, deoxymethasone, mometasone, triamcinolone, betamethasone, alklometasone, 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, SNA152, SHR-0302, JTE052, BMS-986165, filgotinib, baricitinib, upadacitinib, ruxolitinib, peficitinib, PF-04965842, PF-06651600, PF-067008 41, and PF06826647; an aromatic hydrocarbon receptor agonist, including, but not limited to, tapinarof; an IRAK4 inhibitor including, but not limited to, PF-06650833; nonsteroidal anti-inflammatory drugs including, but not limited to, WBI-1001 and MRX-6; a vitamin D analog such as calcipotriene; retinoic acid derivatives, which include, but are not limited to, alitretinoin;

- 23045319 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, which include, but are not limited to, aprepitant and tradipitant; CRTH2 receptor antagonists, which include, but are 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 RORC2 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, R348, cerdulatinib, ibrutinib, entospletinib, tirabrutinib, and JTE-051.

In another embodiment, the present invention provides pharmaceutical combinations for oral administration 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 may be used in combination with the compounds of the present invention for oral administration include, but are not limited to: oral retinoic acid derivatives, 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 inverse ROR 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, upada citinib, ASN-002, AT9283 , ATI-501, ATI-502, AZD1480, AZD4205, BMS-911543, BMS-986165, INCB-52793, INCB-54707, PF-04965842, PF-06263276, PF-06651600, PF-06700841, PF-0 6826647, SHR -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, UR67767, PRN-1008, BMS-935177, PRN-473, ABBV-105, AS-550, M -7583, WXFL-10230486, LOU-064, AEG42766, HCl-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 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 diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention for injection include, but are not limited to: TNF-α inhibitors including, but not limited to, infliximab, adalimumab, golimumab, certolizumab pegol; injectable anti-GE4, IL-12, IL-17, IL-22, IL23, IL-31, IL-33, IgE treatments such as dupilumab, lebrikizumab, nemolizumab, tralokinumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab , omazumimab 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 may be combined in a single composition that may be administered to a patient. For example, one pharmaceutical composition may contain a compound or its pharmaceutically acceptable salt, hydrate, ester or prodrugs according to formula (I)(IA), (IB) and (IC), another therapeutic agent or its pharmaceutically acceptable salt, hydrate, ester or prodrugs; and at least one pharmaceutically acceptable excipient or carrier.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be used in pure form or, when 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 a therapeutically effective amount of a compound of the present invention means a sufficient amount of a compound to treat the diseases, conditions or disorders described herein at a reasonable benefit/risk ratio that would apply to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend on various factors, including disease

- 24 045319 the disease being treated and the severity of the disease; the activity of the particular compound that is used; the specific composition that is used; the age, body weight, general health, gender and diet of the patient; timing of administration, route of administration, and rate of elimination of the particular compound being used; duration of treatment; drugs that are used in combination with or are compatible with the particular compound that is used; and similar factors well known in the medical field.

Pharmaceutical compositions or preparations.

In another embodiment, the present invention provides pharmaceutical compositions, or preparations, containing a therapeutically effective amount of a compound of the present invention, and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions, or preparations, of this invention can 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 in liposome form.

A typical pharmaceutical composition or preparation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Acceptable carriers, diluents and excipients include materials such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient that is used will depend on the means and purposes for which the compound of the present invention is used. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg, PEG400, PEG300) and the like, and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, lubricants, processing aids, coloring agents, sweeteners, fragrances, flavoring agents and other known additives to provide an acceptable appearance to a medicinal product (ie, a compound of the present invention or pharmaceutical compositions thereof) or to assist in the manufacture of a pharmaceutical product (ie, for use in the manufacture of a medicinal product).

The preparations can be prepared using conventional dissolution and mixing procedures. For example, the parent 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 an appropriate solvent in the presence of one or more of the excipients described above. The rate of dissolution of poorly soluble water of compounds can be increased by using a spray-dried dispersion, such as the dispersion described in Takeuchi, H., et al., in Enhancement of the dissolution rate of a poorly watersoluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants J. Pharm. Pharmacol., 39, 769-773 (1987); and Ep0901786 B1 (US 2002/009494), which are incorporated herein by reference. The compound of the present invention is typically formulated into pharmaceutical dosage forms, to ensure easily controlled drug dosing and provide the patient with an aesthetically pleasing and easy-to-use product.

The pharmaceutical composition, or drug, for use may be packaged in different ways depending on the method used to administer the drug. Typically, a distribution article includes a container in which the pharmaceutical preparation is stored in an appropriate form. Acceptable containers include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cans, and the like. The container may also include a tamper-proof kit to prevent inadvertent access to the contents of the package. In addition, there is a label on the container that describes the contents of the container. The label may also contain appropriate warnings.

The term pharmaceutically acceptable carrier refers to a carrier medium that provides adequate delivery of an effective amount of the active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and is reasonably nontoxic to the host or patient. Exemplary 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. Additional examples of materials that may serve as pharmaceutically acceptable carriers include 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; wished

- 25 045319 tin; 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; non-pyrogenic water; isotonic saline solution; 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 coloring agents, releasing agents, coating agents, sweeteners, flavoring and odorant agents, preservatives and antioxidants may also be present in the composition, according to the decision of the formulator.

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

The term topical administration refers to the application of a pharmaceutical agent to the outer surface of the skin of the nails, hair, claws or hooves such that the agent crosses the outer surface of the skin, nails, hair, claw or hoof and enters the tissues that lie below. Topical administration includes applying the composition to intact skin, nails, hair, claw or hoof, or to a broken, damaged or open wound of skin, nail, hair, claw or hoof. Local 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, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if necessary. Compounds that are volatile may require mixing with special formulation agents or special packaging materials to ensure proper dose delivery. In addition, compounds of the present invention that have poor penetration into human skin may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may require formulation with absorption retarding agents or barriers.

Ointments, pastes, creams, lotions, gels, powders and solutions for topical use 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, flavorings, emulsifiers, dyes, inert fillers, anti-irritants, adhesives, aromatics, opacifying agents, antioxidants, gelling agents, stabilizers, surfactants agents, emollients, coloring agents, preservatives, buffering agents, penetration enhancers, or mixtures thereof. Excipients for external use should not interfere with the effectiveness of the biological activity of the active agent and should not be harmful to epithelial cells or their function.

The term penetration enhancer or penetration enhancer refers to increasing the penetration of a drug into the skin, nails, hair, claws or hoofs to increase the rate of penetration of the drug through the skin, nails, hair, claw or hoof. The enhanced penetration achieved by the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through the skin, nails, hair, claw or hoof of animals or humans using a cell diffusion apparatus. The diffusion cell is described in Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The term permeation enhancer or penetration enhancer refers to an agent or mixture of agents that, alone or in combination, act to increase the permeability of the skin, nails, hair or hooves to a drug.

The term transdermal delivery refers to the diffusion of an agent across the barrier of the skin, nails, hair, claws or hooves as a result of topical administration or other application of the composition. The stratum corneum acts as a barrier, and only a few pharmaceuticals are able to penetrate intact skin. On the contrary, the epidermis and dermis are capable of permeation for many soluble substances, and thus the absorption of drugs occurs more easily through the skin, nails, hair, claw or hoof, which is abraded or otherwise stripped of the stratum corneum to expose the epidermis. Transdermal delivery involves injection or other delivery through any portion of the skin, nails, hair, claw or hoof, or mucous membrane and absorption or penetration through the rest

- 26 045319 part. Absorption through intact skin, nail, hair, claw or hoof may be enhanced by disposing of the active agent in an appropriate pharmaceutically acceptable vehicle prior to application to the skin, nail, hair, claw or hoof.

Passive local administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers. As used herein, transdermal delivery is intended to involve delivery by penetration through or through the integumentary surface, i.e. skin, nails, hair, claw or hoof.

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

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

Solid compositions of this 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 coatings, such as enteric and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifying agents and may also be compositions that release the active ingredient(s) only, or predominantly, in a specific part of the intestinal tract in a delayed manner. Examples of administration compositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents that are typically 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 of them.

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

The term parenteral, as used herein, refers to routes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intra-articular and infusion. The pharmaceutical compositions of this invention for parenteral injection contain 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 excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures thereof, vegetable oils (eg olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

Injectable depot forms are prepared by forming microencapsulated drug matrices in biodegradable polymers such as polylactide polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(ortho-complex

- 27 045319 esters) and poly(anhydrides). Depot injectable drugs are also prepared by introducing the drug into liposomes or microemulsions that are compatible with body tissues.

Injectable preparations may be sterilized, for example by filtration through a bacteria-preserving filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium immediately prior to use.

Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can 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 vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Additionally, sterile fixed oils are typically used as a solvent or suspension medium. Any soft fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections.

Pharmaceutical compositions, or preparations, for rectal or vaginal administration are advantageously suppositories, which can be prepared by mixing the compounds of this 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 vaginal cavity and release the active compound.

The compounds of the present invention can also be administered in the form of liposomes. Liposomes are typically derived from phospholipids or other lipid substances and are formed from mono- or multilayer hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid 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 lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which are used alone or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), p 33 et seq.

The pharmaceutical compositions or preparations 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 achieved 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, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved through the use of agents that delay absorption, such as aluminum monostearate and gelatin.

The pharmaceutical compositions, or preparations, of the invention are suspensions. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene 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 the compound represented by formulas (I), (IA), (IB), and (IC), including their pharmaceutically acceptable salts, with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field that are known to be not harmful to the recipient, for example, water, ethanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol, and the like. The term hydrate refers to a complex in which the solvent molecule is water. Solvates and/or hydrates predominantly exist in crystalline form. Other solvents may be used as intermediate solvates in obtaining more desirable solvates. Intermediate solvents include, but are not limited to, methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, 1,4-butyn-diol and the like.

The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and route of administration. The dosage level selected will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of one skilled in the art to begin dosing the compound at levels lower than those necessary 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 this invention that are administered to humans or lower level animals may range from about 0.000001 to about 10 mg/kg/day. For oral administration purposes, more advantageous doses may range from about 0.001 to about 1 mg/kg/day. For topical use, more advantageous doses may range from 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, for example, two to four separate doses per day.

Definitions.

As used throughout the specification and claims that accompany the invention, the following terms have the following meanings:

The term (C ₂ -C ₆ )alkenyl, as used herein, means a straight or branched chain hydrocarbon containing from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. Illustrative 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, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety via an oxygen atom. Illustrative examples of (C ₁ -C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy and hexyloxy.

The term (C ₁ -C ₆ )alkoxy-d ₁ . ₁₃ , as used herein, means (C ₁ -C ₆ )alkyl-d ₁ . ₁₃ , a group, as defined herein, which is attached to the parent molecular moiety via an oxygen atom. Illustrative Examples of (C ₁ -C ₆ )alkoxy-d ₁ . ₁₃ include, but are not limited to, methoxy-d ₃ , ethocal-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 (C1-C ₆ )αalkoxy group, as defined herein, which is attached to the parent molecular moiety through another (C ₁ -C ₆ )alkoxy group as defined herein. Illustrative examples of (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkoxy include, but are not limited to, tert-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, which is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group as defined herein. Illustrative examples of (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl include, but are not limited to, t-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term (C1- _C6 )alkoxycarbonyl, as used herein, means a ( _C1 - _C6 )alkoxy group, as defined herein, which is attached to the parent molecular moiety via a carbonyl group, as defined herein. Illustrative 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, as used herein, means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Illustrative examples of (C ₁ -C ₃ )alkyl include methyl, ethyl, n-propyl and iso-propyl.

The term (C ₁ -C ₃ )alkyl-d ₁ . ₇ , as used herein, means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms, with one to seven hydrogen atoms replaced by deuterium ( ^2H or D). Illustrative 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, as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Illustrative examples of (C1- _C6 )alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 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 chain hydrocarbon containing from 1 to 6 carbon atoms, with one to thirteen hydrogen atoms replaced by deuterium ( ^2H or D). Illustrative examples of (C ₁ -C ₆ )alkyl-d1-13 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-29 045319 butyl-d^ pentyl-du, 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, that is attached to the parent molecular moiety via a carbonyl group, as defined herein. Illustrative examples of (C ₁ -C ₆ )alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1oxopropyl, 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, that is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of (C ₁ -C ₆ )alkylthio include, but are not limited to, methylthio, ethylthio, t-butylthio, and hexylthio.

The term (C1- _C6 )alkylthio(C1- _C6 )alkyl, as used herein, means a ( _C1 - _C6 )alkylthio group, as defined herein, which is attached to the parent molecular moiety via a ( _C1- a C6)alkyl group as defined herein. Illustrative examples of (C1- _C6 )alkylthio(C1- _C6 )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 chain hydrocarbon containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Illustrative 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, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined herein. Illustrative 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, that is attached to the parent molecular moiety via a sulfur atom, as defined herein . Illustrative 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, as used herein, means an aryl group, as defined herein, that is attached to the parent molecular moiety via an oxygen atom. Illustrative 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, that is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of arylthio include, but are not limited to, phenylthio and naphthalenylthio.

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

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

The term carboxy(C ₁ -C ₆ )alkoxy, as used herein, means a carboxy group, as defined herein, that is attached to the parent molecular moiety 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, that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined herein.

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

The term (C ₃ -C ₈ )cycloalkyl as used herein means a saturated cyclic hydrocarbon group containing from 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 (C3-C8)cycloalkyl group, as defined herein, which is attached to the parent molecular moiety via a (C ₁ - A C ₆ )alkoxy group as defined herein.

The term (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl as used herein means

- 30 045319 (C ₃ -C ₆ )cycloalkyl group, as defined herein, which is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined herein. Illustrative 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, which attaches to the parent molecular fragment via a sulfur atom.

The term (C ₃ -C ₈ )cycloalkyloxy, as used herein, means a (C ₃ -C ₈ )cycloalkyl group, as defined herein, that is attached to the parent molecular moiety via an oxygen atom, as defined herein. Illustrative examples of (C3-C8)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, that is attached to the parent molecular moiety via a sulfur atom, as defined herein. Illustrative 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 halogen or halogen atom as used herein means -Cl, -Br, -I or -F.

The term halogen(C ₁ -C ₆ )alkoxy, as used herein, means that at least one halogen atom, as defined herein, is attached to the parent molecular moiety via a (C ₁ -C6)alkoxy group, as defined in this document. Illustrative examples of halogen(C ₁ -C ₆ )alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term halogen(C ₁ -C ₆ )alkyl, as used herein, means that at least one halogen atom, as defined herein, is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined in this document. Illustrative examples of halogen(C ₁ -C ₆ )alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term halogen(C ₁ -C ₆ )alkylthio, as used herein, means that a halogen(C ₁ -C ₆ )alkyl group, as defined herein, is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of halogen(C ₁ -C ₆ )alkylthio include, but are not limited to, trifluoromethylthio.

The term (5-6 membered)heteroaryl as used herein means a 5- or 6-membered monocyclic heteroaryl. 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. A 5- or 6-membered heteroaryl is attached to the parent molecular fragment through any carbon atom or any nitrogen atom that is part of the heteroaryl. Illustrative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.

The term (5-6 membered)heteroaryl(C1- _C6 )alkoxy, as used herein, means a (5-6 membered)heteroaryl, as defined herein, which is attached to the parent molecular moiety via a ( _C1- A C ₆ )alkoxy group as defined herein. Illustrative examples of heteroaryl(C ₁ -C ₆ )alkoxy include, but are not limited to, fur-3ylmethoxy, 1H-imidazol-2-ylmethoxy, 1H-imidazol-4-ylmethoxy, 1-(pyridin-4-yl)ethoxy, pyridine -3ylmethoxy, 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-2ylmethoxy and thien-3-ylmethoxy.

The term (5-6 membered)heteroaryl(C ₁ -C ₆ )alkyl, as used herein, means (56 membered)heteroaryl, as defined herein, which is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group as defined herein. Illustrative 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-3yl)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

- 31 045319 (5-6 membered) heteroaryl (C ₁ -C ₆ ) alkyl group, as defined herein, which is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of heteroaryl(C ₁ -C ₆ )alkylthio include, but are not limited to, fur-3-ylmethylthio, 1H-imidazol-2ylmethylthio, 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 a (5-6-membered)heteroaryl, as defined herein, that is attached to the parent molecular moiety via an oxygen atom. Illustrative examples of heteroaryloxy include, but are not limited to, fur-3-yloxy, 1H-imidazol-2-yloxy, 1H-imidazol-4-yloxy, pyridin-3yloxy, 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 a (5-6-membered)heteroaryl, as defined herein, that is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and quinolin-3-ylthio.

The term (4-7 membered)heterocyclyl or heterocyclyl as used herein means a 4, 5, 6 or 7 membered ring that contains 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 heterocyclyl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom , which is part of the heterocyclyl. Illustrative examples of heterocyclyl include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranil and tritianyl.

The term (4-7 membered)heterocyclyl(C ₁ -C ₆ )alkoxy, as used herein, means a (4-7 membered)heterocyclyl, as defined herein, which is attached to the parent molecular moiety via (C ₁ -C ₆ )alkoxy group as defined herein.

The term (4-7 membered)heterocyclyl(C ₁ -C ₆ )alkyl, as used herein, means a (4-7 membered)heterocyclyl, as defined herein, which is attached to the parent molecular moiety via (C ₁ -C ₆ )alkyl group as defined herein.

The term (4-7 membered)heterocyclyl(C ₁ -C ₆ )alkylthio, as used herein, means a (4-7 membered)heterocyclyl(C ₁ -C ₆ )alkyl group, as defined herein, which attaches to the parent molecular fragment via a sulfur atom.

The term (4-7-membered)heterocyclyloxy, as used herein, means a (4-7-membered)heterocyclyl, as defined herein, that is attached to the parent molecular moiety via an oxygen atom. Illustrative examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy and pyrimidin-2-yloxy.

The term (4-7-membered)heterocyclylthio, as used herein, means a (4-7-membered)heterocyclyl, as defined herein, that is attached to the parent molecular moiety via a sulfur atom. Illustrative examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and pyrimidin-2-ylthio.

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

The term hydroxy(C ₁ -C ₆ )alkoxy, as used herein, means at least one hydroxy group, as defined herein, which is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkoxy group, as defined herein document. Illustrative 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, that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined in this document. Illustrative examples of hydroxy(C ₁ -C ₆ )alkyl include, but are not limited to, hydroxymethyl, 2hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

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

- 32 045319

The term nitro, as used herein, means a -NO2 group.

The term thio(C ₁ -C ₆ )alkyl, as used herein, means a sulfur atom that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group, as defined herein. Illustrative examples of thio(C ₁ -C6)alkyl include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl and 4-thiobutyl.

The term -NRARB, as used herein, refers to two groups, RA and _RB , that are attached to the parent molecular moiety via a nitrogen atom. RA and _RB are each independently hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkylcarbonyl. Illustrative examples of NRARB include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term NR _Α R _B (C ₁ -C ₆ )alkoxy, as used herein, means an NRARB group that is attached to the parent molecular moiety via a (C ₁ -C6)alkoxy group.

The term NR _A R _B (C ₁ -C ₆ )alkyl, as used herein, means an NRARB group that is attached to the parent molecular moiety via a (C ₁ -C6)alkyl group.

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

The term -NRCRD, as used herein, refers to two groups, RC and RD, that are attached to the parent molecular moiety via a nitrogen atom. R _C and RD are each independently hydrogen, (C ₁ -C6)alkyl, or (C ₁ -C6)alkylcarbonyl. Illustrative examples of NRCRD include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino.

The term NR _C RD(C ₁ -C ₆ )alkoxy as used herein means an NRCRD group that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkoxy group.

The term NR _C RD(C ₁ -C ₆ )alkyl, as used herein, means an NRCRD group that is attached to the parent molecular moiety via a (C ₁ -C ₆ )alkyl group.

The term (NR _C RD)carbonyl, as used herein, means an NRCRD group, as defined herein, that is attached to the parent molecular moiety via a carbonyl group, as defined herein.

The compounds of the present invention can form boron-oxygen dative bonds after exposure to water, alcohols (ROH, R is alkyl), and diols (ROH, R is hydroxyalkyl) as depicted in Scheme A.

- 33 045319

Scheme A

When a boron atom is covalently bonded to an oxygen atom and datively bonded to another oxygen atom, the dative bond and the covalent bond can interconvert or form a resonant hybrid, as illustrated by structures (1), (2), (3) and (4) in Diagram A The compounds of the present invention, after exposure to water, alcohols and diols, can exist as neutral compounds, illustrated by compounds (1)-(4), or as negatively charged compounds, illustrated by compounds (5) and (6), in which R1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R9 , R ₁₀ and p are as defined in the Summary of the Invention section herein. In addition to oxygen, boron can form dative 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) that form dative 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-linked dimers after exposure to water. Exemplary dimers of the present invention are shown in Scheme B, wherein R1, _R2 , _R3 , _R4 , _R5 , _R6 , _R7 , R9, _R10 and p are as defined in the Summary of the Invention herein .

Scheme B

It should be understood that the present invention covers oxygen-linked dimers of formula (I), formula (IA), formula (IB) and formula (IC), including, but not limited to

- 34 045319 this, bis((K)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronic acid and bis((8)-3-hydroxy- 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronic acid.

The compounds of the present invention can also form acyclic and cyclic trimers under the influence of water. Exemplary acyclic and cyclic trimers of the present invention are shown in Scheme C, with R _b R ₂ , R ₃ , R 4 , R 5 , Re, R 7 , R 9 , Rio and p being as defined in the Summary of the invention herein.

Scheme C

It should be understood that the present invention covers 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,2R)3,3',3-(1,3,5,2,4,6-trioxatriborinan-2,4,6-triyl)tri(2-(5 -(4-methoxy-3-propoxyphenyl)pyridin-3yl)propan-1-ol) and (28,2'8,28)-3,3',3-(1,3,5,2,4,6 -trioxatriborinan-2,4,6-triyl)tri(2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propan-1 -o l).

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, with R _b R ₂ , R ₃ , R 4 , R 5 , Re , R 7 , R 9 , Rio and P being as defined in the Summary of the invention herein.

-35 045319

Scheme D

It should be understood that the present invention covers anhydrides of formula (I), formula (IA), formula (IB) and formula (IC), including, but not limited to, oxybis(1,2-oxaborolan-2,4-diyl))bis( 3-(4-methoxy-3-propoxyphenyl)pyridine) and bis(1,2-oxaborolane-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine).

The compounds of the present invention can form poly- or these, 5,5'-((4S,4'S)5,5'-((4R,4'R)-oxy-multivalent species, collected from one species or from more than one species according to the present invention.Polymer constructs can be homopolymeric, consisting of identical or related constructs, or heteropolymeric, consisting of a number of different constructs.

The present invention covers compounds that can be formulated with excipients such that one or more excipients react with the compounds of the present invention to form single, poly- or multivalent species, including, for example, species such as esters, dimers, trimers, tetramers and higher homologues. For example, compounds of formula (I), formula (IA), formula (IB) and formula (IC) can form boronic acid esters with propylene glycol or hexylene glycol under appropriate conditions. Exemplary esters of the present invention are shown in scheme E, with R1, R2, _R3 , R4,

_R5 , R6, _R7 , _R9 , R10 and p are as defined in the document.

Diagram E in the Summary of the invention section in this

It should be understood that the present invention covers boronic acid esters of formula (I), formula (IA), formula (IB) and formula (IC) including, but not limited to,

- 36 045319

1-Hydroxypropan-2-yl hydrogen ((R)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, (S)-1hydroxypropan-2-yl hydrogen ( (P)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin3-yl)propyl)borate, ^)-1-hydroxypropan-2-yl hydrogen ((^-3-hydroxy-2 -(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)borate, 2-hydroxypropyl hydrogen (^)-3-hydroxy-2(5-(4-methoxy-3-propoxyphenyl)pyridin-3- yl)propyl)borate, (8)-2-hydroxypropyl hydrogen ((R)-3-hydroxy-2-(5-(4-methohydroxy-3-poπocyphenyl)pyridin-3-yl)πpopyl)borate, (K) -2-hydroxypropyl hydrogen ((R)-3-hydrogen )-3-hydroxy-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, (8)-4-hydroxy-2-methylpentan-2-yl hydrogen ((R)-3 -hydroxy-2-(5-(4-methohydroxy-3-πpoπoκciφenyl)πpyridin-3-yl)πpopyl)boron, (P)-4-hydroxy-2-methylpentan-2-yl hydrogen (^)-3-hydroxy -2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)borate, 4-hydroxy-4-methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5- (4-methoκci-3-πpoπoκciφenyl)πpiridin-3-yl)πpoπyl)boron, (S)-4hydroxy-4-methylpentan-2-yl hydrogen ((^-3-hydroxy-2-(5-(4-methoxy -3propoxyphenyl)pyridin-3-yl)propyl)borate, (^-4-hydroxy-4-methylpentan-2-yl hydrogen ((R)-3-hydroxy-2-(5-(4-meτoκci-3-πpoπoκciφenyl )pyridin-3-yl)πpoπyl)borate, 1hydroxypropan-2-yl hydrogen ((8)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin3-yl)propyl)borate, (8 )-1-hydroxypropan-2-yl hydrogen ((8)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)borate, (P)-1-hydroxypropane-2 -yl hydrogen ((S)-3hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, 2-hydroxypropyl hydrogen ((8)-3-hydroxy-2-( 5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, (8)-2-hydroxypropyl hydrogen ((8)-3-hydroxy-2-(5-(4-methoxy-3- propoxyphenyl)pyridin3-yl)propyl)borate, (^-2-hydroxypropyl hydrogen ((8)-3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)borate, 4- Hydroxy-2-methylpentan-2-yl hydrogen ((S)3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, (8)-4-hydroxy2- methylpentan-2-yl hydrogen ((8)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)borate, (K)-4-hydroxy-2-methylpentane-2 -yl hydrogen ((8)-3-hydroxy-2-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, 4-hydroxy-4-methylpentan-2-yl hydrogen ((8) -3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate, (8)-4-hydroxy-4-methylpentan-2-yl hydrogen ((8)- 3-hydroxy-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)propyl)borate, and (P)-4-hydroxy-4-methylpentan-2-yl hydrogen ((8)-3- hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)borate.

The present invention also covers cyclic esters formed by reacting compounds of formula (I), formula (IA), formula (IB) and formula (IC) with certain diols, including, but not limited to, propylene glycol and hexylene glycol. Exemplary cyclic esters are shown in Scheme F, with R _1? R2, _R3 , R4, _R5 , R6, _R7 , _R9 , _R10 ; and p are as defined in the Summary of the Invention section herein.

Scheme F

It should be understood that the present invention covers cyclic boronic acid esters of formula (I), formula (IA), formula (IB) and formula (IC), including, but not limited to,

- 37 045319 (2 R)-2-(5-(4-methoxy-3propoxyphenyl)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-((5)-4-methyl-1,3,2-dioxaborolan-2yl)propan-1 -ol, (R)-2-(5-(4-methoxy-3-poπocyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2dioxaborolan-2-yl)propane -1-ol, (2R)-2-(5-(4-methoκci-3-πpoπoκciφenyl)πpyridin-3-yl)-3(4,4,6-trimethyl-1,3,2-dioxaborinan-2- yl)propan-1-ol, (R)-2-(5-(4-MeTOKCM-3propoxyphenyl)pyridin-3-yl)-3-((5)-4,4,6-trimethyl-1,3, 2-dioxaborinan-2-yl)propan-1ol, (R)-2-(5-(4-methoκci-3-πpoπocyphenyl)pyridin-3-yl)-3-((R)-4,4,6- τpimethyl-1,3,2dioxaborinan-2-yl)propan-1-ol, (25)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3(4-methyl-1 ,3,2-dioxaborolan-2-yl)propan-1-ol, (5)-2-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-3-((5)-4-methyl -1,3,2-dioxaborolan-2-yl)propan-1-ol, (S)2-(5-(4-methoxy-3-poπocyphenyl)pyridin-3-yl)-3-((R)- 4-methyl-1,3,2-diocaborolan-2yl)propan-1-ol, (25)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4, 4,6-trimethyl1,3,2-dioxaborinan-2-yl)propan-1-ol, (5)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)-3-((5 )-4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol, and (5)-2-(5-(4-methoxy-3πpoπoκciphenyl)πpyridin-3-yl )-3-((R)-4,4,6-τpimetyl-1,3,2-diocaborinan-2-yl)πpopan-1ol.

The salts, esters, anhydrides, dimers and trimers illustrated in Schemes A-F are prodrugs that can hydrolyze back to the parent compounds under aqueous conditions, including conditions for in vivo conversion of the oxaborolane ring.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts formed with organic or inorganic acids. By pharmaceutically acceptable salt we mean those salts that are within the reasonable medical judgment, acceptable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic response, etc., and have a comparable reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977), which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting the free base (basic nitrogen) with a suitable organic or inorganic acid. Exemplary 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-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate , p-toluenesulfonate and undecanoate.

In addition, groups containing basic nitrogen 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-, mystyryl- and stearyl chlorides, -bromides and -iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. In this way, products are obtained that are soluble or dispersible in water or oil. 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 tartaric acid, maleic acid, succinic acid and citric acid.

The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers are present. These stereoisomers are designated R or S depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) as used herein represent configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 1330. In particular, the stereochemistry at the point of attachment Y and Z, as shown in formulas (I), (IA) and (IB) may independently be either (R) or (S), if specifically no other specified. The enantiomers of the present invention are designated (R), (S), or * are substantially free of another enantiomer. Substantially free means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, and more preferably greater than

- 38 045319 than approximately 99%. In the context of enantiomeric excess, the term approximately means ±1.0%. The symbol * denotes a chiral carbon atom as either (R) or (S) in stereochemistry depending on the configuration of 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. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparation of racemic mixtures followed by resolutions well known to those skilled in the art. These separation methods include, but are not limited to, (1) adding a chiral excipient to a mixture of enantiomers, separating the resulting mixture of diastereomers using recrystallization or chromatography, and separating the optically pure product from the excipient, or (2) directly resolving the mixture of optical enantiomers into chiral chromatography columns.

Compounds of the present invention not designated (R), (S), or * may exist as racemates (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers, wherein one enantiomer is in excess. For example, enantiomeric mixtures may include the 51% (R) enantiomer and the 49% (S) enantiomer 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 can exist in different stable conformational forms, which can be separated. Torsional asymmetry due to limited rotation around an asymmetric single bond, for example due to steric hindrance or ring deformation, may allow separation of different conformers. The compounds of the present invention further include each conformational isomer of the compounds of formula (I), (IA), (IB) and (IC) and mixtures thereof.

Tautomers may exist in the compounds of the present invention and are specifically within the scope of the present invention. The term tautomer, as used herein, means the displacement 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 the displacement of protons from one atom to another atom of the same molecule, forming two or more different compounds that are in equilibrium with each other.

The compounds of the present invention can be isolated and used per se or in the form of pharmaceutically acceptable salts thereof. In accordance with the present invention, compounds with several basic nitrogen atoms can form salts with different amounts of equivalents (eq.) of acid. Practitioners will appreciate that all salts are included 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 formulas (I), (IA), (IB) and (IC) and their salts (including solvates and hydrates) are part of this invention and can be obtained by crystallizing the compound of the present invention under various conditions, for example, the use of different solvents or different mixtures of solvents for recrystallization; crystallization at different temperatures; different cooling modes, from very fast to very slow cooling during crystallization. Polymorphs can also be prepared by heating or melting a compound of the present invention followed by further gradual or rapid cooling. The presence of polymorphs can be determined using solid probe nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or such other methods.

This invention also includes isotopically labeled compounds that are identical to the compounds described by formulas (I), (IA), (IB) and (IC), but in that one or more atoms are replaced by an atom having an atomic mass or mass number, different from the atomic mass or mass number typically 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 ^2H , ^3H , 13C, ^14C , ^15N , ^18O , ¹⁷ O, ³⁵ S, ³⁶ CI, ¹²⁵ I, ¹²⁹ 1, ¹⁸ F and ¹⁹ F, respectively. Certain isotope-labeled compounds of the present invention, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in tissue distribution assays of drug and/or substrates. Isotopes of tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly advantageous due to their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic benefits that arise from greater metabolic stability, such as increased in vivo half-life or reduced dosing requirements, and may therefore be advantageous under some circumstances. The isotopically labeled compounds of the present invention can generally be prepared by following the procedures disclosed in the Schemes and/or 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 hydrogens contained in the compounds of the present invention can be replaced by deuterium. Illustrative examples of deuterated compounds of the present invention include, but are not limited to, the compounds below, in which D represents deuterium

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

Compounds of the present invention have been named using Chemdraw Professional version 15.0 or 16.0 or given names that appear to conform to Chemdraw nomenclature.

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

The present invention also relates to pharmaceutically active metabolites that are 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 that is formed by in vivo biotransformation of compounds of formulas (I), (IA), (IB) and (IC). A thorough discussion of biotransformation is presented 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, including methods similar to those well known in the chemical field, especially in light of the description contained herein. Starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (eg, prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19 , Wiley, New York (19671999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including appendices (also available via the Beilstein Internet Database).

For illustrative purposes, the reaction schemes depicted below provide potential routes for the synthesis of the compound of the present invention, as well as intermediate compounds for preparing the compound of the present invention. For a more detailed description of the individual reaction steps, see 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. Although 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 compounds prepared by the methods described below can be further modified in light of this disclosure using traditional chemistry approaches well known to those skilled in the art.

In the preparation of the compound of the present invention, it may be necessary to protect distant functional groups, such as carboxylic acids, amino and/or hydroxy groups of intermediates. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the acquisition methods. Suitable amino protecting groups (NH-PG) include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and 9fluorenylmethyleneoxycarbonyl (Fmoc). Likewise, a hydroxy protecting group refers to a hydroxy substituent that blocks or protects hydroxyl functionality. Suitable hydroxy protecting groups (O-PG) include, for example, allyl, acetyl, silyl, benzyl, paramethoxybenzyl, trityl and the like. Carboxylic acid protecting groups include alkyl esters such as methyl, ethyl, propyl and tert-butyl. The need for such protection

- 40 045319 is easily determined by a specialist in the field. 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 that is compatible with the reagents and materials that are used and are acceptable for the transformations that are carried out. Those skilled in the art of organic synthesis will appreciate that the functionality present in the molecule must correspond to the proposed transformations. This sometimes requires judgment to modify the order of synthetic steps or select one particular process design over another to produce the desired compound of the invention.

It will also be recognized that another important factor in planning any synthetic method in the art is the judicious choice of the protecting group used to protect the reactive functional groups present in the compounds described in this invention. An acclaimed publication describing many alternatives for the skilled 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 can be removed by treatment with an acid such as trifluoroacetic acid or concentrated hydrochloric acid and the SES protecting group can be removed with a fluoride salt such as cesium fluoride or tetrabutylammonium fluoride. The CBZ and Bn protecting groups 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 using aluminum trichloride.

Removal and purification of the compound and intermediates described herein can be accomplished, if desired, using any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low-level liquid chromatography , medium or high pressure, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be provided by reference to the Examples herein below. However, other equivalent separation or separation procedures may also be used.

The compounds of the invention can be prepared by any method known in the art to produce compounds of similar structure. In particular, the compounds of the invention can be prepared by the procedures described with reference to the schemes below, or by the specific methods described in the examples, or by similar methods.

One skilled in the art will appreciate that the experimental conditions set forth in the following schemes illustrate the appropriate conditions for carrying out the transformations shown and that it may be necessary or desirable to vary the exact conditions that are used to prepare the compounds of formulas (I), (IA), (IB) and ( IC). It will further be understood that it may be necessary or desirable to carry out the transformations in a different order than described in the diagrams, or to modify one or more transformations, to obtain the desired compound of the invention.

Derivatives of formulas (I), (IA), (IB) and (IC) can be prepared by the procedures described in the general methods presented below or by conventional modifications thereof. The present invention also covers one or more of these methods for preparing derivatives of formulas (I), (IA), (IB) and (IC), in addition to any new intermediates that are used therein. One skilled in the art will appreciate that the following reactions can be heated thermally or by microwave irradiation.

The following methods, 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 their intermediates can be prepared by methods other than those specifically described herein below, for example, by adapting the methods described herein, for example, by methods known in the art. Acceptable aids regarding synthesis, functional group interconversions, use of protecting groups, and the like 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 R.K. Mackie and D.M. Smith, Longman (1982); Protective Groups in Organic Synthesis by T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc. (1999); and Protecting Groups by P.J. Kocienski, Georg Thieme Verlag (1994); and any updated versions of said standard works.

In addition, the specialist will understand what may be necessary or desirable at any stage

- 41 045319 synthesis of compounds according to the invention to protect one or more sensitive groups, to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect alcohol, amino or carboxylic acid groups. The protecting groups that are used in the preparation of the compounds of the invention can be used in a conventional manner. See, for example, those described in Greene's Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G.M. Wuts, fifth edition (John Wiley and Sons, 2014), included here in a form that also describes how to remove such groups.

In the general synthetic methods below, unless otherwise indicated, the substituents are as defined above with reference to the compounds of formula (I) above. Where solvent ratios are stated, the ratios are by volume unless otherwise stated.

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

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

According to the first method, the compounds of formula (1D) (in which R1, _R2 , _R3 , _R4 , R5, R6, _R7 , _R9 , _R10 and p are as defined in the Summary of the Invention section of this document and v=0, 1, 2, 3, 4, 5) can be obtained from compounds of formula (II) and (III) as illustrated in Scheme 1.

Scheme 1

In Scheme 1, compounds of formula (II) in which R ₁₄ is a suitable protecting group (mainly TBS) are converted into a compound of formula (III) in which R ₁₅ is boronic acid (mainly) or 4,4,5. 5-tetramethyl-1,3,2-dioxaborolane (Bpin) by treatment with a suitable hydroboration source such as catecholborane or bis(pinacolato)diboron in the presence of a suitable catalyst (bis(1,5-cyclooctadiene)di-μmethoxydiiridium(I) or (1,5-cyclooctadiene)(methoxy)iridium(I) dimer) and the ligand (ethylenebis(diphenylphosphine), in a suitable solvent such as EDC or THF at an appropriate temperature (15 to 70° C.). One skilled in the art will also know alternative methods for the hydroboration of alkenes, which are achieved using alternative reagents, solvents and temperatures.The compound of formula (III) is converted to the compound of formula (1D) under aqueous acidic conditions, by treatment with a suitable acid (acetic or hydrochloride) at a suitable temperature. It is well understood by one skilled in the art that a compound of formula (III) is prepared and isolated as described above, or is prepared in situ without isolation by a sequential reaction strategy to yield a compound of formula (1D). In the case of compounds of formula (III) and (1D), when this results 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 SFC chromatography, obtaining both (+), and (-) enantiomers of the compounds of formula (III) and (1D). It will be well understood by one skilled in the art that the individual enantiomers of a compound of formula (III) and (1D) are prepared and isolated as described above, or isolated using alternative separation techniques such as HPLC or SFC, using a suitable chiral stationary phase, eluting with a suitable mobile phase such as it is determined what is necessary to isolate the required enantiomers.

According to the second method, compounds of formula (1E) or (1F) can be prepared from formula (II) as illustrated in Scheme 2.

Scheme 2

In Scheme 2, compounds of formula (1E) or (1F) can be prepared in a manner similar to that shown in Scheme 1 using suitable chiral ligands such as (S,S)-[2-(4'-ipropyloxazoline-2 -yl)ferocynyl]diphenylphosphine or (R,R)-[2-(4'-i-propyloxazolin-2-yl)ferocynyl]diphenylphosphine, producing chiral compounds of formula (IV). One of skill in the art will know that chiral hydroboration strategies can utilize alternative combinations of chiral ligands, catalysts, boron sources, solvents, and temperatures. It will be well understood by one skilled in the art that a compound of formula (IV) can be prepared and isolated as described above, or prepared in situ without isolation by a sequential reaction strategy to yield a compound of formula (1E) or (1F). One skilled in the art will also be aware that compounds of formula (1E) or (1F) can be further enriched using crystallization techniques or chiral chromatography (HPLC or SFC) using a suitable chiral stationary phase, eluting with a suitable mobile phase, as determined to be necessary for isolating the required enantiomers.

According to a third method, compounds of formula (1G) can be prepared from formula (II), as illustrated in Scheme 3.

Scheme 3

In Scheme 3, compounds of formula (II) are converted to compounds of formula (V) when treated with a halogenating agent such as pyridinium tribromide in a suitable solvent such as DCM at an appropriate temperature such as 0°C. One skilled in the art will also know that alternative methods for specifically introducing a suitable halogen group such as Br can be achieved using alternative reagents, solvents and temperatures. Compounds of formula (VI) can be synthesized by this method or by reacting compounds of formula (V) using DBU with a suitable solvent such as DCM at a suitable temperature such as 25°C. Compounds of formula (VI) can be converted to compounds of formula (VII) (in which R ₁₅ =Bpin) using Miyaura borylation conditions. Typical conditions for the formation of borate esters include Pd(dppf)Cl ₂ ·DχM and potassium acetate with bispinacolatoboron in 1,4-dioxane at a suitable temperature, such as 55°C. The compound of formula (VII) can be converted to the compound of formula (1G) under aqueous acidic conditions by treatment with a suitable acid (acetic or hydrochloride) at a suitable temperature.

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

Scheme 4

In Scheme 4, compounds of formula (X) in which R ₁₇ is chlorine, bromine or iodine can be prepared from compounds of formula (VIII) and (IX) using a suitable metal-organic cross-coupling reaction, such as a cross-coupling reaction. Suzuki combination, which, if necessary, precedes the formation of boronic acid or ester. Typical Suzuki cross-coupling conditions involve a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in aqueous dioxane or methanol, at elevated temperatures or by heating or microwave irradiation. Preferred conditions include Pd(OAc) ₂ ,

- 43 045319

Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ s or sodium, cesium or potassium carbonate in aqueous dioxane or methanol at room temperature to 120°C. One of skill in the art will know that organometallic cross-coupling reaction strategies can be used using alternative combinations of metals, catalysts, ligands, bases, solvents and temperatures. Typical conditions for the formation of boronic esters include Pd(dppf)Cl ₂ and potassium acetate with bispinacolatodiboron with compounds of formula (VIII), in which Rl ₆ =chlorine, bromine or iodine, in dioxane at reflux. The compounds of formula (VIII) can also be obtained commercially or synthesized by one skilled in the art in accordance with the literature or by analogy with the methods described herein.

Compounds of formula (II) can be prepared from compounds of formula (X) and (XI), (in which Rl ₈ =boronic acid or Bpin) through a metal-organic cross-coupling reaction similar to those described previously. One skilled in the art will be aware that alternative organometallic cross-coupling reaction strategies can also be used involving 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 aqueous dioxane at room temperature to 120°C.

Alternatively, compounds of formula (II) can be prepared from compounds of formulas (VIII), (IX), (XI) and (XII), in the reverse order of Scheme 4, as illustrated in Scheme 5.

Scheme 5

Compounds of formula (XII) can be prepared from compounds of formula (XI) (in which

Rl ₈ =boronic acid or pinacol) and (IX) (in which R _n is chlorine, bromine or iodine) using an organometallic cross-coupling reaction as described in 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 one skilled in the art in accordance with 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 optionally preceding the formation of the boronic acid or ester. One skilled in the art will be aware that alternative organometallic cross-coupling reaction strategies can also be used involving alternative combinations of metals, catalysts, ligands, bases, solvents, and temperatures.

According to the sixth method, compounds of formula (1H) can be prepared from formula (XIII) and (XIV), as illustrated in Scheme 6.

Scheme 6

Compounds of formula (1H) in which A represents carbon or nitrogen can be prepared by methods analogous to the preparation of compounds of formula (1D), (1E) or (1F) as described in Schemes 1-5. One skilled in the art will appreciate that the individual enantiomers can be obtained using a suitable separation technique such as HPLC or SFC chromatography to provide both the (+) and (-) enantiomers of the compounds of formula (XIV) and (1H). It will also be 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 technique such as HPLC or SFC, using a suitable chiral stationary phase, eluting with a suitable mobile phase , as determined by what is necessary to isolate the required enantiomers. Additionally, compounds of formula (1H) in which the central ring is replaced by a 5-membered substituted heterocyclyl (illustrated as Y in formula (1)) can also be synthesized by methods similar to those known to one skilled in the art.

- 44 045319

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

Abbreviations that have been used in the descriptions of the schemes and examples are as follows: Ac represents acetyl; AcOH is acetic acid; Ac2O is acetic anhydride; Adam's catalyst is platinum(IV) oxide; Br2 represents bromine; n-BuLi represents n-butyllithium; °C represents degrees Celsius; CDCl ₃ is deuterochloroform; CD ₃ OD is deutero-methanol; CO2 represents carbon dioxide; Cs ₂ CO ₃ is cesium carbonate; 5 represents chemical shift; DAST is N,N-diethylamino-S,S-difluorosulfinium tetrafluoroborate; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; EDC is 1,2-dichloroethane; DCM is dichloromethane or methylene chloride; DEA is diethylamine; DMAP is 4-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; DMSO-d ₆ is deutero-dimethyl sulfoxide; Et ₂ O is diethyl ether; EtOAc is ethyl acetate; EtOH represents ethanol; Et ₃ N represents triethylamine; Fe represents iron; g represents gram; HCl is a hydrochloride acid; HCO ₂ H represents formic acid; NMTA is hexamethylenetetramine; HPLC is high performance liquid chromatography; H ₂ represents hydrogen; H ₂ O represents water; h represents a clock; h represents an hour; Hz represents Hertz; IPA is isopropyl alcohol; IPAm: is isopropylamine; [Ir(COD)Cl] ₂ is bis(1,5-cyclooctadiene)diiridium(I) dichloride; [Ir(COD)OMe] ₂ is a (1,5-cyclooctadiene)(methoxy)iridium(1) dimer; K ₂ CO ₃ is potassium carbonate; K ₃ PO ₄ is potassium phosphate tribasic; KBr is potassium bromide; KMnO ₄ is potassium permanganate; COAc is potassium acetate; l represents liter; LC-MS is a liquid chromatography mass spectrometry; LDA is lithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide; LiOH is lithium hydroxide monohydrate; LTMP represents lithium tetramethylpiperidine; M represents molar; m-CPBA is meta-chloroperoxybenzoic acid; MeCN is acetonitrile; MeOH represents methanol; MeNH ₂ is methylamine; mg represents milligram; MgSO ₄ is magnesium sulfate; MHz represents mega Hertz; min represents minutes; ml represents milliliter; mm represents millimeter; mmol represents millimoles; a mole is a mole; MS m/Z represents 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-bromo succinimide; NH ₃ is ammonia; NH ₄ Cl is ammonium chloride; NH2OH-HQ is hydroxylamine hydrochloride; NH4OH is ammonium hydroxide; nM represents nanomolar; PCl ₅ is phosphorus pentachloride; Pd/C is palladium on carbon; Pd(dppf)Cl ₂ is [1,1'-bis(diphenylphosphino)ferocene]dichloropalladium(P); Pd(dppf)Cl ₂ DCM is [1,1'-bis(diphenylphosphino)ferocene]dichloropalladium(P), complexed with dichloromethane; Pd(dppf) tBu is [1,1'-bis(di-tert-butylphosphino)ferocene]dichloropalladium(P); Pd(OAc) ₂ is palladium acetate; PPh ₃ is triphenylphosphine; petroleum ether is petroleum ether; pH represents the amount of hydrogen; Pin ₂ B ₂ is bis(pinacolato)diboron; PinBO-iPr is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2dioxaborolane; psi represents pounds per square inch; m.d. represents parts per million; POCl3 is phosphorus oxychloride; PrOH is 1propanol; PtO ₂ is platinum(IV) oxide; k.t. represents room temperature; RT represents holding time; SEM-Cl is 2-(trimethylsilyl)ethoxymethyl chloride; SFC is supercretic liquid chromatography; TBS is tert-butyldimethylsilyl; TBS-Cl is tert-butyldimethylsilyl chloride; tBu ₃ P is tri-tert-butylphosphine; TFO is trifluoroacetic acid; TPOA 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 a complex of isopropylmagnesium chloride, lithium chloride; 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(P ).

The 1H and ^19F nuclear magnetic resonance (NMR) spectra in all cases corresponded to the proposed structures. Characteristic chemical shifts (δ) are given in parts per million of weak field from

- 45 045319 tetramethylsilane (for 1H-NMR) and high field from trichlorofluoro-methane (for %-NMR), using generally accepted abbreviations to designate the main peaks: for example, c, singlet; d, doublet; t, triplet; kv, quartet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; m, multiplet; w, wide. The following abbreviations have been used for common solvents: CDCl ₃ , deuterochloroform; DMSO-d ₆ , deutero-dimethyl sulfoxide; and CD3OD, deutero-methanol. If necessary, tautomers can be recorded within the NMR data; and some exchanged protons may not be visible.

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

Where appropriate, unless otherwise noted, m/z data provided are for the isotopes ¹⁹ F, ³⁵ Cl, ⁷⁹ Br and ¹²⁷ I.

When using preparative TLC or column chromatography (silica), one skilled in the art can select any combination of appropriate solvents to purify the desired compound.

Specific rotations that are based on the equation

[u]=(100u)/(1xc) are presented as dimensionless numbers, where the concentration c is indicated in g/100 ml and the travel distance I is indicated in decimeters. Units of specific rotation, (deg.ml)/g dm) are internal and are not included with the value presented.

The following are analytical and preparative chromatographic methods that are used for the analysis and purification of the compounds of the invention.

Preparative SFC methods.

Rev. SFC method A: Column: Chiralpak IC-H, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /EtOH, 60/40 (v/v); Flow rate: 65 ml/min.

Rev. SFC method B: Column: Lux Amylose-1 250 mmx30 mm, 5 µm; Mobile phase - Isocratic conditions: CO ₂ /MeOH + 0.2% (7N ammonia in MeOH) 80/20 (v/v); Flow rate: 150 ml/min.

Rev. SFC method C: Column: Chiralpak IC-H, 250 mmx50 mm, 5 μm; Mobile phase Isocratic conditions: CO2/IPA 85/15 (v/v); Flow rate: 250 ml/min.

Rev. SFC method D: Column: Chiralcel OJ, 250 mmx30 mm, 5 µm; Mobile phase - Isocratic conditions: CO2/IPA, 65/35 (v/v); Flow rate: 50ml/min.)

Rev. SFC method E: Column: Daicel Chiralpak AD, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 60/40 (v/v); Flow rate: 50 ml/min.

Rev. SFC method F: Column: Daicel Chiralpak IC, 250 mmx30 mm, 5 μm; Mobile phase Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 60/40 (v/v); Flow rate: 200 ml/min.)

Rev. SFC method G: Column: Daicel Chiralpak AD, 250 mmx50 mm, 10 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 55/45 (v/v); Flow rate: 200 ml/min.

Rev. SFC method H: Column: Chiralpak IC-H, 250 mmx30 mm, 5 μm; Mobile phase Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 75/25 (v/v); Flow rate: 200 ml/min.

Rev. SFC method I: Column: Chiralpak IC, 250 mmx30 mm, 10 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 60/40 (v/v); Flow rate: 60.0 ml/min.

Rev. SFC method J: Column: Chiralpak IC 250 mmx30 mm, 10 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 80/20 (v/v); Flow rate: 60 ml/min.

Rev. SFC method K: Column: Chiralpak AD, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /MeOH (0.1% NH4OH), 75/25 (v/v); Flow rate: 50.0 ml/min.

Rev. SFC method L: Column: Chiralpak AD, 250 mmx30 mm, 10 μm; Mobile phase Isocratic conditions: CO ₂ /MeOH (0.1% NH4OH), 75/25 (v/v); Flow rate: 200.0 ml/min.

Rev. SFC method M: Column: Chiralpak IC, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 55/45 (v/v); Flow rate: 50.0 ml/min.

Rev. SFC method N: Column: Chiralpak IC, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 75/25 (v/v); Flow rate: 60.0 ml/min.

Rev. SFC method O: Column: Daicel Chiralpak AD, 250 mmx50 mm, 10 μm; Mobile phase - Isocratic conditions: CO ₂ /MeOH, 60/40 (v/v); Flow rate: 200 ml/min.

Rev. SFC method P: Column: Chiralcel OJ-H, 250 mmx30 mm, 5 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.1% NH4OH), 85/15 (v/v); Flow rate: 50 ml/min.

Rev. SFC method Q: Column: Daicel Chiralpak AD, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO2/IPA (0.1% NH4OH), 75/25 (v/v); Flow rate: 60 ml/min.

Rev. SFC method R: Column: Chiral Technologies AD-H, 250 mmx21 mm, 5 μm; Mobile phase Isocratic conditions: CO ₂ /MeOH (0.2% NH4OH), 80/20 (v/v); Flow rate: 75 ml/min.

Rev. SFC method S: Column: Princeton PPU, 250 mmx30 mm, 5 μm; Mobile phase - Isocratic conditions: CO ₂ /MeOH, 80/20 (v/v); Flow rate: 80 ml/min.

Analytical SFC methods.

- 46 045319

Analytical SFC method A: Column: Chiralpak IC, 250 mm x 4.6 mm, 5 μ; Mobile phase A: CO ₂ ,

Mobile phase B: EtOH (0.05% isopropylamine); Gradient: A:B=65:35; Flow rate: 2.5 ml/min.

Analytical SFC method B: Column: Lux Amylose-1, 250 mm x 4.6 mm, 5 μ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% MeNH2); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (1.0 min, 95%A, 5%B), (9.0 min, 40%A, 60%B), (10 min, 95%A, 5%B); Flow rate: 3.0 ml/min.

Analytical SFC method C: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3 µm; 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 SFC method D: Column: Chiralpak AD-3, 150 mmx4.6 mm, 3 µm; 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, 6o%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

Analytical SFC method E: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3 µm; 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 SFC method F: Column: Chiralpak AD-3, 50 mm x 3.0 mm, 3 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.0 ml/min.

Analytical SFC method G: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3 µm; Mobile phase A: CO2, Mobile phase B: MeOH (0.05% DEA); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (5.0 min, 6o%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

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

Analytical SFC method I: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3 μ; 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 SFC method J: Column: Chiralpak AD-3, 150 mm x 4.6 mm, 3 μ; 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, 6o%A, 40%B), (7.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

Analytical SFC method K: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 3 μ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% NH4OH); Gradient elution (time,%A,%B): (5 min, 60%A, 40%B, [Flow rate: 1.5 ml/min.

Analytical SFC method L: Column: ChiralCel OJ-H, 150 mm x 4.6 mm, 5 μ; Mobile phase A: CO2, Mobile phase B: EtOH (0.05% DEA); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (5.0 min, 6o%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

Analytical SFC method M: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5 µm; Mobile phase A: CO2, Mobile phase B: MeOH (0.2% 7N NH3 in MeOH); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (1.0 min, 95%A, 5%B), (9.0 min, 40%A, 60%B), (9.5 min, 40%A, 60%B), (10 min, 95%A, 5%B), Flow rate: 3.0 ml/min.

Analytical SFC method N: Column: Chiralcel OJ-H 250 mm x 4.6 mm, 5 μ; Mobile phase A: CO ₂ , Mobile phase B: IPA (0.05% IPAm), Gradient elution: B to A from 10 to 40% in 10 min, Flow rate: 2.5 ml/min.

Analytical SFC method О: Column: ChiralPak AY-3 150 mmx4.6 mm, 3 µm; 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 SFC method P: Column: Chiralcel OJ-3 100 mm x 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 SFC method Q: Column: ChiralCel OD-3, 150 mm x 4.6 mm, 3 μ; Mobile phase A: CO2, Mobile phase B: EtOH (0.05% DEA); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (5.0 min, 60%A, 40%B), (5.5 min, 95%A, 5%B), (7 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

- 47 045319

Analytical SFC method R: Column: Chiralpak AD-3, 100 mm x 4.6 mm, 3 μ; Mobile phase Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.08 ml/min.

Analytical SFC method S: Column: Chiral Technologies OJ-H, 100 mm x 4.6 mm, 5 µm; Mobile phase - Isocratic conditions: CO ₂ /EtOH (0.2% NH4OH), 95/5 (v/v); Flow rate: 3.0 ml/min.

Analytical SFC method T: Column: Chiralpak IC, 100 mm x 4.6 mm, 3 μ; 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 SFC method U: Column: Lux Amylose-2, 100 mm x 4.6 mm, 5 μ; Mobile phase A: CO ₂ , Mobile phase B: MeOH (0.2% NH4OH); Gradient elution (time,%A,%B): (0 min, 70%A, 30%B), (5.0 min, 70%A, 30%B); Flow rate: 1.5 ml/min.

Analytical SFC method V: Column: Chiral Technologies AD-H, 100 mm x 4.6 mm, 5 µm; 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 SFC method W: Column: Chiral Tech IG, 250 mm x 4.6 mm, 5 µm; 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 SFC method X: Column: ChiralPak AY, 150 mm x 4.6 mm, 3 μ; Mobile phase A: CO2, Mobile phase B: EtOH (0.05% DEA); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (5.0 min, 4o%A, 60%B), (7.5 min, 40%A, 60%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

Analytical SFC method Y: Column: Chiral Tech OJ-H, 100 mm x 4.6 mm, 5 µm; Mobile phase A: CO2, Mobile phase B: MeOH (0.2% NH4OH); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (10 min, 95%A, 5%B), Flow rate: 1.5 ml/min.

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

Analytical SFC method AA: Column: ChiralPak AD-3 100 mm x 4.6 mm, 3 µm; 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 SFC method VA: Column: Chiralpak IC-3, 150 mm x 4.6 mm, 3 µm; 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 SFC 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 SFC method DA: Column: Lux Cellulose-2, 150 mm x 4.6 mm, 5 μ; 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, 6o%A, 40%B), (8.5 min, 60%A, 40%B), (10 min, 95%A, 5%B), Flow rate: 2.5 ml/min.

Analytical SFC method EA: Column: Chiralcel OJ-3, 150 mm x 4.6 mm, 3 μ; Mobile phase Isocratic conditions: CO ₂ /EtOH (0.05% DEA), 60/40 (v/v); Flow rate: 2.5 ml/min.

Analytical SFC method FA: Column: ChiralPak AD-3, 250 mm x 4.6 mm, 5 µm; Mobile phase A: CO2, 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 SFC method GA: Column: Chiral Tech IC, 250 mm x 4.6 mm, 5 µm; Mobile phase A: CO ₂ , Mobile phase B: IPA (0.2% NH3 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.

Rev. HPLC method A: Column: Xtimate C18, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B MeCN; B%: 18-58%, 12 min; Flow rate: 25 ml/min.

Rev. HPLC method B: Column: Phenomenex XB-C18, 250 mm x 21.2 mm, 5 μ; Mobile phase A: water (0.1% HCO2H), Mobile phase B: MeCN (0.1% HCO2H); Gradient elution (time,%A,%B): (0 min, 95%A, 5%B), (1.5 min, 95%A, 5%B), (10.0 min, 0%A, 100%B), (11 min, 0%A, 100%B), (12.5 min, 95%A, 5%B); Flow rate: 27 ml/min.

Rev. HPLC method C: Column: Waters Atlantis C18, 50 mm x 4.6 mm, 5 μ; Mobile phase A: water (0.05% TFO), Mobile phase B: MeCN (0.05% TFO); 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.

- 48 045319

Rev. HPLC method D: Column: Xtimate C18, 150 mm x 25 mm, 5 μ; Mobile phase A: water (0.05% ammonium hydroxide), Mobile phase B: MeCN; B%: 25 - 65%, 12 min, Flow rate: 25 ml/min.

Rev. HPLC method E: Column: Waters Xbridge, 150 mmx25 mm, 5 µm; Mobile phase A: water (10mm NH ₄ HCO ₃ ), Mobile phase B: MeCN; B%: 20-50%, 12 min.

Rev. HPLC method F: Column: Phenomenex luna C18, 250 mmx80 mm, 10 μ; Mobile phase A: water (0.1% TFO), Mobile phase B: MeCN; B%: 1-25%, 20 min.

Rev. HPLC method G: Column: Phenomenex Synergi Max-RP, 250 mmx80 mm, 10 μ; Mobile phase A: water (0.1% TFO), Mobile phase B: MeCN; B%: 10-40%, 20 min.

Rev. HPLC method H: Column: Boston Green ODS, 150 mmx30 mm, 5 µm; Mobile phase A: water (0.225% HCO ₂ H), Mobile phase B: MeCN; B%: 5-53%, 11 min, Flow rate: 25 ml/min.

Rev. HPLC method I: Column: Agela Durashell C18, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.225% HCO2H), Mobile phase B: MeCN; B%: 9-39%, 12 min, flow rate: 25 ml/min.

Rev. HPLC method J: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% ammonium hydroxide), Mobile phase B: MeCN; B%: 5-25%, 15 min, flow rate: 100 ml/min.

Rev. HPLC method K: Column: Agela Durashell C18, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.225% HCO2H), Mobile phase B: MeCN; B%: 0-32%, 11 min, Flow rate 25 ml/min.

Rev. HPLC method L: Column: Xtimate C18, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 15-55%, 12 min, Flow rate: 25 ml/min.

Rev. HPLC method M: Column: Agela Durashell 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 30-60%, 2.5 min, Flow rate: 25 ml/min.

Rev. HPLC method N: Column: Phenomenex luna C18, 250 mmx80 mm, 10 μ; Mobile phase A: water (0.1% TFO), Mobile phase B: MeCN; B%: 25-55%, 20 min, Flow rate: 25 ml/min.

Rev. HPLC method O: Column: Agela Durashell, 150 mmx25 mm, 5 μm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 25-55%, 10 min, Flow rate: 25 ml/min.

Rev. HPLC method P: Column: Agela Durashell, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 30-60%, 10 min, flow rate: 25 ml/min.

Rev. HPLC method Q: Column: Agela Durashell, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 23-53%, 10 min, flow rate: 25 ml/min.

Rev. HPLC method R: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; Gradient elution (time,%A,%B): (0 min, 9o%A, 10%B), (15 min, 60%A, 40%B), (18 min, 0%A, 10o%B) , Flow rate: 11θ ml/min.)

Rev. HPLC method S: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; Gradient elution (time,%A,%B): (0 min, 8o%A, 20%B), (15 min, 60%A, 40%B), (18 min, 0%A, 10o%B) , Flow rate: 11θ ml/min.

Rev. HPLC method T: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 20-40%, 15 min, flow rate 110 ml/min.

Rev. HPLC method U: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; Gradient elution (time,%A,%B): (0 min, 75%A, 25%B), (15 min, 55%A, 45%B), (18 min, 0%A, 10o%B) , Flow rate: 11θ ml/min.

Rev. HPLC method V: Column: Phenomenex Synergi Max-RP, 150 mmx50 mm, 10 μ; Mobile phase A: water (0.225% HCO2H), Mobile phase B: MeCN; B%: 0-30%, 25 min, flow rate 120 ml/min.

Rev. HPLC method W: Column: Xtimate C18, 150 mmx25 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 17-57%, 12 min, Flow rate: 25 ml/min.

Rev. HPLC method X: Column: Agela Durashell C18, 150 mmx30 mm, 5 µm; 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.

Rev. HPLC method Y: Column: Boston Green ODS, 150 mmx30 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 45-65%, 9 min, Flow rate 25 ml/min.

Rev. HPLC method Z: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; Gradient elution (time,%A,%B): (0 min, 8o%A, 20%B), (15 min, 60%A, 40%B), (18 min, 0%A, 10o%B) , Flow rate: 11θ ml/min.

Rev. HPLC method AA: Column: Gemini C18, 15 mm x 21.2 mm, 5 μ; Mobile phase A: water (0.1% HCO2H) Mobile phase B: MeCN (0.1% HCO2H); In% 25-35%; 25 ml/min.

Rev. HPLC method VA: Column: Agela Durashell C18, 150 mmx30 mm, 5 µm; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; B%: 20-55%, 15 min, Flow rate: 25 ml/min.

Rev. HPLC method CA: Column: Phenomenex Gemini C18, 250 mmx50 mm, 10 μ; Mobile phase A: water (0.05% NH4OH v/v), Mobile phase B: MeCN; Gradient elution (time,%A,%B): (0 min, 75%A, 25%B), (15 min, 55%A, 45%B), (18 min, 0%A, 100%B) ; Flow rate: 110 ml/min.

- 49 045319

Examples

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

Into a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)prop-1-en-2-yl)- 5-(3,4-dimethoxyphenyl)pyridine (preparation 2, 1.6 g, 3.13 mmol) in EtOAc (50 ml) was added with Pd/C (0.5 g, 10% load). The mixture was stirred under H ₂ (5 psi) at 20° C. for approximately 3 hours. The mixture was filtered and concentrated to give 3-(1-((t-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 was used directly without further purification. ^1H NMR ( _CDCl3 , 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 [MN] ⁺ .

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

Solution of 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (preparation 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 N2 for 12 hours. The mixture was concentrated and the residue was purified using column chromatography (silica) and eluted with petroleum 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- (3,4dimethoxyphenyl)pyridine (900 mg, 98%). 1H NMR (CDC13, 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). LC-MS m/z=512 [MH] ⁺ .

Preparation 3: 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propan-2-yl)-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 similar manner to Preparation 1 using 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(3-ethoxy-4-methoxyphenyl)pyridine (preparation 4, 4.0 g, 7.6 mmol), which was used without further purification.

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

3-(3-((tert-Butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2yl)-5- (3-ethoxy-4-methoxyphenyl)pyridine (7.5 g, 97%) was prepared in a manner similar to preparation 2 using 3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-ene- 2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (preparation 38, 7.0 g, 14.6 mmol). 1H NMR (CDC13, 400 MHz): δ 8.69-8.73 (m, 2H), 8.03 (s, 1H), 7.14

- 50 045319 (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 ).

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

Into a solution of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)prop-1-en-2-yl)- 5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 8, 4.00 g, 7.41 mmol) in EtOAc (100 ml) was added with Pd/C (1.0 g, 10% load) under N2. The mixture was stirred under H ₂ (14 psi) at approximately 25° C. for approximately 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 used without further purification.

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

HE

I

Method A.

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (receiving 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)ferocynyl]diphenylphosphine (CAS 163169-29-7, 3.20 g, 6.65 mmol) was added anhydrous THF (403 ml). The mixture was stirred for approximately 15 minutes at approximately 20°C under N2 atmosphere. The flask was cooled in an ice-water bath until the solution temperature was approximately 0°C. Catecholborane (181.48 mL, 181 mmol, 1.0 M in THF) was added dropwise over 1 hour. After catecholborane was added, the flask was removed from the cooling bath and stirred at approximately 20°C for approximately 3 hours. The mixture was quenched adding methanol (25 ml) dropwise at approximately 0°C (ice bath). The solution was 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 was used directly without additional cleaning. LC-MS 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 approximately 20°C for approximately 1 hour. A solution of (R)-3 was slowly added to the mixture -(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 42, 46.8 g, 86.5 mmol) in anhydrous THF (270 ml), which was stirred at approximately 20°C for approximately 20 minutes. A solution of trimethyl borate (96.4 mL, 865 mmol) in THF (107 mL) was added dropwise and stirred at approximately 20° C. for approximately 30 minutes. The mixture was concentrated and partitioned between water (500 ml) and EtOAc (200 ml). The aqueous layer was extracted with EtOAc (3x100 ml). The combined EtOAc layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptanes/EtOAc (80:20 to 0:100) followed by EtOAc/MeOH (100:0 to 90:10) to give (R)-(3-( (tert-butyldimethylsilyl)oxy)-2(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (29.0 g, 73%). 1H NMR (CD3OD, 400 MHz): δ 8.51 (d, J=2.3 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.85 (w s, 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 (w s, 2H), 3.07-3.14 (m, 1H), 1.761.85 (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). LC-MS m/z=460 [MH] ⁺ .

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

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To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 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'-1-propyloxazolin-2-yl )ferocynyl]diphenylphosphine (CAS 541540-70-9, 58.2 mg, 0.12 mmol) was added anhydrous THF (8.1 ml). The mixture was stirred at approximately 20°C for approximately 10 minutes. The reaction mixture was cooled to approximately 0°C and catecholborane (6.04 mL, 6.04 mmol, 1.0 M in THF) was added dropwise. The reaction mixture was heated to approximately 20°C and stirred for approximately 8 hours. The reaction mixture was cooled to approximately 5°C and quenched with MeOH. The mixture was concentrated and purified using column chromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) to give (8)-(3-((tert-butyldimethylsilyl)oxy)-2-(5- (4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronic acid (889 mg, 80%). 1H NMR (CD3OD, 400 MHz): δ 8.51 (d, J=2.3 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.85 (w s, 1H ), 7.147.17 (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 (w s, 2H), 3.07-3.14 (m, 1H), 1.76-1.85 (m, 2H ), 1.10-1.33 (m, 2H), 1.03 (t, J=7.81 Hz, 3H), 0.79 (s, 9H), -0.08 (d, J=12 .9 Hz, 6H). LC-MS m/z=460 [MH] ⁺ .

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

3-(1-Bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 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) was heated to approximately 60°C under N2 for approximately 16 hours. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (5:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (6.10 g, 99%). ^1H NMR ( _CDCl3 , 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).

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

bis(1,5-Cyclooctadiene)di-μ-methoxydiiridium(I) (CAS 12148-71-9, 96 mg, 0.15 mmol) and ethylene bis(diphenylphosphine) (CAS, 1663-45-2, 116 mg, 0 .29 mmol) in anhydrous DCE (10 ml) was stirred for approximately 15 minutes under N ₂ at approximately 15°C. 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine (preparation 51, 600 mg, 1.45 mmol) was added to the mixture in atmosphere N ₂ at approximately 15°C. After stirring for approximately 5 minutes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 25015-63-9, 913 mg, 7.13 mmol) was added at approximately 70°C and stirred for for an additional 15 minutes. The reaction was quenched with MeOH and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether:EtOAc (100:0 to 85:15) to give 3(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3isopropoxy-4-methoxyphenyl)pyridine (750 mg, 96%). LC-MS m/z=542 [MH] ⁺ .

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

- 52 045319

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 manner similar to Preparation 9 using 3 -(3 -((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5 -(3 -cyclopropoxy-4-methoxyphenyl)pyridine (receipt 52, 600 mg, 1.46 mmol). LC-MS m/z=540 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-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 similar manner to Preparation 9 using 3-(3-(2-((tert-butyldimethylsilyl) oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (preparation 53, 2.0 g, 3.8 mmol). LC-MS m/z=658 [MH] ⁺ .

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

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

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(3- (2-fluoroethoxy)-4-methoxyphenyl)pyridine (700 mg, 89%) was prepared in a manner similar to preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)- 5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (obtaining 55, 600 mg, 1.4 mmol). LC-MS m/z=433 [MH] ⁺ .

Preparation 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, 3,2Dioxaborolan-2-yl)propoxy)dimethylsilane was prepared in a manner similar to preparation 9, using

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

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(2- (difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (300 mg, 46%) was prepared in a similar manner to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(2-(difluoromethyl)-3ethoxy-4-methoxyphenyl)pyridine (receipt 57, 361 mg, 1.13 mmol). LC-MS m/z=578 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(3- Ethoxy-5-fluoro-4-methoxyphenyl)pyridine (650 mg, 75%) was prepared in a manner similar to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)- 5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridine (receipt 58, 660 mg, 1.58 mmol). LC-MS m/z=546 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(3- Chloro-5-ethoxy-4-methoxyphenyl)pyridine (800 mg, 77%) was prepared in a manner similar to Preparation 9 using 3 -(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)- 5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine (receipt 59, 800 mg, 1.8 mmol). LC-MS m/z=562 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(5- Ethoxy-2-fluoro-4-methoxyphenyl)pyridine (2.0 g, 85%) was prepared in a manner similar to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (preparation 60, 1.80 g, 4.31 mmol). 1H 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 (kv, 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). LC-MS m/z=546 [MH] ⁺ .

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

- 54 045319

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 similar to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine (preparation 61, 2.17 g, 5.0 mmol). 'll NMR (CDC1 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 (kv, J=7.0 Hz, 2H), 3.89 (s, ZN), 3.64-3.74 (m, 2H), 3.06-3.13 (m, 1H), 1.45 (t, J=7.0 Hz, ZN), 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).

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-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 similar manner to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (receipt 62.6 g, 8.3 mmol). LC-MS m/z=560 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(4- (difluoromethoxy)-3-propoxyphenyl)pyridine (2.25 g, 88%) was prepared in a manner similar to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)- 5-(4-(difluoromethoxy)-3propoxyphenyl)pyridine (preparation 63, 2.0 g, 4.5 mmol). 'n NMR (CDC1 ₃ , 400 MHz): δ 8.61 (d, J=2.2 Hz, 1H), 8.57 (d, J=2.l Hz, 1H), 7.73 (t, J=2.l Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.09-7.12 (m, 2H), 6.61 (t, J=75.3 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.67-3.77 (m, 2H), 3.09-3.16 (m, 1H), 2.16 (s, 2H), 1.84-1.93 (2H), 1.06-1.11 (m, 15H), 0.81 (s, 9H), -0.07-0.05 (d, J=5.8 Hz, 6H). LC-MS m/z=578 [MH] ⁺ .

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

5'-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2yl)-3-fluoro-5 -methoxy-6-propoxy-2,3'-bipyridine (4.02 g, quant.) was prepared in a manner similar to Preparation 9 using 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene- 2-yl)-3-fluoro-5-methoxy-6propoxy-2,3'-bipyridine (preparation 64, 3.1 g, 7.17 mmol). 'n NMR (CDC1 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, ZN), 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, 1=7.5 Hz, ZN), 0.81 (s, 9H), -0.07-0.06 (d, J=7.5 Hz, 6H). LC-MS m/z=561 [MH] ⁺ .

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

-55045319

5'-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2yl)-6-methoxy-5 -Propoxy-3,3'-bipyridine (2.55 g, 81%) was prepared in a similar manner to Preparation 9 using 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl) -6-methoxy-5-propoxy-3,3'-bipyridine (preparation 65, 2.4 g, 5.8 mmol). LC-MS m/z=543 [MH] ⁺ .

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

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

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

4-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)2-(4- methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (0.94 g, 59%) was prepared in a manner similar to Preparation 9 using 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene-2 -yl)-2-(4-methoxy-3propoxyphenyl)-6-(trifluoromethyl)pyrimidine (preparation 67, 1.27 g, 2.63 mmol). 1H 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). LC-MS m/z=611 [MH] ⁺ .

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

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

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

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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 (receipt 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 was stirred at approximately 25°C for approximately 1 hour. The mixture was concentrated. The reaction mixture was used directly in the next step without further purification. LC-MS m/z=519 [MH] ⁺ .

Preparation 28: 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

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 similar manner to Preparation 9 using ethyl 2-(6-(3-((tert-butyldimethylsilyl)oxy) prop-1-en-2-yl)-2-(4methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (receipt 69, 500 mg, 0.99 mmol). LC-MS m/z=629 [MH] ⁺ .

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

4-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-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 similar manner to Preparation 9 using 4-(((tert-butyldimethylsilyl)oxy)methyl )-6-(3((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine (preparation 70, 1.4 g, 2.5 mmol ). LC-MS m/z=687 [MH] ⁺ .

Preparation 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

A mixture of methyl (Z)-2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy) acrylate (receipt 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

- 57 045319 approximately 80°C for approximately 2 hours in an N2 atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum 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%). ^1H NMR ( _CDCl3 , 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).

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

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

Preparation 32: (E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)but-2-ene- 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 approximately 0°C (ice bath) under N ₂ atmosphere . N-BuLi (2.56 mL, 6.41 mmol, 2.5 M in hexanes) was added dropwise to the solution and stirred for approximately 30 minutes. at approximately 0°C. A solution of 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2dioxaborolane) was added dropwise (receipt 149, 1810 mg, 6.41 mmol) in THF (2 ml), which was stirred for approximately 5 minutes. before cooling to approximately -78°C. A solution of 2-((tert-butyldimethylsilyl)oxy)-1 -(5 -(4-methoxy-3-propoxyphenyl)pyridin-3-yl)ethan-1-one was added dropwise (receiving 75.666 mg, 1.60 mmol) in THF (3.0 ml) and stirred under N ₂ at approximately -78°C for approximately 1 hour. The reaction mixture was placed in an ice bath and stirred for an additional hour. The reaction was quenched with water and diluted with EtOAc. EtOAc was separated, washed with brine and dried over MgSO ₄ . The solution was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (9:1) to give (E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5 -tetramethyl-1,3,2dioxaborolan-2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (400 mg, 45%). LC-MS m/z=554 [MH] ⁺ .

Preparation 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

In a mixture of ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propanoate (receiving 110, 249 mg , 0.625 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (receipt 114, 357 mg, 1.22 mmol) in 1,4-dioxane (8.5 ml) a solution of K3PO4 in water (2.0 M, 0.625 ml, 1.25 mmol) was added. The mixture was degassed using N2 at approximately 20°C for approximately 10 minutes. Bis(tri-tert-butylphosphine)palladium(0) (CAS 53199-318, 16.0 mg, 0.03 mmol) was added and the mixture was allowed to stir at approximately 20°C for 2 hours. The mixture was diluted with EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100) to give ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2 -methyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (134 mg, 44%). 1H 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,

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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).

LC-MS m/z=399 [MH] ⁺ .

Preparation 34: 5-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)butan-2-yl)-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 similar manner to Preparation 9 using 5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4 -methoxy-3-propoxyphenyl)pyridazine (receipt 72, 300 mg, 0.7 mmol). LC-MS m/z=557 [MH] ⁺ .

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

3-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)5-(3- Ethoxy-4-methoxyphenyl)-4-methylpyridine (0.28 g, 26%) was prepared in a similar manner to Preparation 9 using 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl) -5-(3-ethoxy-4-methoxyphenyl)-4methylpyridine (preparation 73, 0.8 g, 1.93 mmol). 1H 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 (kv, J=7.0 Hz, 2H), 3.91 (s, 3H), 3.743 .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), 1.031.08 (m, 12H), 0.79 (s, 9H), -0.11-0.08 (m , 6H). LC-MS m/z=542 [MN] ⁺

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

4-(1-((tert-Butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)2-(3- Ethoxy-4-methoxyphenyl)thiazole (0.41 g, 39%) was prepared in a manner similar to Preparation 9 using 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2- (3-ethoxy-4-methoxyphenyl)thiazole (preparation 74, 0.8 g, 1.97 mmol). ^1H NMR ( _CDCl3 , 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 (kv, J=7.0 Hz, 2H), 3.88-3.92 (s, 4H ), 3.77-3.81 (m, 1H), 3.273.34 (m, 1H), 1.51 (t, J=7.0 Hz, 3H), 1.27-1.30 (m, 2H), 1.15 (d, J=13.6, 12 N), 0.85 (s, 9H), -0.03 (s, 6H). LCMS m/z=534 [MN] ⁺ .

Preparation of phenyl)pyridine

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

In solution

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine (preparation 48, 30.00 g, 77.81 mmol) in DCM (500 ml) pyridinium tribromide (CAS 39416-48-3, 24.9 g, 77.8 mmol) was added in portions at approximately 0°C. The mixture was stirred at approximately 20°C for approximately 1 hour and poured into cold aqueous Na ₂ SO ₃ (100 ml). The mixture was extracted with DCM (3x50 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) was added to the above mixture in DCM (500 ml) at approximately 20°C. The mixture was stirred at approximately 20°C for approximately 16 hours and poured into aqueous NH4Cl (500 ml). The mixture was extracted with DCM (3 x 200 ml). The combined DCM extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum 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%). ^1H 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).

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

Τη<

Mixture with 3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (preparation 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) were stirred at approximately 25°C for approximately 16 hours. The mixture was washed with 1 N . HCl (300 ml), brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum 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%). 1H 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 (kv, 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).

Preparation 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-i-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 47b, 10.0 g, 17.44 mmol) DBU (CAS 6674-22-2, 5.26 mL, 34.88 mmol) was added to DCM (150 mL), which was stirred at approximately 25° C. for approximately 16 hours under N2. The mixture was washed with 1N. HCl (400 ml), brine (400 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 3-(1-bromo-3-((t-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5 -(4-methoxy-3-propoxyphenyl)pyridine (5.60 g, 65%). 1H 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), 1.871.96 (m, 2H), 1 .08 (t, J=7.6 Hz, 3H), 0.82 (s, 9H), 0.08 (s, 6H).

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

Into a solution of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-hydroxyacrylate (preparation 41, 14.5 g, 39.47 mmol) in toluene (500 ml) was added LiOH (11.59 g, 276.27 mmol) in water (30 ml). Tf ₂ O (CAS 358-23-8, 15.63 ml, 94.72 mmol) was added dropwise to the mixture at approximately 0°C. The mixture was stirred at approximately 0°C for approximately 1 hour. The reaction was quenched with water (500 ml) and extracted with EtOAc (2x500 ml). The combined EtOAc extracts were washed with brine (2 x 300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (15:1) to give methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl] -3yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate (15.00 g, 74%). 1H NMR ( _CDCl3 , 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).

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

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To a mixture of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl) acetate (receipt 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) at approximately 0°C. The mixture was stirred at approximately 20°C for approximately 1 hour. Water (150 ml) was added and the mixture was extracted with DCM (2x150 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 directly without further purification. 1H 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).

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

Mixture of (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3 yl)propyl methanesulfonate (preparation 43, 45.5 g, 89.28 mmol) and lithium iodide (38.2 g, 286 mmol) in acetone (446 ml) were stirred at approximately 30°C for 3 days. The reaction mixture was heated to approximately 50°C for approximately 45 minutes. The mixture was cooled to approximately 20°C and concentrated to remove acetone. The residue was diluted with DCM and washed with water (2x100 ml). The DCM extract was dried over MgSO ₄ , filtered and concentrated. The residue was triturated with heptanes/EtOAc (1:1, 100 ml) for approximately 45 minutes. The solid was filtered and purified using column chromatography (silica) and eluted with heptanes/EtOAc (85:15 to 30:70) to give (R)-3-(1-((tert-butyldimethylsilyl)oxy)-3- iodopropan-2-yl)5-(4-methoxy-3-propoxyphenyl)pyridine (41.2 g, 85%). 1H 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 =2.0 Hz, 1H), 7.09-7.15 (m, 2H), 6.98 (d, J=8.2 Hz, 1H), 4.06 (t, J=7.0 Hz , 2H), 3.98-4.02 (m, 1H), 3.93 (s, 3H), 3.84-3.88 (m, 1H), 3.68-3.72 (m, 1H ), 3.43-3.47 (m, 1H), 3.09-3.15 (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). LC-MS m/z=542 [MH] ⁺ .

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

In an ice-cooled solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol (preparation 44, 42, 8 g, 99.2 mmol) in DCM (600 ml) was added Et ₃ N (25.1 ml, 178 mmol) and stirred for approximately 30 minutes. MsCl (9.98 mL, 129 mmol) was added dropwise and allowed to warm and stir at approximately 20° C. overnight. The mixture was washed with water, dried over MgSO ₄ , filtered, passed through a pad of silica gel and concentrated to give (R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridine- 3-yl)propyl methanesulfonate (45.5 g), which was used in the preparation of 42. LC-MS m/z=510 [MH] ⁺ .

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

In an ice-cooled solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (preparation 45, 45.7 g, 96 .5 mmol) in THF (400 ml) was added aqueous

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NaOH (154 ml, 1 N). The mixture was allowed to heat and stir at approximately 20°C for 2 days. The organic phase was separated and concentrated. The residue was dissolved in DCM (300 ml). The aqueous layer was extracted with DCM. The combined DCM extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridine -3-yl)propan-1-ol (42.8 g), which was used in Preparation 43. LC-MS m/z=432 [MH] ⁺ .

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

In an ice-cold solution of (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl acetate (preparation 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) were added. The reaction mixture was heated to approximately 20°C and stirred overnight. The mixture was filtered and the solids were washed with EtOAc. The combined filtrates were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40) to give (S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4- methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate (48.3 g, 85%). 1H

NMR (CDCl3, 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=7.4 Hz, 3H), 0.87 (s, 9H), 0.01 (d, J=2.3 Hz , 6H). LC-MS m/z=474 [MH] ⁺ .

Preparation 46: (R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl acetate .O\/OH

To a mixture of 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3-diol (receiving 82, 38.3 g, 121 mmol) in 2-MeTHF (1088 ml) Rhizomucor miehei immobilized lipase (1.53 g, Lipozyme® RM IM, Novozymes A/S, Denmark) was added. The mixture was stirred at approximately 20°C for approximately 5 minutes. Vinyl acetate (89.0 ml, 965 mmol) was added to the mixture followed by the addition of 2-MeTHF (100 ml). The mixture was stirred at approximately 20°C for approximately 39 hours. The mixture was filtered and the filtered 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 45.

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

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine (preparation 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 approximately 0° C. under N2 atmosphere. The mixture was stirred at approximately 25°C for approximately 3 hours. The DCM mixture was washed with aqueous Na2SO3 (100 ml), brine (100 ml), dried over Na2SO4 and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum 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 was used directly in the next step. 1H 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).

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

- 62 045319 propoxyphenyl)pyridine

To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (receipt 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 approximately 0° C. under N2 atmosphere. The mixture was stirred at approximately 25°C for approximately 3 hours. The DCM 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 using column chromatography (silica) and eluted with petroleum 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 was used directly in the next step. ^1H NMR ( _CDCl3 , 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).

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

Mixture of 3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (preparation 91a, 2.0 g, 5.86 mmol), 2-bromolyloxy-tert-butyldimethylsilane (receipt 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) were heated to approximately 90°C for approximately 12 hours. The mixture filtered and the filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with DCM/MeCN (5:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4 -dimethoxyphenyl)pyridine (2.10 g, 5.45 mmol, 93%). 1H 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).

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

A mixture of 3-bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine (receipt 92, 20 g, 64.9 mmol), tert-butyldimethyl ((2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 146, 23.23 g, 77.88 mmol), Pd(dppf)Cl ₂ (1.42 g, 1.95 mmol), K2CO3 (17 .94 g, 129.8 mmol) and KOAc (9.55 g, 97.35 mmol) in 1,4-dioxane (300 ml) and water (10 ml) were degassed and heated to approximately 90°C for approximately 16 h in an N ₂ atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (3:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-( 3-ethoxy-4methoxyphenyl)pyridine (18.0 g, 69%). 1H 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 (kV, 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).

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

Mixture of 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 93a, 15.0 g, 46.55 mmol), tert-butyldimethyl ((2-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 146,

- 63 045319

18.05 g, 60.51 mmol), Pd(dppf)Cl ₂ (1.70 g, 2.33 mmol), K2CO3 (12.87 g, 93.10 mmol) and KOAc (6.85 g, 69 .83 mmol) in 1,4-dioxane (250 ml) and water (5 ml) were degassed and heated to approximately 90°C for approximately 16 hours under N2. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (3:1) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-( 4-methoxy-3propoxyphenyl)pyridine (13.50 g, 70%). 1H 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).

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

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine (1.1 g, 75%) was prepared in a manner similar to 50 using 3-bromo-5-(3-isopropoxy-4methoxyphenyl)pyridine (preparation 94, 1.15 g, 3.6 mmol) at approximately 90°C for approximately 2 hours. LC-MS m/z=414 [MN] ⁺ .

Preparation 52: 3-(3-((tert-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 similar to preparation 50. using 3-bromo-5-(3cyclopropoxy-4-methoxyphenyl)pyridine (preparation 95, 0.75 g, 2.34 mmol). 1H 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). LC-MS m/z=412 [MH] ⁺ .

Preparation 53: 3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl) 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 similar to Preparation 50 using 3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine ( Preparation 96, 9.3 g, 21 mmol). ^1H NMR ( _CDCl3 , 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), 4.024.07 (m, 2H), 3.92 (s, 3H), 0.92- 0.95 (m, 9H), 0.90 (s, 9H), 0.12 (s, 6H), 0.10 (s, 6H). LC-MS m/z=530 [MH] ⁺ .

Preparation 54: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl) 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 similar to Preparation 50, using 3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine (Preparation 97, 10.8 g, 23.8 mmol). ^1H NMR ( _CDCl3 , 400 MHz): δ 8.71 (d, J=2.5 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.2 Hz, 1H), 7.11-7.16 (m, 2H), 6.98 (d, J=8.3 Hz, 1H), 5.49-5.54 (m, 2H ), 4.56 (t, J=1.5 Hz, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.92 (s, 3H), 3.85 (t, J =5.9 Hz, 2H), 2.05-2.13 (m, 2H), 0.92-0.94 (m, 9H), 0.89 (s, 9H), 0.12 (s, 6H), 0.05 (s, 6H). LC-MS m/z=544 [MH] ⁺ .

- 64 045319

Preparation 55: 3-(3-((tert-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)-4methoxyphenyl)pyridine (preparation 98, 1.4 g, 4.7 mmol). 1H 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). LC-MS m/z=433 [MH] ⁺ .

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

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared in a manner similar to preparation 50 using 3- bromo-5-(3-(3-fluoropropoxy)-4methoxyphenyl)pyridine (preparation 99).

Preparation 57: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridine

A solution of 2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol (receipt 76, 321 mg, 0.71 mmol) and imidazole (97.2 mg, 1.43 mmol) in DCM (20 ml) was added TBS-Cl (129 mg, 0.86 mmol) at approximately 0°C. The reaction mixture was stirred at approximately 20°C for approximately 15 hours. Additional TBS-Cl (129 mg, 0.86 mmol) was added and the reaction mixture was stirred at approximately 20°C for approximately 20 hours. The reaction mixture was concentrated and purified using column chromatography (silica) and eluted with petroleum 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%). 1H NMR (CDCl3, 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). LC-MS m/z=450 [MN] ⁺ .

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

A mixture of 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (receipt 86.795 mg, 2.42 mmol), 2-(3-ethoxy- 5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (receipt 132, 652 mg, 2.2 mmol), Pd(dppf)Cl ₂ DCM and K ₂ CO ₃ (760 mg, 5.5 mmol) was suspended in 1,4-dioxane (20 ml) and water (0.7 ml). The mixture was degassed and heated to approximately 85°C under N2 for approximately 9 hours. The mixture was concentrated and MTBE (50 mL) was added with stirring for approximately 20 minutes. The mixture was filtered and the filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 80:20) to give 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-5-(3ethoxy-5-fluoro-4-methoxyphenyl)pyridine (660 mg, 72%). 1H 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), 4.544.57 ( m, 2H), 4.18 (kv, J=7.0 Hz, 2H), 3.98 (s, 3H), 1.50 (t, J=7.1 Hz, 3H), 0.92 ( s, 9H), 0.12 (s, 6H). LC-MS

- 65 045319 m/z=418 [MN] ⁺ .

Preparation 59: 3-(3-((tert-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 prepared by the method similar to preparation 58 using 2-(3-chloro-5-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 133, 1.0 g, 3.2 mmol) . 1H NMR (CDCl3, 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=7.2 Hz, 2H), 3.94 (s, 3H), 1.51 (t, J=6.9 Hz, 3H ), 0.90-0.97 (m, 9H), 0.08-0.15 (m, 6H).

Preparation 60: 3-(3-((tert-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 prepared by the method similar to preparation 50 using 3-bromo-5-(5-ethoxy-2-fluoro-4methoxyphenyl)pyridine (preparation 101, 350 mg, 1.07 mmol). 1H 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 (kv, 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). LC-MS m/z=418 [MH] ⁺ .

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

-(3 -((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5 -(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine (2.1 g, 48%) was prepared by the method , similar to preparation 58 using 2-(2-chloro-5-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 135, 3.13 g, 10.0 mmol ). LC-MS m/z=434 [MH] ⁺ .

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

-(3 -((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5 -(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (5.0 g, 99%) was prepared by the method , similar to preparation 50 using 3-bromo-5-(2-fluoro-4-methoxy5-propoxyphenyl)pyridine (preparation 102, 7.0 g, 9.0 mmol). ^1H 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). LC-MS m/z=432 [MH] ⁺ .

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

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine (2.1 g, 62% ) was prepared in a similar manner to Preparation 58 using 2-(4(difluoromethoxy)-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 142, 2.46 g, 7. 5 mmol). 1H 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). LC-MS m/z=450 [MN] ⁺ .

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

O N W SL / |1 J I Yx

Ν ¹

In a mixture of 5'-chloro-3-fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (preparation 103, 3.0 g, 10.11 mmol) and tert-butyldimethyl((2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 146, 12.1 g, 40.4 mmol) in 1,4-dioxane (300 ml) added 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 was degassed, heated to approximately 70°C for approximately 16 hours under N2 atmosphere. The mixture was diluted with EtOAc (50 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 85:15) to give 5'-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene-2- yl)-3fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (3.1 g, 71%). 1H 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). LC-MS m/z=433 [MH] ⁺ .

Preparation 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 by , similar to preparation 58 using 2-methoxy-3-propoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (preparation 124, 3.95 g, 13.5 mmol). 1H 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).

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

3-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine (preparation 87, 1.28 g, 3.7 mmol) and 2-(3 -ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 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) were suspended in 1,4dioxane (60 ml) and water (2 ml). The mixture was degassed and heated to approximately 80° C. under N ₂ for approximately 5 hours. The mixture was concentrated and MTBE (100 ml) was added to the residue and stirred for approximately 20 minutes. The mixture was filtered and the filtered cake was washed with MTBE (50 ml). The combined filtrates were dried and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 85:15) to give 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl )-3-(3ethoxy-4-methoxyphenyl)-2-methylpyridine (640 mg, 41%). 1H 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=1.5 Hz, 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). LC-MS m/z=414 [MH] ⁺ .

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

- 67 045319

Into a mixture of 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pi-

rimidine (receipt 90, 1.33 g, 3.77 mmol) in 1,4-dioxane (40 ml) was added 2-(4-methoxy-3propoxyphenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (preparation 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 was degassed and heated to approximately 90°C for approximately 5 hours under N2 atmosphere. The mixture was concentrated and the residue was purified using column chromatography (silica) and eluted with petroleum ether:EtOAc (100:0 to 90:10) to give 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene- 2-yl)-2-(4methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine (1.27 g, 70%). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=483 [MH] ⁺

Preparation 68: 2-(3-((tert-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 prepared in a manner similar to 50 using 2-bromo-6-(3-ethoxy-4methoxyphenyl)pyrazine (preparation 104, 1.5 g, 4.9 mmol). 1H 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). LC-MS m/z=401 [MH] ⁺ .

Preparation 69: Ethyl 2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3propoxyphenyl)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%) was prepared in a manner similar to that of 50 using ethyl 2-(6chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (preparation 105.5 g, 13.7 mmol). 1H NMR (CD3OD, 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), 0.130.16 (m, 6H). LC-MS m/z=501 [MH] ⁺ .

Preparation 70: 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-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 obtained in a manner similar to preparation 58,

- 68 045319 using 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2yl)-2-chloropyrimidine (preparation 89, 2.0 g, 5.2 mmol) and 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (preparation 114, 0.817 g, 2.8 mmol) at approximately 90 °C and replacing K3PO4 (1.55 g, 5.80 mmol) with K2CO3. ^1H NMR (CDCl3, 400 MHz): δ 8.02-8.08 (m, 2H), 7.52 (s, 1H), 6.946.99 (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). LC-MS m/z=559 [MH] ⁺ .

Preparation 71: 2-(4-((tert-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 similar to preparation 50. using 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine (preparation 93b, 1000 mg, 3.10 mmol) and tert-butyldimethyl ((3-(4,4,5,5-tetramethyl-1, 3,2dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (receipt 148, 969 mg, 3.10 mmol). LC-MS m/z=428 [MH] ⁺ .

Preparation 72: 5-(3-((tert-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 prepared in a manner similar to 50 using 5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (preparation 107, 2.2 g, 7.9 mmol) and tert-butyldimethyl ((3-(4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane (preparation 147, 4.9 g, 15.8 mmol). 1H 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). LC-MS m/z=429 [MH] ⁺ .

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

3-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (0.8 g, 77%) was prepared by , similar to preparation 50 using 3-bromo-5-(3-ethoxy-4methoxyphenyl)-4-methylpyridine (preparation 108, 0.81 g, 3.28 mmol) and tert-butyldimethyl((2-(4.4, 5,5tetramethyl-1,3,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 146, 0.98 g, 3.28 mmol). 1H 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 (t 1H), 5.10-5.12 (m, 1H), 4 ,31-4.32 (m, 2H), 4.12 (kv, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.21 (s, 3H), 1.48 ( t, J=7.0 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 6H). LC-MS m/z=414 [MH] ⁺ .

Preparation 74: 4-(3-((tert-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 was prepared (0.8 g, 91%) in a manner similar to 50 using 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (preparation 109, 0.68 g, 2.16 mmol) and tert-butyldimethyl ((2-(4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)alyl)oxy)silane (preparation 146, 0.84 g, 2.81 mmol). 1H NMR (CDCl ₃ , 400 MHz): δ 7.57 (d, J=2.3 Hz, 1H), 7.58 (dd, J=2.3, 8.3 Hz, 1H), 7.17 (s, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.07-6.08 (m, 1H), 5.50-5.52 (m, 1H), 4, 60-4.61 (m, 1H), 4.22 (kv, J=7.0 Hz, 2H), 3.93 (s, 3H), 1.52 (t, J=7.0 Hz, 3H ), 0.99 (s, 1H),

- 69 045319

0.95 (s, 9H), 0.13 (s, 6H). LC-MS m/z=406 [MH] ⁺ .

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

In a mixture of 1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one (receipt 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 a solution of 2-(4-methoxy-3-propoxyphenyl)-4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 114, 1200 mg, 3.633 mmol) in 1,4-dioxane (24 ml) was added water (2.4 ml). The mixture was degassed and heated to approximately 90°C for approximately 16 hours under N2 atmosphere. The reaction mixture was filtered through a pad of MgSO ₄ and silica gel, washing with DCM and EtOAc. The filtrate was concentrated and the residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 95:5) to give 2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy) -3propoxyphenyl)pyridin-2-yl)ethan-1-one (1.21 g, 80%). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=416 [MH] ⁺ .

Preparation 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 similar manner to preparation 50 using 3-Bromo-5-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)pyridine (preparation 100, 558 mg, 1.56 mmol) at approximately 100°C for approximately 15 hours. 1H 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 ( w s, 1H), 1.43 (t, J=7.0 Hz, ZN,). LC-MS m/z=336 [MH] ⁺ .

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

Into a solution of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (receiving 78.140 mg, 0. 30 mmol) in acetone (1.20 ml), lithium iodide (201 mg, 1.50 mmol) was added. The solution was stirred at approximately 50°C for approximately 16 hours. The reaction mixture was cooled to approximately 50°C, diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using 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%). 1H 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 =2.0 Hz, 1H), 7.08-7.17 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 4.25-4.37 (m, 2H) , 4.14-4.23 (m, 2H), 4.07 (t, J=6.8 Hz, 2H), 3.93 (s, 3H), 3.81 (s, 2H), 1, 92 (kvd, J=7.2, 14.3 Hz, 2H), 1.49 (d, J=18.3 Hz, 6H), 1.08 (t, J=7.4 Hz, 3H). LC-MS m/z=498 [MH] ⁺ .

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

Into a mixture of (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol (receiving 79, 128 mg, 0 .33 mmol) in DCM (7.0 ml) was added Me ₃ N (84 µl, 0.60 mmol), followed by the addition of MsCl (33 µl, 0.43 mmol). The solution was stirred at approximately 20° C. for approximately 3.5 hours. The mixture was concentrated and the residue was purified using 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)methyl methanesulfonate (144 mg, 94%). ^1H NMR ( _CDCl3 , 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).

Preparation 7 9: (5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol

Into a solution of 2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1,3-diol (receiving 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) were added. The solution was stirred at approximately 40°C for approximately 24 hours and approximately 20°C for approximately 4 days. The solution was concentrated and the residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100 gradient) to give (5-(5-(4-methoxy-3-propoxyphenyl)pyridine-3- yl)2,2-dimethyl-1,3-dioxan-5-yl)methanol (129 mg, 28%). 1H 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 (sq d, 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). LC-MS m/z=388 [MH] ⁺ .

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

In a solution of methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propanoate (receipt 81, 250 mg, 0.67 mmol) in methanol (2.0 ml) LiBH ₄ (17.5 mg, 0.80 mmol) was added. The solution was stirred at approximately 20°C for approximately 21 hours. The mixture was treated with saturated aqueous NH ₄ Cl and extracted with DCM. 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%). 1H NMR (CDCl3, 400 MHz): δ 8.49 (w s, 1H), 8.28 (w s, 1H), 7.90 (w s, 1H), 6.83-7.00 (m, 2H), 6.77 (d, J=8.6 Hz, 1H), 4.78 (w s, 2H), 4.04 (w s, 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). LC-MS m/z=348 [MH] ⁺ .

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

To a solution of methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (receiving 84.65 g, 210 mmol) in DMSO (200 ml) was added paraformaldehyde (6.81 g, 227 mmol ), followed by DMSO (300 ml). NaOMe (2.23 g, 41.2 mmol) was added, followed by another 100 mL of DMSO. The mixture was stirred at approximately 20°C for approximately 18 hours. The mixture was diluted with water (1200 ml) and extracted with diethyl ether and EtOAc. The combined diethyl ether and EtOAc extracts were washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The residue was stirred with EtOH (200 ml) at approximately 65°C until the residue was dissolved. The solution was cooled to approximately 20°C with stirring over approximately 2 hours. The mixture was cooled to approximately 0°C (ice-water bath) over an additional 1 hour. The mixture was filtered and the filtered cake was washed with ice-cold EtOH. The combined EtOH filtrates were concentrated and the residue was purified using column chromatography (silica), eluting with EtOAc/MeOH (95:5) to give methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-(4methoxy-3-propoxyphenyl) pyridin-3-yl)propanoate (5.46 g, 7%). 1H 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) .

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

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LiBH was added to an ice-cooled solution of methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propanoate (preparation 83, 26.4 g, 73.5 mmol) in MeOH (350 mL). ₄ (3.2 g, 147 mmol) in 3 servings. The mixture was stirred for approximately 1 hour. The mixture was concentrated and diluted with DCM. The mixture was washed with 2N. NaOH. The DCM layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) to give 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propane-1,3 -diol (20.3 g, 87%). 1H NMR (DMSO-d^ 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). LC-MS m/z=318 [MH] ⁺ .

Preparation 83: Methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate

Mixture with methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl) acetate (receipt 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 approximately 20°C for approximately 16 hours. The mixture was diluted with water (1200 ml) and extracted with diethyl ether and EtOAc. The combined diethyl ether and EtOAc extracts were washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in hot EtOH (120 ml). The solution was cooled to approximately 20°C with stirring. Further cooling to approximately 0° C. (ice bath) gave a precipitate which was filtered to give methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propanoate (15.6 g). The filtrate was concentrated and purified using column chromatography (silica) to provide additional solid (10.8 g). The solids were combined to give methyl 3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (26.4 g, 78%). 1H NMR (CDCI3, 400 MHz): δ 8.72 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.76 (t, J= 2.0 Hz, 1H), 7.07-7.12 (m, 2H), 6.97 (d, J=8.6 Hz, 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). LC-MS m/z=346 [MH] ⁺ .

Preparation 84: Methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate

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 (receiving 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) were degassed and stirred at approximately 20°C for approximately 20 minutes. in an N ₂ atmosphere. Pd(dppf)Cl ₂ (9.85 g, 12.1 mmol) was added to the mixture, which was heated to approximately 85°C for approximately 18 hours under N2. The reaction mixture was cooled to approximately 20°C and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica), eluting with heptane/EtOAc (85:15 to 40:60) to give methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)acetate (75, 4 g, 88%). 1H NMR (CDCI3, 400 MHz): δ 8.72 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.77 (t, J= 2.0 Hz, 1H), 7.13 (dd, J=2.3, 8.6 Hz, 1H), 7.09 (d, J=2.3 Hz, 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). LC-MS m/z=316 [MH] ⁺ .

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

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Solution of 6-bromo-3-methoxy-2-propoxybenzonitrile (preparation 171, 10.0 g, 37.02 mmol), (3-(2methoxy-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) were degassed and heated to approximately 90°C for approximately 5 hours under N2 atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (4:1) to give methyl 2-(2'-cyano-4'methoxy-3'-propoxy-[1,1'-biphenyl]- 3-yl)acetate (12.0 g, 96%). ^1H NMR ( _CDCl3 , 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).

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

A mixture of tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 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) were suspended in 1,4-dioxane (300 ml) and water (20 ml). The mixture was degassed and heated to approximately 85°C for approximately 5 hours under N ₂ atmosphere. The mixture was removed from the heater and allowed to stand over the weekend. The mixture was concentrated, MTBE (100 ml) was added and stirred for approximately 20 minutes. The mixture was filtered and the filtered cake was washed with MTBE (50 ml). The combined MTBE filtrates were dried and concentrated. The residue was purified using column chromatography (silica), eluting with petroleum ether/EtOAc (100:0 to 95:5) to give 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-ene -2-yl)pyridine (8.5 g, 51.8%). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=329 [MH] ⁺ .

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

Mixture of tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)alyl)oxy)silane (preparation 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) was suspended in 1,4-dioxane (150 ml) and water (5 ml). The mixture was degassed and heated to approximately 80°C for approximately 5 hours under N ₂ atmosphere. The mixture was concentrated and MTBE (100 ml) was added, stirring for approximately 20 minutes. The mixture was filtered and the filtered cake was washed with MTBE (50 ml). The combined MTBE filtrates were concentrated and the residue was purified using column chromatography (silica), eluting with petroleum 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%). 1H 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).

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

A solution of 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one (yield 237.977 mg, 4.52 mmol) and DCM (30 ml) was cooled to approximately 0°C and imidazole (770 mg) was added , 11.3 mmol) and TBS-Cl (750 mg, 4.97 mmol). The mixture was stirred at approximately 0°C for approximately 2.5 hours. The reaction was quenched with water and the layers were separated. The DCM layer was washed with water and brine. The DCM layer was passed through a layer of MgSO ₄ and silica gel. The filtrate was concentrated to give 1-(6bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one (1.35 g, 90%). 1H NMR ( _CDCl3 , 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).

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

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4-(((tert-Butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2chloropyrimidine (0.9 g, 34%) was prepared by similar 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 as base. ^1H NMR ( _CDCl3 , 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). LC-MS m/z=429[MH] ⁺ .

Preparation 90: 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)py rimidine

4-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine (1.33 g, 66%) was prepared in a manner similar to preparation 50. using 2,4-dichloro-6(trifluoromethyl)pyrimidine (CAS 16097-64-6, 1.24 g, 5.72 mmol) and replacing K3PO4 (4.57 g, 17.1 mmol) with K2CO3. ^1H NMR ( _CDCl3 , 400 MHz): δ 7.77 (s, 1H), 6.38-6.39 (m, 1H), 5.99-6.00 (m, 1H), 4.65 (t, J=1.5 Hz, 2H), 0.92-0.94 (m, 9H), 0.13 (s, 6H). LC-MS m/z=353 [MH] ⁺ .

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

Mixture of 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (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) were degassed and stirred at approximately 110°C for approximately 4 hours under N2. The mixture was concentrated and the residue was purified using column chromatography (silica), eluting with petroleum 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%). ^1H NMR ( _CDCl3 , 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 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) were degassed and stirred at approximately 90°C for approximately 8 hours under N ₂ atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (20:1 to 1:1) to give 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (20.2 g, 59% ). ^1H NMR (DMSO-d6.400 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), 7.287.35 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s , 3H). LC-MS m/z=294 [MH] ⁺ .

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

A mixture of 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 113,

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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) were degassed and heated to approximately 100°C for approximately 5 hours in N2 atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (5:1) to give 3-bromo-5-(3-ethoxy-4methoxyphenyl)pyridine (20 g, 90%). ^1H NMR ( _CDCl3 , 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 93a: 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 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) were degassed and heated to approximately 100°C for approximately 5 hours under N ₂ atmosphere. The mixture was filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (5:1) to give 3-bromo-5-(4-methoxy-3propoxyphenyl)pyridine (15.00 g, 49%). 1H 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 93b: 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 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) were degassed and heated to approximately 80°C overnight. The mixture was diluted with brine (150 ml) and EtOAc (150 ml). The layers were separated and the EtOAc layer was washed with brine (75 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using 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 %). 1H 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 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 93a using 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane (preparation 115.2 g, 6.8 mmol) at approximately 120°C for approximately 2 hours. 1H NMR ( _CDCl3 , 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). LC-MS m/z=323 [MH] ⁺ .

Preparation 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 93a using 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (preparation 117, 1.5 g, 5.2 mmol) at approximately 120°C for approximately 2 hours. 1H NMR (CDCl3, 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). LC-MS m/z=321 [MH] ⁺ .

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

3-Bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine 3-bromo-5-(3-(2((tert-butyldimethylsilyl)oxy)ethoxy)- 4-methoxyphenyl)pyridine (6.8 g, 32%) was prepared in a similar manner to 93a using tert-butyl(2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan2-yl)phenoxy)ethoxy)dimethylsilane (preparation 120.20 g, 49 mmol) at approximately 120°C for approximately 3 hours. 1H NMR ( _CDCl3 , 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 (sq d, 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). LC-MS m/z=439 [MH] ⁺ .

Preparation 97: 3-bromo-5-(3-(3-((tert-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 93a using tert-butyl(3 -(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane (receipt 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). LC-MS m/z=454 [MH] ⁺ .

Preparation 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 similar manner to 93a using 2-(3-(2-fluoroethoxy)-4- methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 122, 2.2 g, 7.4 mmol) at approximately 120°C for approximately 2 hours. 1H 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), 4.254.36 (m, 1H), 3, 88-3.97 (m, 3H). LC-MS m/z=325 [MH] ⁺ .

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

3-Bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared in a manner similar to the preparation of 93a, using 2-(3-(3-fluoropropoxy)-4-methoxyphenyl)-4,4,5, 5-tetramethyl-1,3,2-dioxaborolane (preparation 123).

Preparation 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 similar manner to 93a using 2-(2-(difluoromethyl)-3-ethoxy- 4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 127, 4.09 g, 12.46 mmol) by heating to approximately 100°C for approximately 15 hours. 1H 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). LC-MS m/z=359 [MH] ⁺ .

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

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3-Bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (350 mg, 27%) was prepared in a similar manner to 93a using 2-(5-ethoxy-2-fluoro-4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 134, 1.2 g, 4.05 mmol). 1H 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 (kv, J=7.0 Hz , 2H), 3.92 (s, 3H), 1.49 (t, J=7.0 Hz, 3H). LC-MS m/z=327 [MH] ⁺ .

Preparation 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 similar manner to 93a using 2-(2-fluoro-4-methoxy-5- propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (preparation 138, 10 g, 32 mmol). 1H 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). LC-MS m/z=339 [MH] ⁺ .

Preparation 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 similar manner to 93a using 3-fluoro-2-iodo-5- methoxy-6-propoxypyridine (yield 220, 4.18 g, 13.44 mmol) and (5-chloropyridin-3-yl)boronic acid (2.11 g, 13.4 mmol) at approximately 90°C for approximately 16 h ^1H NMR ( _CDCl3 , 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). LC-MS m/z=328 [MH] ⁺ .

Preparation 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 93a using 2-(3-ethoxy-2-fluoro-4-methoxyphenyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 113.5 g, 18 mmol) and 2,6-dibromopyrazine (6.4 g, 27 mmol) at approximately 110°C for approximately 16 part 1H 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). LC-MS m/z=309 [MH] ⁺ .

Preparation 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-1,6dihydropyrimidin-4-yl)acetate (preparation 106, 42.98 g, 124 .08 mmol), followed by the addition of pyridine hydrochloride (14.3 g, 124 mmol) at approximately 25°C. The resulting mixture was heated to approximately 80°C for approximately 0.5 hours. The mixture was diluted with EtOAc (200 ml) and added dropwise to water. The EtOAc layer was treated with NaHCO ₃ . The EtOAc layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using 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%). ^1H NMR ( _CDCl3 , 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 (kv, 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). LC-MS m/z=365 [MH] ⁺ .

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

A mixture of 4-methoxy-3-propoxybenzimidamide (receipt 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 approximately 100°C for approximately 24 hours. The mixture was filtered and the filter cake was 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%). ^1H NMR ( _CDCl3 , 400 MHz): δ 12.44 (w s, 1H), 7.73-7.86 (m, 2H), 6.99 (d, J=8.3 Hz, 1H) , 6.33 (s, 1H), 4.23 (kv, 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). LC-MS m/z=346 [MH] ⁺ .

Preparation 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 93a using 2-(4-methoxy-3-propoxyphenyl)-4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane (preparation 114, 4.3 g, 14.7 mmol) and 3,5-dichloropyridazine (2.3 g, 15.5 mmol). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=278 [MH] ⁺ .

Preparation 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 similar manner to 93a using 2-(3-ethoxy-4-methoxyphenyl)-4. 4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 113, 2.0 g, 7.19 mmol) and 3,5-dibromo-4-methylpyridine (2.71 g, 10.8 mmol) at approximately 120°C for approximately 2 hours ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.61 (s, 1H), 8.32 (s, 1H), 6.94 (d, J=8 ,0 Hz, 1H), 6.81-6.83 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 4.10 (kv, J=7.0 Hz, 2H ), 3.92 (s, 3H), 2.34 (s, 3H), 1.47 (t, J=7.0 Hz, 3H). LC-MS m/z=323 [MH] ⁺ .

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

Into 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 over approximately 10 minutes, 2-(3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added (preparation 113, 1.0 g, 3.60 mmol), 2. 4-dibromothiazole (0.83 g, 3.42 mmol) and K3PO4 (2.44 g, 11.5 mmol). The combined mixture was degassed and heated to approximately 60°C for approximately 16 hours. The mixture was concentrated and the residue was purified using column chromatography (silica), eluting with petroleum ether: EtOAc (100:0 to 85:15) to give 4-bromo -2-(3-ethoxy-4-methoxyphenyl)thiazole (0.68 g, 60%). ^1H NMR ( _CDCl3 , 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 (kv, J=7.0 Hz, 2H), 3.93 (s, 3H), 1, 51 (t, J=7.0 Hz, 3H). LC-MS m/z=315 [MH] ⁺ .

Preparation 110: Ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)propanoate

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2-(chloromethyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (187 mg, 1.06 mmol) and stirred at approximately 20°C for approximately 30 minutes. The mixture was filtered through a pad of Celite® and the filtrate was concentrated. The residue was dissolved and concentrated with anhydrous THF (3x5 ml). The residue was dissolved in THF (6.0 ml) and added to a cold suspension of NaH (60% suspension in mineral oil, 349 mg, 8.73 mmol) and ethyl 2-(6-bromopyridin-2-yl)propanoate (preparation 111, 1.502 g, 5.819 mmol) in THF (13.0 ml), which was degassed under N2. The combined mixtures were stirred at approximately 20°C for approximately 18 hours. The mixture was treated with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in DMSO (5 ml) and purified using preparative HPLC (Biotage C18 RP column, 60 g), eluting with MeCN (0.1% NH ₄ CO ₂ H)/water (0:100 to 100:0) with producing ethyl 2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (339 mg, 14% ). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=399 [MH] ⁺ .

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

A solution of LiHMDS in THF ( 1.0 M, 29.3 ml, 29.3 mmol). The solution was stirred for approximately 1 hour and iodomethane (3.33 g, 23.4 mmol, 1.46 ml) was added dropwise. The reaction mixture was allowed to warm to approximately 20°C over approximately 19 hours. The reaction mixture was 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 using column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 80:20) to give ethyl 2-(6-bromopyridin-2-yl)acetate (5.06 g, 84%). 1H 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 (kv, J=7.0 Hz, 2H), 3.93 (kv, J=7.0 Hz, 1H), 1.57 (d, J=7.4 Hz, 3H ), 1.25 (t, J=7.0 Hz, 3H). LC-MS m/z=259 [MH] ⁺ .

Preparation 112: Ethyl 2-(6-bromopyridin-2-yl)acetate

A solution of _LDA in THF (2.0 M, 59 mL, 118 mmol) slowly with stirring. The solution was stirred at approximately -78°C for approximately 30 minutes. Diethyl carbonate (8.6 mL, 70.9 mmol) was added to the mixture at approximately -78°C. The mixture was allowed to warm to approximately 20°C overnight. The reaction mixture was cooled to approximately 0°C and diluted with a saturated aqueous NH ₄ Cl solution. The aqueous layer was extracted with DCM and the combined DCM extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40) to give ethyl 2-(6bromopyridin-2-yl)acetate (7.7 g, 53%). 1H 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 (kv, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.26-1.34 (m, 3H). LC-MS m/z=245 [MH] ⁺ .

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

A mixture of 4-bromo-2-ethoxy-1-methoxybenzene (receipt 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) were degassed and heated to approximately 90°C for approximately 16 hours under N ₂ . Mixture

- 79 045319 filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 2-(3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 g, 86%). ^1H NMR ( _CDCl3 , 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 (kv, J=7.2 Hz, 2H), 3.90 (s, 3H), 1.47 (t, J=7.2 Hz,

3H), 1.34 (s, 12H).

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

A mixture of 4-bromo-1-methoxy-2-propoxybenzene (preparation 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) were degassed and stirred at approximately 80°C for approximately 16 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (51.0 g, 99%). ^1H NMR (CDCl3.400 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 were prepared using the corresponding bromide and 4,4,4',4',5,5,5',5'octamethyl-2,2'-bis(1,3,2-dioxaborolane), the following procedure is described in receiving 114.

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Receiving no. Structure/Name Source Analytical data 115 I । ⁰ 'K 2-(3-isopropoxy-4-methoxyphenyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane Receipt 152 ^1H NMR (CDCI 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, ZN), 1.36-1.39 (m, 6H), 1.34 ( s, 12H). LC-MS m/z = 293 [MH] ⁺ . 116 O'^^V^h/ I ι OU 2-(3-isobutoxy-4-methoxyphenyl)4,4,5,5-tetramethyl-1,3,2- dioxaborolane Receipt 153 ^1H NMR (CDCI3, 400 MHz): 6 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, ZN), 3.82 (d, 7 = 6.9 Hz, 2H), 2.16-2.23 (m, 1H) , 1.33-1.37 (m, 12H), 1.05 (d, 7=6.4 Hz, 6H). LC-MS m/z = 307 [MH] ⁺ . 117 Λ 2-(3-cyclopropoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 154 ^1H NMR (CDCI3, 400 MHz): 6 7.62 (d, J= 1.0 Hz, 1H), 7.40-7.48 (m, 1H), 6.83-6.91 (m, 1H), 3.87 (s, ZN), 3.81-3.86 (m, 1H), 1.33-1.36 (m, 12H), 0.80-0.88 (m, 4H) . LC-MS m/z = 291 [MH] ⁺ . 118 ό A '—S 2-(4-methoxy-3-((tetrahydrothiophen3-yl)oxy)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Receipt 155 ^1H NMR (CDCI3, 400 MHz): 6 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, ZN), 3.09-3.18 (m, ZN), 2.89-2.96 (m, 1H), 2.39 -2.47 (m, 1H), 2.042.07 (m, 1H), 1.34 (s, 12H). LC-MS m/z = 337 [MH] ⁺ . 119 О^^Ъ^Ч/ ό А S 2-(4-methoxy-3-((tetrahydro-2Nthiopyran-4-yl)oxy)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane Receipt 156 ^1H NMR (CDCI3, 400 MHz): 6 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, ZN), 2.87-3.01 (m, 2H), 2.51-2.62 (m, 2H) , 2.13-2.25 (m, 2H), 1.982.10 (m, 2H), 1.29-1.36 (m, 12H).

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120 \^Si B'°\/ 4 ¹ ύηΟ tert-butyl(2-(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)ethoxy)dimethylsilane Receipt 157 ^1H NMR (CDCI ₃ , 400 MHz): 6 7.42 (dd, J = 1.5, 7.8 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 6, 86-6.90 (m, 1H), 4.104.18 (m, 2H), 3.99-4.03 (m, 2H), 3.88 (s, ZN), 1.34 (s, 12H) , 0.90-0.92 (m, 9H), 0.09-0.11 (m, 6H). LC-MS m/z = 409 [MH] ⁺ . 121 >i m/ ^Sl । o-U tert-butyl(3-(2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)propoxy)dimethylsila n Receipt 158 ^1H NMR (CDCI3, 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 = Q,Q Hz, 2H), 3.88 (s, ZN), 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). LC-MS m/z = 423 [MH] ⁺ . 122 ^F ^- _o B^°\/ ' /\ O--U 2-(3-(2-fluoroethoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 159 ^1H NMR (CDCI3, 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), 4.834.88 (m, 1H), 4.71-4.75 (m, 1H), 4.34-4.38 (m, 1H), 4.27-4 .31 (m, 1H), 3.90 (s, ZN), 1.34 (s, 12H). LC-MS m/z = 297 [MH] ⁺ . 123 O-/ 2-(3-(3-fluoropropoxy)-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 160 ^1H NMR (CDCI3, 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, 7 = 5.9 Hz, 1H), 4.62 (t, 7 = 5.9 Hz, 1H), 4.20 (t , 7 = 6.4 Hz, 2H), 3.89 (s, ZN), 2.27-2.30 (m, 1H), 2.20-2.23 (m, 1H), 1.32- 1.37 (m, 12H). LC-MS m/z = 311[MH] ⁺ . 124 in ⁰ '^ O-U 2-methoxy-3-propoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)pyridine Receipt 215 ^1H NMR (CDCI3, 400 MHz): 6 8.12 (d, 7= 1.5 Hz, 1H), 7.34 (d, 7= 1.5 Hz, 1H), 4.03 (s, ZN ), 3.98-4.02 (m, 2H), 1.851.94 (m, 2H), 1.35 (s, 12H), 1.05 (t, 7= 7.5 Hz, ZN). LC-MS m/z = 294 [MH] ⁺ .

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125 ON Ooh 2, 3-d and meto xy-6- (4,4,5,5tetramethyl-1,3,2-dioxaborolane-2- yl)benzonitrile Receipt 162 1H NMR (CDCI 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, ZN), 3.93-3.89 (m, ZN), 1.37 (s, 12N). 126 /X/k F°~Ά 2- (3 is xy-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Receiving 170a ^1H NMR (CDCI3, 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, ZN), 1.33-1.40 (m, 15H). 127 F^F 2-(2-(difluoromethyl)-3-ethoxy-4methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 168 ^1H NMR (CDCI3.400 MHz): b 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, ZN), 1.46 (t, J= 7.0 Hz, ZN), 1.34 (s, 12H). ¹⁹ RNMR (CDCI3, 376 MHz): δ114.25 (w s, 1F). LCMS m/z = 296 [MN] ⁺ . 128 В°\у I । F 2-(2-fluoro-4-methoxy-3- propoxyphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Receiving 170b LC-MS m/z = 311 [MH] ⁺ . 129 В°\у I N I 3-methoxy-2-propoxy-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile Receipt 171 Ή NMR (CDCI3 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, ZN), 1.791.90 (m, 2H), 1.35-1.38 (m, 12H), 1.03-1.08 (m, ZN). LC-MS m/z = 318 [MH] ⁺ . 130 °\Oh?' 2-(2,4-dimethoxy-3-propoxyphenyl)4,4,5,5-tetramethyl-1,3,2- dioxaborolane Receipt 210 ^1H NMR (CDCI3 400 MHz): δ 7.42 (d,7= 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), 1.331.38 (m, 12H), 1.001.08 (m, ZN). LC-MS m/z = 345 [M+Na] ⁺ .

- 83 045319

131 CN 0— 2-(cyclopentyloxy)-3-methoxy-6(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile Receipt 207 ^1H NMR (CDCI ₃₄₀₀ MHz): δ 7.52 (d, 4= 8.3 Hz, 1H), 7.00-7.10 (m, 1H), 4.98-5.11 (m, 1H), 3.88 (s, ZN), 1.91-2.01 (m, 4H), 1.65-1.76 (m, 2H), 1.53-1.64 (m, 2H) , 1.37 (s, 12H). LC-MS m/z = 344 [MH] ⁺ . 132 F ^Ox^L । O-A 2-(3-ethoxy-5-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 172 ^1H NMR (CDCh 400 MHz): δ 7.17 (dd, J = 1.0, 10.5 Hz, 1H), 7.11 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 1.0 Hz, ZN), 1.56 (s, 6H), 1.46 (t, 4 = 7.0 Hz, ZN), 1.34 ( s, 12H). LCMS m/z= 297 [MN] ⁺ . 133 C.I. ^O^Jx 1 /\ 0-Z 2-(3-chloro-5-ethoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Receipt 177 ^1H NMR (CDCI3 400 MHz): δ 7.44 (d, J= 1.0 Hz, 1H), 7.22 (d, 4= 1.0 Hz, 1H), 4.10-4.17 ( m, 2H), 3.91 (s, ZN), 1.46 (t, 4 =7.0 Hz, ZN), 1.34 (s, 12H). LC-MS m/z = 312 [MH] ⁺ . 134 । /\ O-/ 2-(5-ethoxy-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Receipt 182 ^1H NMR (CDCI3 400 MHz): δ 7.14 (d, 4=5.5 Hz, 1H), 6.59 (d, 4 = 10.0 Hz, 1H), 4.02-4.16 ( m, 2H), 3.86 (s, ZN), 1.40-1.52 (m, ZN), 1.34 (s, 12H). LC-MS m/z = 297 [MH] ⁺ . 135 1 2-(2-chloro-5-ethoxy-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Receipt 183 ^1H NMR (CDCI3 400 MHz): δ 7.18 (s, 1H), 6.86 (s, 1H), 4.12 (sq, 4 = 7.0 Hz, 2H), 3.87 (s, 1H), ZN), 1.46 (t, 4= 7.0 Hz, ZN), 1.36 (s, 12N). LCMS m/z= 312 [MN] ⁺ . 136 1 /\ ο-Ύ 2-(5-ethoxy-4-methoxy-2methylphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 187 ^1H NMR (CDCI3 400 MHz): 6 7.28 (s, 1H), 6.69 (s, 1H), 4.13 (sq, 4 = 6.9 Hz, 2H), 3.88 (s, ZN), 2.50 (s, ZN), 1.46 (t, 4= 7.1 Hz, ZN), 1.33 (s, 12N). LC-MS m/z = 292 [MH] ⁺ .

- 84 045319

137 /O^/X/F I ι /\ F 2-(3-ethoxy-2,6-difluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Receipt 193 ^1H NMR (CDCI ₃₄₀₀ MHz): δ 6.34-6.48 (m, 1H), 4.04 (kv, J= 7.0 Hz, 2H), 3.85 (s, ZH), 1 .32-1.42 (m, 15N). LC-MS m/z = 315 [MH] ⁺ . 138 in°\/ ABOUT-/ 2-(2-fluoro-4-methoxy-5propoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane Receipt 188 ¹ H NMR (CDCI3, 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, ZN), 1.81-1.90 (m, 2H), 1.25-1.30 (m, 12H), 1.05 (t, 7 =7.6 Hz, ZN). 139 । /\ O-/ 2-(4-ethoxy-3-methoxyphenyl)4,4,5,5-tetramethyl-1,3,2- dioxaborolane Receipt 198 ^1H NMR (CDCh 400 MHz): 6 7.41 (dd, J = 1.2, 8.1 Hz, 1H), 7.29 (d, 7 = 1.5 Hz, 1H), 6.88 ( d, 7= 8.3 Hz, 1H), 4.14 (sq, 7= 7.0 Hz, 2H), 3.92 (s, ZN), 1.48 (t, 7 = 6.9 Hz, ZN), 1,341.36 (m, 12N). LC-MS m/z = 279 [MH] ⁺ . 140 I । /\F 2-(4-ethoxy-2-fluoro-3- methoxyphenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane Receipt 199 ^1H NMR (CDCI3 400 MHz): δ 7.37 (dd, 7 = 6.4, 8.3 Hz, 1H), 6.646.73 (m, 1H), 4.07-4.18 (m, 2H ), 3.90 (d, 7 = 1.0 Hz, ZN), 1.46 (t, 7 = 6.9 Hz, ZN), 1.35 (s, 12H). LC-MS m/z = 297 [MH] ⁺ . 141 Β'θκ^। /\ O-/ 2-(3,4-diethoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane Receipt 197 H NMR (400 MHz, CDCI3) δ 7.39 (dd, 7 = 1.2, 8.1 Hz, 1H), 7.30 (d, 7 = 1.0 Hz, 1H), 6.88 (d , 7 =8.3 Hz, 1H), 4.08-4.17 (m, 4H), 1.411.49 (m, 6H), 1.33 (s, 12H). LC-MS m/z = 293 [MH] ⁺ . 142 ^F O-/ 2-(4-(difto r methoxy)-3propoxyphenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane Receipt 223 ^1H NMR (CDCI3 400 MHz): δ 7.40 (d, 7= 1.2 Hz, 1H), 7.38 (s, 1H), 7.15 (dd, 7=0.7, 7.6 Hz, 1H), 6.41-6.82 (m, 1H), 4.04 (t, 7 =6.5 Hz, 2H), 1.80-1.91 (m, 2H), 1.33 -1.37 (m, 12H), 1.06 (t, 7= 7.3 Hz, ZN).

- 85 045319

143 in°\^o—/ 2-(3-methoxy-4-(methylthio)phenyl)4,4,5,5-tetramethyl-1,3,2- dioxaborolane Receipt 203 ^1H NMR (CDCI ₃₄₀₀ 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, ZN), 2.45 (s, ZN), 1.35 (s, 12H). LC-MS m/z = 281 [MH] ⁺ . 144 O-V 2-(3-ethoxy-4-(methylthio)phenyl)4,4,5,5-tetramethyl-1,3,2- dioxaborolane Receipt 204 ^1H NMR (MeOD- _d3 , 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 (kv, J= 7.1 Hz, 2H), 2.39 (d, J= 1.0 Hz, ZN), 1.39-1.44 (m, ZN) , 1.34 (s, 12H). LCMS m/z = 295 [MN] ⁺ . 145 ό 2-(3-(cyclopentyloxy)-4(methylthio)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane Receipt 205 ^1H NMR (CDCI ₃₄₀₀ 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, ZN), 1.82-1.96 (m, 6H), 1.61-1.67 (m, 2H) , 1.32-1.37 (m, 12H). LC-MS m/z = 335 [MH] ⁺ .

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

Method A.

Five reactions were carried out in parallel. Mixture of ((2-bromolyl)oxy)(tert-butyl)dimethylsilane (preparation 227, 300 g, 1.19 mol), KOAc (234 g, 2.39 mol), 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (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) was degassed and stirred at approximately 80°C for approximately 16 hours. Solids were removed by filtration and the filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (1:0) to give tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )alyl)oxy)silane (520 g, 30%). GC (Column: Agilent J&W HP-5MS 30Mx0.25 mm IDx0.25 µm film thickness; injection temperature 250°C; splitting ratio 100:1; ion source temperature 230°C; separation surface temperature 250°C; column temperature from 50 °C 1 min to 100 °C @ 30 °C/min to 250 °C @ 10 °C/min; transit time 17.67 min; flow rate 1.5 ml/min; RT=11.67 min. 1H 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.

In a mixture of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (250 mg, 1.47 mmol), sodium tertbutoxide (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'bis(1,3,2-dioxaborolane) (410 mg, 1.61 mmol) under N2 atmosphere, a solution of tBu ₃ P (1.0M toluene solution, 0.176 mL, 0.12 mmol) in anhydrous toluene (2.5 mL) was added dropwise. MeOH (94 mg, 2.94 mmol) was added dropwise to the mixture and the mixture was stirred at approximately 20° C. overnight. The reaction was quenched with MeOH (20 ml) and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 80:20) to give tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)alyl)oxy)silane (2.2 g, 50%). 1H NMR (CDCl3, 400 MHz): δ 5.97 (w 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).

Preparation 147: tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2yl)oxy)silane

- 86 045319

In 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(I) chloride (537 mg, 5.42 mmol) and Pin ₂ B ₂ (15.2 g, 59.7 mmol) in toluene (120 ml), a solution of tBu ₃ P (13.2 g) was added under N2 atmosphere , 6.51 mmol) in anhydrous toluene (10 ml) dropwise. MeOH (3.48 g, 108 mmol) was added dropwise and the mixture was stirred at approximately 20°C for approximately 16 hours. The reaction was quenched with MeOH (10 ml) and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 97:3) to give tert-butyldimethyl((3-(4,4,5,5-tetramethyl1,3,2- dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane (8.2 g, 48.4%). 1H 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).

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

Al I

V-°

Mixture of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (preparation 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) were suspended in anhydrous 1,4-dioxane (10 ml). The mixture was degassed for approximately 10 minutes. at approximately 18°C in an N2 atmosphere. Pd(PPh ₃ ) ₂ Cl ₂ (106 mg, 0.15 mmol) was added and the mixture was heated to approximately 90°C for 16 hours. The reaction mixture was cooled to approximately 20°C and filtered. The filtered cake was washed with 1,4-dioxane and the combined filtrates were concentrated. The residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (100:0 to 80:20) to give tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (1.15 g, 49%). LC-MS m/z=313 [MH] ⁺ .

Preparation 149: 2,2'-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

A mixture of 1,1-dibromethane (14.9 g, 58.6 mmol), lithium methoxide (3.03 g, 79.8 mmol) and copper(I) iodide (5.07 g, 26.6 mmol) was suspended in DMF (150 ml) under N ₂ atmosphere. Additional lithium methoxide (5.0 g, 2.43 ml) in DMF (10 ml) was added to the mixture. The reaction mixture was heated to approximately 40°C and stirred for approximately 48 hours under N ₂ atmosphere. The solution was cooled to approximately 20°C and extracted with heptane (3x300 ml). The heptane extracts were washed with water (100 ml), brine (100 ml) and passed through a layer of MgSO ₄ and silica gel. The layer was washed with DCM (100 ml). The combined filtrates were concentrated. The residue was purified using column chromatography (silica) and eluted with DCM to give 2,2'-(ethane-1,1diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3,6 d, 48%).1H NMR ( _CDCl3 , 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 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 approximately 25°C for approximately 16 hours. The mixture was filtered and water (500 ml) was added to the filtrate. The mixture was extracted with EtOAc (2x400 ml). The combined EtOAc extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 4-bromo-2-ethoxy-1methoxybenzene (48.0 g), which was used directly in the next step. 1H 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=7.2 Hz, 2H), 3.88 (s, 3H), 1.47 (t, J=7.2 Hz, 3H) .

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

1Ί

In 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

- 87045319 ml) 1-iodopropane (28.9 ml, 295 mmol) was added portionwise at approximately 20°C. The mixture was stirred at approximately 20°C for approximately 1 hour. The mixture was poured into ice water (500 ml) and extracted with EtOAc (3x300 ml). The combined EtOAc extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (40:1) to give 4-bromo-1-methoxy-2-propoxybenzene (43.0 g, crude). 1H 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 152: 4-bromo-2-isopropoxy-1-methoxybenzene

4-Bromo-2-isopropoxy-1-methoxybenzene (16 g, 95%) was prepared in a similar manner to 150 using 2-bromopropane (12.7 g, 103.4 mmol). ^1H NMR ( _CDCl3 , 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). LC-MS m/z=245 [MH] ⁺ .

Preparation 153: 4-bromo-2-isobutoxy-1-methoxybenzene

In 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 approximately 0° C., DIAD (37.3 g, 185 mmol) was added dropwise under N ₂ atmosphere. The mixture was stirred at approximately 0°C for approximately 2 hours. Additional DIAD (2.53 g, 12.5 mmol) and 2-methylpropan-1-ol (1.03 g, 13.9 mmol) were added and the mixture was stirred at approximately 10°C for approximately 5 days, then filtered. The filtrate was concentrated under reduced pressure. MTBE (500 ml) was added and the mixture was stirred at approximately 10°C for approximately 20 minutes. The white precipitate was filtered off. The filtrate was concentrated. The residue was dissolved in water (200 ml) and extracted with MTBE (2x300 ml). The combined MTBE extracts were concentrated and the residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:1 to 90:10) to give 4-bromo-2-isobutoxy-1-methoxybenzene (22 g, 69% ). 1H 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 .5 Hz, 6H).

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

4-Bromo-2-cyclopropoxy-1-methoxybenzene (6.15 g, 64%) was prepared in a similar manner to 150 using bromocyclopropane (8.0 g, 39 mmol). 1H 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).

Preparation 155: 3-(5-bromo-2-methoxyphenoxy)tetrahydrothiophene

In 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 approximately 0° C., DIAD (2.39 g, 11.8 mmol) was added dropwise under N2. The mixture was stirred at approximately 0°C for approximately 2 hours. The mixture was stirred for approximately 3 days. The mixture was filtered and the filtrate was concentrated. MTBE (50 ml) was added to the residue and stirred at approximately 10°C for approximately 20 minutes. The white precipitate was filtered off. The filtrate was concentrated again. The residue was dissolved in water (20 ml) and extracted with MTBE (2x30 ml). The combined MTBE extracts were concentrated and the residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:1 to 90:10) to give 3-(5-bromo-2methoxyphenoxy)tetrahydrothiophene (2.0 g, 88 %). ^1H NMR ( _CDCl3 , 400 MHz): δ 7.05-7.11 (m, 2H), 6.74-6.79

- 88 045319 (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 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 155 using tetrahydro-2H-thiopyran-4-ol (3.2 g, 27, 1 mmol). ^1H NMR ( _CDCl3 , 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).

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

Br d ¹ (2-(5-Bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane (60 g, 86%) was prepared in a manner similar to preparation 155 using 2-((tert-butyldimethylsilyl)oxy)ethane- 1-ol (34 g, 190 mmol). 1H 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).

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

R' XI / ^Sl Br (3-(5-Bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane (19.8 g, 86%) was prepared in a manner similar to preparation 155 using 3-((tert-butyldimethylsilyl )oxy)propan-1-ol (preparation 236, 12.5 g, 61.6 mmol). 1H NMR ( _CDCl3 , 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).

Preparation 159: 4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene

4-Bromo-2-(2-fluoroethoxy)-1-methoxybenzene (12 g, 98%) was prepared in a similar manner to 155 using 2-fluoroethan-1-ol (3.79 g, 59 mmol). ^1H NMR ( _CDCl3 , 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), 4.204.24 (m, 1H), 3.86 (s, 3H).

Preparation 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 155 using 3-fluoropropan-1-ol (3.69 g, 47.3 mmol). 1H 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 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 approximately 15°C for for approximately 12 hours under N2 atmosphere. The reaction mixture was quenched with water (300 ml) and extracted with DCM (2x300 ml). The combined DCM extracts were washed with brine (2x100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 1-bromo-2-fluoro-3,4-89 045319 dimethoxybenzene (35.0 g, 66%). 1H NMR ( _CDCl3 , 400 MHz): δ 7.17-7.21 (m, 1H), 6.60-6.63 (m, 1H), 3.93 (s,

3H), 3.87 (s, 3H).

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

To a solution of 6-bromo-2,3-dimethoxybenzaldehydoxime (preparation 163, 30.0 g, 115 mmol) in DCM (500 ml) was added TPOA (24.0 ml, 173 mmol) and Et ₃ N (48.0 ml, 346.0 mmol). The mixture was stirred at approximately 20°C for approximately 2 hours. The mixture was quenched with water (200 ml) at approximately 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 using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1 to 3:1) to give 6-bromo-2,3-dimethoxybenzonitrile (25.0 g, 90%). 1H NMR (CDCl ₃ , 400 MHz): δ 7.347.29 (m, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.04-4.01 (m, 3H), 3 .90-3.88 (m, 3H).

Preparation 163: 6-bromo-2,3-dimethoxybenzaldehydoxime

HE

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde (preparation 164, 15.0 g, 61.2 mmol) in EtOH (150 ml) was added NaHCO ₃ (7.7 g, 91.8 mmol) and NH ₂ OH- HCl (6.4 g, 91.8 mmol). The mixture was stirred at approximately 20°C for approximately 2 hours. The mixture was quenched by adding water (300 ml) at approximately 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-dimethoxybenzaldehydoxime (15.0 g), which was used in the preparation of 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 164: 6-bromo-2,3-dimethoxybenzaldehyde

6-Bromo-2,3-dimethoxybenzaldehyde (35.0 g, 82.5%) was prepared in a similar manner 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). 1H 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).

Preparation 165: 6-bromo-2-hydroxy-3-methoxybenzaldehyde

NaHCO ₃ (13.5 g, 161, 1 mmol) and LiOH (12.3 g, 293.0 mmol). The mixture was stirred at approximately 20°C for approximately 12 hours. The reaction mixture was adjusted to pH 5-6 and extracted with DCM. The DCM layer was concentrated to give 6-bromo-2-hydroxy3-methoxybenzaldehyde (40.0 g) which was used in the preparation of 164. 1H 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) .

Preparation 166: 3-bromo-2-formyl-6-methoxyphenylacetate

To a solution of 2-formyl-6-methoxyphenylacetate (receipt 167, 50.0 g, 257.5 mmol) in water (500 ml) was added Br ₂ (53.5 g, 334.7 mmol) and KBr (46.0 g , 386.2 mmol). The mixture was stirred at approximately 20°C for approximately 10 hours. The precipitate was filtered off, washed with ethyl acetate and recrystallized with EtOAc/petroleum ether to give 3-bromo-2-formyl-6-methoxyphenyl acetate (40.0 g, 57 %). ^1H NMR ( _CDCl3 , 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).

Preparation 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 approximately 20°C for approximately 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (100 ml) and extracted with DCM (2x100 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-methoxyphenylacetate (60.0 g, 94%). ^1H NMR ( _CDCl3 , 400 MHz): δ 10.1210.17 (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).

Preparation 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 6bromo-2-ethoxy-3-methoxybenzaldehyde (preparation 169, 4.64 g, 17. 9 mmol) in DCM (20 ml) at approximately -20°C. The reaction mixture was heated to approximately 25°C for 0.5 hours and then at approximately 25°C for approximately 15 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (200 ml) at approximately 0°C and the mixture was extracted with DCM (2x100 ml ). The combined DCM extracts were concentrated and the residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 97:3) to give 1-bromo-2(difluoromethyl)-3-ethoxy-4-methoxybenzene ( 4.77 g, 95%). ^1H NMR ( _CDCl3 , 400 MHz): δ 7.31 (d, J=8.8 Hz, 1H), 7.10 (t, J=54.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 4.11 (kv, J=7.0 Hz, 2H), 3.87 (s, 3H), 1.40 (t, J=7.0 Hz, 3H) .

Preparation 169: 6-bromo-2-ethoxy-3-methoxybenzaldehyde

Iodoethane (16, 9 g, 108 mmol). The mixture was heated to 60°C and stirred for 4 hours, followed by heating to 100°C for 19 hours. The mixture was cooled to room temperature. and condensed under reduced pressure. The residue was purified using column chromatography (silica) and eluted with petroleum ether:EtOAc (100:0 to 90:10) to give 6-bromo-2-ethoxy-3-methoxybenzaldehyde (5.1 g, 92%) as light yellow oil. ^1H NMR ( _CDCl3 , 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 (kv, J=7.0 Hz, 2H), 3.88 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).

Preparation 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 155 using 3-bromo-2-fluoro-6-methoxyphenol (38 g, 170 mmol) and iodoethane (40.2 g, 258 mmol). ^1H NMR ( _CDCl3 , 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 of 170b: 1-bromo-2-fluoro-4-methoxy-3-propoxybenzene

- 91 045319

1-Bromo-2-fluoro-4-methoxy-3-propoxybenzene (10.2 g 57%) was prepared in a similar manner to 155 using 3-bromo-2-fluoro-6-methoxyphenol (15 g, 68.2 mmol ) and 1-bromopropane (10.8 g, 88.6 mmol). 1H 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 171: 6-bromo-3-methoxy-2-propoxybenzonitrile

6-Bromo-3-methoxy-2-propoxybenzonitrile (10.9 g 92%) was prepared in a manner similar to preparation 155 using 6-bromo-2-hydroxy-3-methoxybenzonitrile (10 g, 44 mmol) and 1-bromopropane ( 7 g, 57 mmol). 1H 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). LC-MS m/z=270 [MH] ⁺ .

Preparation 172: 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene

K ₂ CO ₃ (2.07 g, 15 mmol). The mixture was heated to approximately 50°C and stirred for approximately 5 hours. The mixture was cooled to approximately 20°C and filtered. The filtrate was concentrated and the residue was triturated with MTBE (20 ml) for approximately 20 minutes. The mixture was filtered and the filtrate was concentrated to give 5-bromo-1-ethoxy-3fluoro-2-methoxybenzene (1.85 g, 74%). 1H NMR (CDCl3, 400 MHz): δ 6.88-6.91 (m, 1H), 6.82-6.83 (m, 1H), 4.07 (kv, J=7.0 Hz, 2H ), 3.90 (d, J=0.7 Hz, 3H), 1.46 (t, J=7.0 Hz, 3H).

Preparation 173: 5-bromo-3-fluoro-2-methoxyphenol

To a mixture of 5-bromo-3-fluoro-2-methoxyphenyl formate (preparation 174, 4.98 g, 20.0 mmol) in MeOH (30 ml) and water (30 ml), LiOH (1.68 g, 40, 0 mmol). The mixture was stirred at approximately 25°C for approximately 16 hours. The mixture was concentrated. The resulting aqueous phase was diluted with water and NaHCO ₃ was added until pH 8. The aqueous phase was washed with MTBE (2x30 ml) and the combined MTBE extracts were concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 85:15) to give 5-bromo-3-fluoro-2-methoxyphenol (2.4 g, 54% over 2 steps ). 1H NMR ( _CDCl3 , 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).

Preparation 174: 5-bromo-3-fluoro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-fluoro-2-methoxybenzaldehyde (preparation 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 approximately 25°C for approximately 16 hours. The reaction mixture was concentrated to provide 2-(5-bromo-3-fluoro-2-methoxyphenyl)acetaldehyde (3.74 g), which was used in Preparation 173.

Preparation 175: 5-bromo-3-fluoro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (preparation 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 was heated to

- 92 045319 approximately 50°C for approximately 16 hours. The reaction mixture was filtered and the filtrate was 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%). 1H 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) .

Preparation 176: 5-bromo-3-fluoro-2-hydroxybenzaldehyde

F

Vg

To a mixture of 4-bromo-2-fluorophenol (20.0 g, 104.7 mmol) dissolved in TFO (100 ml), HMTA (CAS 100-97-0, 29.4 g, 209.0 mmol) was added portionwise ). The mixture was heated at approximately 90°C for approximately 16 hours. The mixture was poured into water (800 ml) and the solid that formed was filtered. The cake was washed with water (2x150 ml) and dried to obtain 5-bromo-3-fluoro-2hydroxybenzaldehyde (18.9 g, 82%). 1H NMR (CDC13, 400 MHz): δ 10.90 (s, 1H), 9.88 (d, J=2.0 Hz, 1H), 7.49-7.53 (m, 2H).

Preparation 177: 5-bromo-1-chloro-3-ethoxy-2-methoxybenzene

C.I.

A A

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). 1H NMR (CDC13, 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).

Preparation 178: 5-bromo-3-chloro-2-methoxyphenol

C.I.

NST^^g

To a mixture of 5-bromo-3-chloro-2-methoxyphenyl formate (preparation 179, 15.6 g, 58.76 mmol) in MeOH (100 ml) and water (100 ml) was added portionwise LiOH (4.93 g, 118.0 mmol). The mixture was stirred at approximately 25°C for approximately 16 hours. The mixture was concentrated and the resulting aqueous phase was diluted with aqueous NaHCO ₃ (50 ml). The solution was extracted with MTBE (2x30 ml) and the combined MTBE extracts were dried and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether:EtOAc (100:0 to 90:10) to give 5-bromo-3-chloro-2-methoxyphenol (1.3 g, 7% in 2 steps ). 1H NMR (CDC13, 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).

Preparation 179: 5-bromo-3-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-chloro-2-methoxybenzaldehyde (preparation 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 approximately 25°C for approximately 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 178. LC -MS m/z=266 [MN] ⁺ .

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

To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (preparation 181, 10 g, 42.5 mmol) dissolved in MeCN (150 ml), iodomethane (24.1 g, 170 mmol) and K ₂ CO were added ₃ (11.7 g, 84.9 mmol). The mixture was heated to approximately 50°C and stirred for approximately 24 hours. The mixture was cooled to approximately 20°C and filtered. The filtrate was concentrated and the residue was triturated with MTBE (30 ml) for approximately 20 minutes. before filtering. The filtrate was concentrated and the residue was diluted with water (20 ml) and extracted with EtOAc (2x100 ml). The combined EtOAc extracts were concentrated to give 5-bromo-3-chloro-2-methoxybenzaldehyde (8.9 g, 84%), which was used in the preparation

- 93 045319

179. 1H NMR (CDCI3, 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).

Preparation 181: 5-bromo-3-chloro-2-hydroxybenzaldehyde

To a mixture of 4-bromo-2-chlorophenol (20.0 g, 94.41 mmol) in TFO (150 ml) HMTA (CAS 100-97-0, 27.0 g, 193 mmol) was added portionwise. The mixture was stirred at approximately 90°C for approximately 16 hours. The mixture was poured into water (800 ml) and a precipitate formed. The precipitate was filtered off, washed with water (2x150 ml) and dried to give 5-bromo-3-chloro-2-hydroxybenzaldehyde (22.7 g) which was used in the preparation of 180. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.40 (w s, 1H), 9.86 (s, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H) .

Preparation 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 similar manner to Preparation 172 using 5-bromo-4-fluoro-2-methoxyphenol (Preparation 192, 7.0 g, 32.0 mmol). 1H NMR ( _CDCl3 , 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 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 similar manner to Preparation 172 using 5-bromo-4-chloro-2-methoxyphenol (Preparation 184, 5.2 g, 21.9 mmol). 1H 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).

Preparation 184: 5-bromo-4-chloro-2-methoxyphenol

To a mixture of 5-bromo-4-chloro-2-methoxyphenyl formate (preparation 185, 3.2 g, 12.05 mmol) in MeOH (50 ml) and water (50 ml) was added NaOH (0.72 g, 18, 1 mmol). The mixture was stirred at approximately 20°C for approximately 1 hour. The mixture was acidified using 1N. HCl to pH 3. The mixture was concentrated and the aqueous phase that remained was extracted with EtOAc (3x100 ml). The combined EtOAc extracts were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-4-chloro-2-methoxyphenol (2.8 g, 98%). 1H NMR ( _CDCl3 , 400 MHz): δ 7.16 (s, 1H), 6.93 (s, 1H), 5.58 (s, 1H), 3.28 (s, 3H).

Preparation 185: 5-bromo-4-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-4-chloro-2-methoxybenzaldehyde (preparation 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 approximately 18°C for approximately 16 hours. The mixture was partitioned between DCM (400 ml) and saturated sodium metabisulfite 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 using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 5-bromo-4-chloro-2-methoxyphenyl formate (3.2 g, 25%). 1H NMR ( _CDCl3 , 400 MHz): δ 8.22 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 3.85 (s, 3H).

Preparation 186: 5-bromo-4-chloro-2-methoxybenzaldehyde

Vg

To a mixture of 1-bromo-2-chloro-4-methoxybenzene (15.0 g, 67.73 mmol) in TFO (100 ml) HMTA (CAS 100-97-0, 14.2 g, 102 mmol) was added portionwise. . The mixture was stirred at approximately 80°C for approximately 12 hours. The mixture was poured into water (1000 ml) and stirred at approximately 20°C for approximately 1 hour, and a precipitate formed. The precipitate was filtered off, dissolved in EtOAc (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc

- 94 045319 (from 100:0 to 90:10) to obtain 5-bromo-4-chloro-2-methoxybenzaldehyde (6.7 g, 40%). 1H NMR (CDC13,

400 MHz): δ 10.33 (s, 1H), 8.03 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H).

Preparation 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 similar manner to Preparation 172 using 5-bromo-2-methoxy-4-methylphenol (Preparation 189, 7.16 g, 33.0 mmol). 1H NMR (CDCl ₃ , 400 MHz): δ 7.01 (s, 1H), 6.74 (s, 1H), 4.05 (kv, J=7.0 Hz, 2H), 3.85 (s , 3H), 2.33 (s, 3H) 1.46 (t, J=7.0 Hz, 3H).

Preparation 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). 1H 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).

Preparation 189: 5-bromo-2-methoxy-4-methylphenol (Ox/x)

NaOH (4.72 g, 118, 1 mmol). The mixture was stirred at approximately 20°C for approximately 1 hour. The mixture was acidified using 1N. HCl to pH 3. The mixture was concentrated and the aqueous phase that remained was extracted with EtOAc (3x150 ml). The combined EtOAc extracts were dried, filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 80:20) to give 5-bromo-2-methoxy-4-methylphenol (10.25 g, 60% in 2 steps ). 1H NMR ( _CDCl3 , 400 MHz): δ 7.10 (s, 1H), 6.72 (s, 1H), 5.46 (w s, 1H), 3.87 (s, 3H), 2. 33 (s, 3H).

Preparation 190: 5-bromo-2-methoxy-4-methylphenyl formate

Υ O^O^^^Br

To a mixture of 5-bromo-2-methoxy-4-methylbenzaldehyde (preparation 191, 18.0 g, 78.58 mmol) in DCM (200 mL) was added m-CPBA (33.9 g, 157.0 mmol). The mixture was stirred at approximately 18°C for approximately 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was washed with aqueous sodium metabisulfite (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.

Preparation 191: 5-bromo-2-methoxy-4-methylbenzaldehyde

Vg

To a mixture of 1-bromo-4-methoxy-2-methylbenzene (25.1 g, 125.0 mmol) in TFO (120 ml) HMTA (26.3 g, 188 mmol) was added portionwise. The mixture was stirred at approximately 80°C for approximately 12 hours. The mixture was poured into water (500 ml) and stirred at approximately 20°C for approximately 2 hours, and a precipitate formed. The precipitate was filtered, suspended in water at approximately 60°C for approximately 20 minutes, cooled to approximately 20°C and filtered. The residue 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%). 1H NMR ( _CDCl3 , 400 MHz): δ 10.34 (s, 1H), 7.95 (s, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 2.45 (s, 3H).

Preparation 192: 5-bromo-4-fluoro-2-methoxyphenol

ΛΑ

HC/^Er

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 DXM (20 ml). The solution was stirred for approximately 16 hours at approximately 20°C. The mixture was washed with water (3x200 ml) and NaOH (1N). DXM

- 95 045319 the layer was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 5bromo-4-fluoro-2-methoxyphenol (6.0 g, 77%). 1H 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).

Preparation 193: 2-ethoxy-1,5-difluoro-3-methoxybenzene

T T

F

To a mixture of 2-ethoxy-3,5-difluorophenol (6.0 g, 34.45 mmol) and iodomethane (receiving 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 was heated to approximately 60°C and stirred for approximately 5 hours. The mixture was cooled to approximately 20°C, filtered and concentrated. The residue was dissolved in EtOAc (200 ml). The EtOAc layer was washed with water (80 ml), brine (50 ml), dried over MgSO ₄ , filtered and concentrated to give 2-ethoxy-1,5-difluoro-3-methoxybenzene (5.0 g, 77%), which was used in the preparation of 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).

Preparation 194: 2-ethoxy-3,5-difluorophenol

HO^^^F

F

To a mixture of 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (receiving 195, 13.0 g, 45.76 mmol) in THF (100 ml) was added H ₂ O ₂ (30%, 7.78 g, 68.6 mmol) and aqueous NaOH (1M, 48.0 ml, 48.0 mmol) at approximately 0°C. The mixture was allowed to warm to approximately 25°C for approximately 2 hours. The mixture was acidified with 1N. HCl to pH 5. Saturated brine (100 ml) was added and the mixture was extracted with EtOAc (2x200 ml). The combined EtOAc extracts were dried over NaSO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 2-ethoxy-3,5-difluorophenol (6.0 g, 75%). ^1H NMR ( _CDCl3 , 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 (kv, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).

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

Combined mixture of 1-bromo-2-ethoxy-3,5-difluorobenzene (preparation 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 1,4dioxane (200 ml) were degassed, heated and stirred at approximately 80°C for approximately 24 hours in an N ₂ atmosphere. The suspension was filtered and the filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 70:30) to give 2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5- tetramethyl-1,3,2dioxaborolane (13.0 g, 99%). 1H NMR (CDCl ₃ , 400 MHz): δ 7.14-7.17 (m, 1H), 6.90-6.95 (m, 1H), 4.06 (kv, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.37 (s, 12H). LC-MS m/z=285 [MH] ⁺ .

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

K ₂ CO ₃ (13, 2 g, 95.7 mmol). The mixture was heated to approximately 60°C and stirred for approximately 16 hours. The mixture was cooled to approximately 20°C, filtered and the filtrate was concentrated. The residue was 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 was used in the preparation of 195. 1H 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 197: 4-bromo-1,2-diethoxybenzene

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4-Bromo-1,2-diethoxybenzene (6.3 g, 97%) was prepared in a similar manner to 172 using 4-bromobenzene-1,2-diol (5.0 g, 26 mmol). 1H 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 198: 4-bromo-1-ethoxy-2-methoxybenzene

4-Bromo-1-ethoxy-2-methoxybenzene (5.1 g, 98%) was prepared in a similar manner to 172 using 4-bromo-2-methoxyphenol (4.57 g, 22.5 mmol). 1H 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 (kv, J=6.9 Hz, 2H), 3.86 (s, 3H), 1.46 (t, J=6.9 Hz, 3H). LC-MS m/z=231 [MH] ⁺ .

Preparation 199: 1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene

1-Bromo-4-ethoxy-2-fluoro-3-methoxybenzene was prepared as a yellow oil (6.3 g, 99%) in a similar manner to preparation 172 using 3-bromo-6-ethoxy-2-fluorophenol (preparation 200 , 6 g, 25.5 mmol) and iodomethane (10.9 g, 76.6 mmol). 1H 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 200: 3-bromo-6-ethoxy-2-fluorophenol

Into a solution of 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (preparation 201, 15.2 g, 44.1 mmol) in THF (150 ml) was added with H ₂ O ₂ (30%, 7.49 g, 66.1 mmol) and aqueous NaOH (1M, 46.3 ml, 46.3 mmol) at approximately 0°C. The mixture was allowed to warm to approximately 25°C for approximately 1.5 hours. The mixture was acidified with 1N. HCl to pH 5. Saturated brine (150 ml) was added and the mixture was extracted with EtOAc (2x200 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%). ^1H NMR ( _CDCl3 , 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).

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

A solution of LDA (37.7 mL, 75.3 mmol, 2 M in THF) at approximately -78°C. The solution was stirred at approximately -78°C for approximately 1 hour and PinBO-Pr (14.0 g, 75.3 mmol) was added dropwise. After stirring at approximately -78°C for approximately 2 hours, the solution was quenched with aqueous NH ₄ Cl (1 M, 100 ml) and extracted with MTBE (3x300 ml). The combined MTBE extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5tetramethyl-1,3 ,2-dioxaborolane (15.2 g, 88%). 1H NMR (CDCl3, 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).

Preparation 202: 1-bromo-4-ethoxy-2-fluorobenzene

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1-Bromo-4-ethoxy-2-fluorobenzene (11 g, 96%) was prepared in a similar manner to 172 using 4-bromo-2-methoxyphenol (10 g, 52 mmol). 1H 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 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) 4-bromo-2-methoxybenzenamine (50 g, 247.46 mmol) was slowly added. The mixture was stirred at approximately 70°C for approximately 3 hours. The reaction mixture was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give (4-bromo-2-methoxyphenyl)(methyl)sulfane (50 g, 87%). Ή

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). LC-MS m/z=233.0 [MH] ⁺ .

Preparation 204: (4-bromo-2-ethoxyphenyl)(methyl)sulfane

(4-Bromo-2-ethoxyphenyl)(methyl)sulfane (35.0 g, 83%) was prepared in a similar manner to Preparation 172 using 5-bromo-2-(methylthio)phenol (Preparation 20, 16 g, 73 mmol) . 1H 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 (kv, J=7.1 Hz, 2H), 2.41 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

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

(4-Bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane (6.0 g, 92%) was prepared in a similar manner to 153 using 5-bromo-2-(methylthio)phenol (5 g, 22.8 mmol) and cyclopentanol (2.36 g, 27.4 mmol). ^1H NMR ( _CDCl3 , 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 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 approximately -78°C was added BBg ₃ (179 ml, 179 mmol, 1M in DCM) drop by drop in an N2 atmosphere. The reaction mixture was allowed to warm to approximately 20°C and stirred for approximately 2 hours. The mixture was quenched with MeOH at approximately 0°C and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 70:30) to give 5-bromo-2-(methylthio)phenol (16.3 g, 91%). 1H 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 (w s, 1H), 2.32 (s, 3H).

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

A mixture of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehydoxime (preparation 208, 7 g, 22.3 mmol), TPOA (7.16 g, 33.45 mmol) and Et ₃ N (6.76 g, 66.9 mmol) in DCM (100 ml) was stirred at approximately 20°C for approximately 16 hours. Water (200 ml) was added to the mixture and extracted with DCM (2x200 ml). The combined DCM extracts were washed with brine (200 ml), dried and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile (1.6 g, 24%). 1H NMR ( _CDCl3 , 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).

Preparation 208: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehydoxime

To a solution of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (preparation 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 approximately 20°C for approximately 2 hours. The reaction mixture was concentrated to give 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehydoxime (7 g), which was used in Preparation 207.

Preparation 209: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde

6-Bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (6.8 g, 90%) was prepared in a similar manner to Preparation 172 using 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Preparation 165, 6 g, 30 mmol ) and bromocyclopentane (4.26 g, 28.6 mmol) at approximately 60°C for approximately 3 hours. 1H NMR (CDCl3, 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). LC-MS m/z=323 [M+Na] ⁺ .

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

1-Bromo-2,4-dimethoxy-3-propoxybenzene (10 g, 85%) was prepared in a manner similar to Preparation 172 using 3-bromo-2,6-dimethoxyphenol (Preparation 211, 10 g, 43 mmol) and 1- iodopropane (14.6 g, 86 mmol). ^1H NMR (CDCl3, 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). LC-MS m/z=276 [MH] ⁺ .

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

To a stirred solution of 2,6-dimethoxyphenol (1 g, 6.5 mmol) in CCl ₄ (35 ml) at approximately -10° C., Br ₂ (1.04 g, 6.5 mmol) was added and stirred for approximately 2 h. The reaction mixture was diluted with CCl ₄ (20 ml), washed with water (3x60 ml) and the CCl ₄ layer was washed with saturated saline, dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 80:20) to give 3-bromo-2,6-dimethoxyphenol (1.46 g, 97%). ^1H NMR ( _CDCl3 , 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 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 approximately 15°C for approximately 6 hours. 1H 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). LC-MS m/z=293 [MH] ⁺ .

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

Sodium propan-1-olate (21.8 g, 265 mmol) was added to 2-bromo-6-iodopyridin-3-ol (yielding 214, 26.5 g, 88.4 mmol) in DMF (200 ml) and reaction the mixture was stirred for approximately 16 hours at approximately 110°C under N2 atmosphere. After cooling to approximately 20°C, the reaction mixture was partitioned between brine (200 ml) and EtOAc (250 ml). The aqueous layer was extracted with EtOAc (200 ml). The combined EtOAc extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 80:20) to give 6-iodo-2-propoxypyridin-3-ol (11.2 g, 45%). ^1H NMR (CDCl3, 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 214: 2-bromo-6-iodopyridin-3-ol

NSH^

Βγ'ΧΙ'ί

To a solution of 2-bromo-3-hydroxypyridine (20.0 g, 114.95 mmol) in water (250 ml) was added K2CO3 (31.8 g, 230 mmol) and l ₂ (29.2 g, 115 mmol). The mixture was stirred at approximately 20°C for approximately 5 hours. The mixture was cooled to 0°C and treated with concentrated HCl. The precipitate was filtered to obtain 2-bromo-6-iodopyridin-3-ol (30 g, 87%). 1H NMR (DMSO-d ₆ , 400 MHz): δ 11.10 (w s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H). LC-MS m/z=299 [MH] ⁺ .

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

To a solution of 2-methoxy-3-propoxypyridine (yield 216, 5.68 g, 34 mmol) dissolved in DCM (60 ml) was added HOAc (2.04 g, 34 mmol). NBS (6.35 g, 35.7 mmol) was added to the mixture in portions with stirring. The mixture was stirred at approximately 12°C for approximately 16 hours. The mixture was concentrated. The residue was diluted with water (200 ml) and extracted with EtOAc (2x100 ml). The combined EtOAc extracts were dried and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum 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 was cooled to approximately -10°C overnight. The precipitate that formed was separated from the oil by centrifugation (3x5 min @ 3000 rpm) to give 5-bromo-2-methoxy-3-propoxypyridine (3 g, 53%). 1H 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 216: 2-methoxy-3-propoxypyridine

2-Methoxy-3-propoxypyridine (5.7 g, 85%) was prepared in a manner similar to preparation 172 using 2-methoxypyridin-3-ol (5 g, 40 mmol) and 1-iodopropane (13.6 g, 80 mmol ). 1H 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 217: 2-bromo-5-methoxy-4-propoxypyridine

To a solution of 2-bromo-4-iodo-5-methoxypyridine (preparation 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 approximately 20°C. The mixture was heated to approximately 60°C for approximately 1 hour. The solution was quenched with aqueous NH ₄ Cl (1 M, 30 ml) and extracted with EtOAc (3x100 ml). The combined EtOAc extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 89:11) to give 2-bromo-5-methoxy-4-propoxypyridine (2 g, 64%). 1H NMR (CDCl3, 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). LC-MS m/z=247.8 [MH] ⁺ .

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

Sodium hydride (1.27 g, 31.8 mmol, 60%) was suspended in MeOH (2.55 g, 79.5 mmol) and DMF (80 ml) at approximately 25°C. The mixture was added to a solution of 2-bromo-5-fluoro-4-iodopyridine (yield 219.8 g, 26.50 mmol) in DMF (10 ml) at approximately 0°C. The mixture was stirred at approximately 0°C for approximately 1 hour. The solution was quenched with aqueous NH ₄ Cl (1M, 60 ml) and extracted with MBTE (3x200 ml). The combined MTBE extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 2-bromo4-iodo-5-methoxypyridine (4 g, 48.1%). ^1H NMR ( _CDCl3 , 400 MHz): δ 7.88 (s, 1H), 7.85 (s, 1H), 3.97 (s, 3H).

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

ΙΊΠ

A solution of 2-bromo-5-fluoropyridine (24.6 g, 140 mmol) in THF (300 ml) was cooled to approximately -78°C. LDA (2M in THF, 90.9 mL, 182 mmol) was added dropwise and the mixture was stirred for approximately 20 minutes. A solution of iodine (49.7 g, 196 mmol) in THF (100 ml) was added dropwise to the mixture. The reaction mixture was heated to approximately 0°C and stirred for approximately 30 minutes. The reaction was quenched with 10% aq. Na ₂ S ₂ O ₃ solution and extracted with EtOAc (3x500 ml). The combined EtOAc extracts were washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1) to give 2-bromo-5-fluoro-4-iodopyridine (50 g, 67% purity). The substance was further purified using preparative HPLC (Column: Phenomenex Synergi Max-RP 150 mm x 50 mm, 10 μ; Mobile phase: [water (0.225% HCO ₂ H)-ACN]; B%: 3060%, 25 min. Flow rate 120 ml/min.) to obtain 2-bromo-5-fluoro-4-iodopyridine (16.8 g, 40%). 1H NMR (CDCl ₃ , 400 MHz): δ 8.15 (s, 1H), 7.92 (s, 1H). LC-MS m/z=303 [MH] ⁺ .

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

To a solution of 5-fluoro-3-methoxy-2-propoxypyridine (preparation 221, 2.80 g, 15.1 mmol) in EtOH (50 ml) was added Ag ₂ SO ₄ (7.07 g, 22.7 mmol) and I2 (5.76 g, 22.7 mmol). The reaction mixture was stirred at approximately 10°C for approximately 16 hours. The mixture and solution were partitioned between EtOAc (3x100 ml) and water (100 ml). EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine (4.38 g, 93%). 1H 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 [MN] ⁺ .

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

Mixture of tBuXPhos-Pd-G3 (CAS 14447963-75-8, 443 mg, 0.557 mmol), PrOH (803 mg, 13.4 mmol), 2chloro-5-fluoro-3-methoxypyridine (receipt 222, 1800 mg, 11 .14 mmol) and Cs2CO3 (7260 mg, 22.3 mmol) were dissolved in PrOH (40 ml) under N2 atmosphere. The mixture was heated at approximately 90°C for approximately 16 hours. The mixture was dried and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 5-fluoro-3-methoxy-2-propoxypyridine (1280 mg, 77%). 1H 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). LC-MS m/z=185 [MH] ⁺ .

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

2-Chloro-5-fluoro-3-methoxypyridine (1.8 g, 72%) was prepared in a manner similar to preparation 153 using 2-chloro-5-fluoropyridin-3-ol (2.3 g, 16 mmol) and methanol (5 g, 156 mmol). 1H NMR (CDCl ₃ , 400

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MHz): δ 7.89 (d, J=2.70 Hz, 1H), 7.00 (dd, J=2.5, 9.1 Hz, 1H), 3.93 (s, 3H). Preparation 223: 4-bromo-1-(difluoromethoxy)-2-propoxybenzene

Powdered KOH (1.34 g, 23.8 mmol) was added to a stirred solution of 4-bromo-2propoxyphenol (yield 224, 5.5 g, 23.8 mmol) in NMP (150 mL) at approximately 15°C under N2 atmosphere . The mixture was heated at approximately 50°C for approximately 45 minutes, then cooled to approximately 15°C. Difluorochloromethane was bubbled through the reaction mixture (approximately 20 minutes) until saturation and the mixture was stirred for an additional 20 minutes. Potassium hydroxide (2.68 g in 3 ml water) was added dropwise, maintaining the temperature below 33°C. The mixture was stirred for an additional 40 minutes. Additional potassium hydroxide (1.34 g, in 3 ml water) was added dropwise and the mixture was stirred for 1 hour. N2 was bubbled through the reaction mixture and water was added. The pH of the resulting mixture was adjusted to 8 by adding potassium hydroxide (aq) and the mixture was extracted using MTBE (2x100 ml). The combined MBTE extracts were washed with water (50 ml), brine (3x100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 4-bromo-1(difluoromethoxy)-2-propoxybenzene (4.8 g, 72%). 1H 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).

Preparation 224: 4-bromo-2-propoxyphenol

NaOH (4200 mg, 105 mmol) was added to a solution of 4-bromo-2-propoxyphenyl formate (yield 225, 10.9 g, 42 mmol) in MeOH (75 mL) and water (75 mL). The mixture was stirred at approximately 10°C for approximately 1 hour. The mixture was allowed to stand overnight. The mixture was acidified with HCl (1N) to pH 3. The mixture was concentrated and filtered. The filtered cake was washed with water (20 ml). The cake was dissolved in MTBE (200 ml) and EtOAc (50 ml). The combined MTBE and EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 75:25) to give 4-bromo-2-propoxyphenol (6.11 g, 63%). ^1H NMR ( _CDCl3 , 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).

Preparation 225: 4-bromo-2-propoxyphenyl formate

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

Preparation 226: 4-bromo-2-propoxybenzaldehyde

4-Bromo-2-propoxybenzaldehyde (11.5 g, 95%) was prepared in a manner similar to preparation 172 using 4-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol) and 1-iodopropane (11 g, 65 mmol). 1H NMR (CDCl3, 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).

Preparation 227: ((2-bromolyl)oxy)(tert-butyl)dimethylsilane

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Five reactions were carried out in parallel. To a solution of 2-bromoprop-2-en-1-ol (preparation 60, 150 g, 1.10 mol) and imidazole (preparation 228, 74.6 g, 0.985 mol) in DMF (900 ml) TBS-Cl was added in portions (140 g, 0.93 mol) at approximately 30°C. The mixture was then stirred at approximately 35°C for 1 hour. The mixture was poured into water (5.0 L). The combined mixtures were extracted with MTBE (3x2.5 L). The organic layer was washed with brine (2.0 L), dried over Na ₂ SO ₄ and concentrated to give ((2-bromolyl)oxy)(tert-butyl)dimethylsilane (1250 g, 92%). 1H 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 228: 2-bromoprop-2-en-1-ol

Five reactions were carried out in parallel. To a solution of 2,3-dibromoprop-1-ene (300 g, 1.50 mol) in DMF (900 ml) KOAc (221 g, 2.25 mol) was added portionwise with stirring at approximately 20°C. The mixture was stirred at approximately 20°C for approximately 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 approximately 20 °C. The mixture was stirred at approximately 20°C for approximately 1 hour. The mixture was concentrated and poured into ice water (2.0 L). The mixture was extracted with EtOAc (3x1.5 L). 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%). 1H NMR ( _CDCl3 , 400 MHz): δ 5.87-6.02 (m, 1H), 5.45-5.62 (m, 1H), 4.17 (s, 2H), 3.70 ( w s, 1H).

Preparation 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 approximately 18°C for approximately 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2x200 ml). The combined EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether to give ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (16.0 g, 91%). 1H 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).

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

TBS- Cl (3.24 g, 22.4 mol) at approximately 0°C. The mixture was stirred at approximately 0°C for approximately 2 hours. The mixture was poured into ice water (50 ml) and extracted with EtOAc (3x50 ml). The combined EtOAc extracts were washed with brine (2x30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 90:10) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6dichloropyrimidine (3.1 g , 54%). 1H NMR ( _CDCl3 , 400 MHz): δ 7.48-7.57 (m, 1H), 4.72-4.82 (m, 2H), 0.931.03 (m, 9H), 0.14 ( s, 6H). LC-MS m/z=293 [MH] ⁺ .

Preparation 231: 2,6-dichloropyrimidin-4-yl)methanol

2,6-Dichloropyrimidine-4-carbonyl chloride (preparation 232, 10 g, 47.3 mmol) was dissolved in a mixture of MeCN (60 ml) and THF (70 ml). The mixture was cooled to approximately -78°C and treated dropwise with a solution of NaBH ₄ (3.58 g, 94.6 mmol) in DMF (30 ml). The mixture was stirred at approximately -78°C for approximately 2 hours and diluted with aqueous HCl solution (1M, 10 ml). The mixture was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (2x100 ml). The combined EtOAc extracts were dried over MgSO ₄ , filtered and concentrated to give 2,6-dichloropyrimidin-4-yl)methanol (8

- 103 045319 g, 95%), which was used in the preparation of 230. 1H NMR (CDCl ₃ , 400 MHz): δ 7.51 (s, 1H), 4.78 (s, 2H).

Preparation 232: 2,6-dichloropyrimidine-4-carbonyl chloride

ABOUT

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) was heated to reflux (120°C) for approximately 16 hours. The resulting mixture was concentrated and distilled under reduced pressure (120°C, 10 mm Hg) to give 2,6-dichloropyrimidine-4-carbonyl chloride (21 g, 31%), which was used in obtaining 231.

Preparation 233: 4-methoxy-3-propoxybenzimidamide

Ethyl 4-methoxy-3-propoxybenzimidate (preparation 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 approximately 28°C for approximately 24 hours. After concentration, MTBE (150 ml) was poured into the residue, stirred for 1 hour and filtered and concentrated to give 4-methoxy-3-propoxybenzimidamide (33.8 g, 100%). 1H 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). LC-MS m/z=209 [MH] ⁺ .

Preparation 234: Ethyl 4-methoxy-3-propoxybenzimidate °Ί

Acetyl chloride (69.0 g, 879 mmol) was added dropwise to a solution of 4-methoxy-3-propoxybenzonitrile (yield 235, 21.0 g, 110 mmol) in dry EtOH (60.7 g, 1320 mmol), stirred at ca. 30°C for approximately 12 hours. The mixture was concentrated and MTBE (150 ml) was added to the residue. The mixture was stirred for approximately 1 hour and filtered to obtain ethyl 4methoxy-3-propoxybenzimidate (26.1 g, 100%). 1H NMR (CDCl ₃ , 400 MHz): δ 12.28 (w s, 1H), 11.56 (w s, 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 (kv, 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). LC-MS m/z=238 [MH] ⁺ .

Preparation 235: 4-methoxy-3-propoxybenzonitrile

4-Methoxy-3-propoxybenzonitrile (32.10 g, 100%) was prepared in a similar manner to 172 using 3-hydroxy-4-methoxybenzonitrile (25 g, 170 mmol) and 1-iodopropane (57 g, 335 mmol). 1H 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, 3N). LC-MS m/z=191 [MH] ⁺ .

Preparation 236: 3-((tert-butyldimethylsilyl)oxy)propan-1-ol ι γ

Propane-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 ) was suspended in DCM (300 ml). The mixture was stirred at approximately 18°C overnight. The reaction mixture was partitioned between DCM (3x300 ml) and water (300 ml). The combined DCM extracts were concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (100:0 to 97:3) to give 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (50 g, 100%) , which was used in obtaining 158.

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Preparation 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) was heated to approximately 70°C. Bromine (1.4 mL, 27.5 mmol) was added dropwise over 30 min. The solution was stirred at approximately 70°C for approximately 19 hours. The solution was cooled with EtOAc (50 ml) and hexanes (50 ml) were added. The precipitate was filtered off and washed with heptane (2x50 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 directly 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 approximately 20°C for approximately 22 hours. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The aqueous layers were extracted with EtOAc. The combined EtOAc extracts were washed with brine (20 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with heptane/EtOAc (90:10 to 70:30) to give 1-(6bromopyridin-2-yl)-2-hydroxyethan-1-one (977 mg), which used in the preparation of 88. 1H 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) was further purified using preparative SFC (prev. SFC Method A) to give 4-(5(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (233 mg, 46%). 1H NMR (DMSO-th 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), 1.281.34 (m, 1H), 1.12-1.18 (m, 1H). LC-MS m/z=300 [MN] ⁺ ; RT [Analytical SFC 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 using preparative SFC (teacher SFC method B). The solids were recrystallized with EtOAc (442 mg in 2 ml) to give 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1 (253 mg, 11 %) in the form of a crystalline solid. 1H NMR (DMSO- _d6 , 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). LC-MS m/z=314 [MH] ⁺ ; RT [Analytical SFC method B]=6.59 min. [a] 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

Additional elution of the preparative SFC column (prev. SFC method B), described in example 2, provided enantiomer 2, which was recrystallized with EtOAc to give (R) 4-(5-(3ethoxy-4-methoxyphenyl)pyridin-3-yl) -1,2-oxaborolan-2-ol (610 mg, 27%) as a crystalline solid. 1H NMR (DMSO- _d6 , 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). LC-MS m/z=314 [MH] ⁺ ; RT [Analytical SFC method B]=7.07 min. [a] ²⁰ D -22.5 (c=0.2, EtOH).

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

Method A.

Into a mixture of (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronic acid (receiving 6.55 g, 120 mmol ) in IPA (247 ml) was added 5M hydrochloride in IPA (37 ml, 185 mmol) at approximately 20°C. The mixture was stirred for approximately 3 hours and concentrated. The residue was diluted with EtOAc (500 ml) and 1N was added. HCl (500 ml). The layers were separated and the EtOAc layer was extracted with 0.5 N. HCl (2x200 ml). The aqueous extracts were combined with the separated acidic aqueous layer and washed with EtOAc (3x250 ml). The combined acidic aqueous layers were treated with K ₃ PO ₄ to pH 5-6. The mixture was extracted with EtOAc (1x500 ml, 2x200 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-ola (34.5 g, 88%), which was further purified using preparative SFC (prev. SFC method C) to give 29 g as crude product. The crude product was dissolved in methanol (250 ml) and water (50 ml) and stirred at 20°C for approximately 30 minutes. before concentration. The concentrated solution was partitioned between brine and EtOAc. The aqueous layer was separated and extracted with EtOAc. The EtOAc extracts were combined with the 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 was added until no precipitate was observed and the resulting mixture was stirred overnight under N2. The solid was filtered to obtain 8.08 g of product. The filtrate was concentrated and the residue was dissolved in EtOAc (50 ml). Heptane (25 ml) was added slowly and the mixture was stirred overnight open to air. The solid was filtered to obtain a second batch (6.16 g). This was repeated twice to obtain 3.0 g. The filtrate was stirred overnight to obtain additional batches (2.09 g and 3.1 g), respectively. Batches of solids were combined to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (22.3 g, 57%) in form of a crystalline solid. ^1H NMR (DMSO-d6, 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). LC-MS m/z=328 [MH] ⁺ ; RT [Analytical SFC method B]=7.30 min. [a] ²⁰ D -23.7 (c=0.9, EtOH). Elemental analysis: calculated (%) for C18H ₂₂ BNO ₄ : C 66.08, H 6.78, N 4.28. found: C 65.86, H6.59, N4.18.

Method B.

Step 1: 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4methoxy-3-propoxyphenyl)pyridine was added to THF (18.0 ml) (preparation 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) ferocenyl]-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 approximately 50°C for approximately 5 minutes. Catecholborane (10.9 mL, 1.0 M in THF) was added to the mixture and stirred at approximately 50°C for approximately 1 hour. The mixture was cooled to approximately 20°C and treated with HCl (12.2 M, 1.51 mL) for 1 minute. The mixture was kept at approximately 20°C for approximately 1 hour, after which a precipitate formed. The mixture was cooled to approximately 10°C and filtered. The filtered solid was washed with THF (6.0 ml) and dried overnight at 35°C in vacuo to give (R)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2 -oxaborolan-2-ol hydrochloride monohydrate (3.98 g, 91%) as a crystalline solid. 1H NMR (CD3OD, 400 MHz): δ 8.98 (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 (w s, 1H), 1.85 (m, 2H), 1.31-1.42 (m , 2H), 1.08 (t, J=7.4 Hz, 3H). LC-MS m/z=328 [MH] ⁺ .

Step 2: Into 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) was added 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 was stirred at approximately 20°C for approximately 5 minutes. The layers were separated and the aqueous layer was extracted with EtOAc (2x10 ml). The combined EtOAc extracts were concentrated. The residue was dissolved in THF/MTBE (1:3, 22 ml) and stirred at approximately 20°C overnight. The precipitate was filtered and dried in vacuo to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)1,2-oxaborolan-2-ol (1.17 g, 68%) in the form of a crystalline solid. 1H NMR (DMSO-d ₆ , 400

- 106 045319

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), 7.237.26 (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). LC-MS m/z=328 [MH] ⁺ .

Method C.

Into a solution of (R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)propyl)boronic acid (preparation 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 approximately 1.5 hours. The mixture was concentrated. The mixture was diluted with 1M HCl and extracted with EtOAc (3x100 ml). The combined EtOAc extracts were washed with 1 M HCl (3x50 ml). The combined aqueous extracts were neutralized with K ₃ PO ₄ to pH 7-8 and extracted with EtOAc (3x100 ml). The combined EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-4-(5-(4-methoxy-3-npropoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2ol (19, 0 g, 92%), which was further purified using preparative SFC (prev. SFC method C) to obtain 18 g of crude product. The crude product was dissolved in MeOH (100 ml) and water (50 ml). The mixture was partitioned between brine and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc.

The combined EtOAc extracts were washed with brine, dried over 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 approximately 3 hours. The mixture was stirred at approximately 20°C overnight. The precipitate was filtered and dried to obtain (8.08 g). This process was repeated 2 or more times to obtain additional batches (2.01 g and 1.03 g), respectively. Three batches were combined in heptane (100 ml), cooled to approximately -78°C over approximately 10 minutes, filtered and dried to give (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3- yl)-1,2oxaborolan-2-ol (10.4 g, 51%) as a crystalline solid. ^1H NMR (DMSO- _d6 , 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), 7.237.26 (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). LC-MS m/z=328 [MH] ⁺ .

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

Mixture of 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (receipt 50.3ο g, 73 mmol), [ Ir(COD)Cl] ₂ (CaS 12112-67-3, 1.22 g, 1.81 mmol), (R,R)-[2-(4'-ipropyloxazolin-2-yl)ferocenyl]diphenylphosphine (CAS 541540-70-9, 1.75 g, 3.63 mmol) and THF (240 ml) were cooled in an ice bath for approximately 30 minutes. A solution of catecholborane (109 ml, 109 mmol, 1.0 M in THF) was added slowly over approximately 20 minutes, after which the mixture was stirred at approximately 20°C for approximately 3 hours. The reaction was quenched with MeOH (30 ml). The mixture was concentrated and dried overnight. The residue was treated with 3M aqueous HCl/THF (1:1, v/v) for approximately 2 hours and washed with EtOAc. The aqueous layer was separated and neutralized to pH 7-8 and extracted with EtOAc. The EtOAc extract was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in THF/MTBE (1:1, 180 ml) and stirred with Biotage MP-TMT resin (28 g, Biotage P/N 801470) at approximately 20° C., under N ₂ atmosphere, overnight. The mixture was filtered and the resin was washed with THF (2x50 ml). The combined THF/MTBE filtrates were concentrated to give (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (23.5 g, 71% ), which was further purified using SFC purification (prev. SFC method C) to obtain 12 g of crude product. The crude product was dissolved in MeOH (35 ml) and water (15 ml). The mixture was partitioned between brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in EtOAc (30 ml) and heptane was added until cloudiness appeared. The mixture was stirred overnight. The precipitate was filtered and dried to give (S)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (5.39 g, 45%) as crystalline solid matter. 1H NMR (DMSO^, 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). LC-MS m/z=328 [MH] ⁺ ; RT [Analytical SFC method B]=6.35 min. [a] 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

- 107 045319

4-(5-(3-Isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 35, 90 mg, 0.28 mmol) was further purified using preparative SFC (prep SFC method D) followed by preparative HPLC (Method A) to obtain 4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 ( 17 mg, 19%). ^1H NMR (DMSO-66, 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). LC-MS m/z=328 [MH] ⁺ . RT [Analytical SFC method C]=5.425 min.

Example 7: 4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(3-Cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 36, 5.0 g, 4.54 mmol) was further purified using preparative SFC (prev. SFC method E) to give 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (205 mg, 41%). ^1H NMR (DMSO-b 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). LC-MS m/z=326 [MH] ⁺ . RT [Analytical SFC 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 using preparative SFC (prev. SFC method F) to obtain 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (261 mg, 27%). ^1H NMR (DMSO-d6, 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), 4.254.30 (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). LC-MS m/z=348 [MH+H ₂ O] ⁺ ; RT [Analytical SFC method D]=3.357 min. [α]2% -25.9 (c=0.1, EtOH).

Example 9: (-) 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(3-(3-Hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 38, 1.2 g, 7.28 mmol) was further purified using preparative SFC (prep. SFC method G) to obtain 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (639 mg, 35%). ^1H NMR (DMSO-dg, 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). LC-MS m/z=344 [MH] ⁺ ; RT [Analytical SFC method F]=1.060 min. [a] ²⁰ D -19.5 (c=0.02, EtOH).

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

- 108 045319

4-(5-(2-(Difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 41, 800 mg, 2.20 mmol) was further purified using preparative SFC (prev. SFC method H) to obtain 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (308 mg, 39%). The material was recrystallized with EtOAc/heptane (1:1, v/v) to obtain a crystalline solid. ^1H NMR (DMSO-d6, 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). LC-MS m/z=364 [MH] ⁺ ; RT [Analytical SFC method E]=3.640 min. [a] ²³ D-27.5 (c=0.2, EtOH).

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

Additional elution of the preparative SFC column (prev. SFC method H), described in example 10, provided 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2- Oxaborolan-2ol, enantiomer 2 (259 mg, 32%). ^1H NMR (DMSO-06, 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). LC-MS m/z=364 [MH] ⁺ ; RT [Analytical SFC method E]=4.050 min. [a] 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 using preparative SFC (prep. SFC method I) to obtain 4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (18 mg, 30%). ^1H NMR (DMSO- _d6 , 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). LC-MS m/z=350 [MH+H ₂ O]+; RT [Analytical SFC method D]=4.282 min.

Example 13: 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol enantiomer 1

4-(5-(3-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 45, 150 mg, 0.43 mmol) was further purified using preparative SFC (prep. SFC method J) to obtain 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (411 .3 mg, 37%). ^1H NMR (DMSO-Y6, 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). LC-MS m/z=348 [MH] ⁺ ; RT [Analytical SFC method D]=4.932 min.

Example 14: 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

- 109 045319

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 using preparative SFC (prev. SFC Method K) to obtain 4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (122 mg, 32%). ^1H NMR (DMSO-d6, 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 (kv, 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). LC-MS m/z=332 [MH] ⁺ ; RT [Analytical SFC method D]=4.111 min.

Example 15: (-) 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(2-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 47, 1.6 g, 4.60 mmol) was further purified using preparative SFC (prep. SFC method L) to obtain 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (550 mg, 34%). 1H NMR (DMSO-06, 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=7.0 Hz, 2H), 3.81-3.85 (m, 4H), 3.47-3.55 (m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H ). LC-MS m/z=348 [MH] ⁺ ; RT [Analytical SFC method G]=4.089 min. [a] ²⁰ D18.0 (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

OH U

II J *4 o N

4-(3-Fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol (Example 48, 770 mg, 2.22 mmol ) were further purified using preparative SFC (prep. SFC method M) to obtain 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2- Oxaborolan-2-ol, enantiomer 1 (298 mg, 39%). 1H NMR (DMSO-b 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), 1.731.81 (m, 2H), 1.31-1.37 (m, 1H), 1.03-1 .09 (m, 1H), 0.98 (t, J=7.5 Hz, 3H). LC-MS m/z=347 [MH] ⁺ ; RT [Analytical SFC method D]=4.347 min. [a] 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 using preparative SFC (prev. SFC method N) to obtain 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1 (165 mg, 33% ). 1H NMR (DMSO-b ₆ , 400 MHz): δ 8.74 (d, J=2.1 Hz, 1H), 8.72 (s, 1H), 8.49 (d, J=2.0 Hz , 1H), 8.00 (t, J=2.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.28-7.31 (m, 2H), 7 .09 (t, J=74.5 Hz, 1H), 4.28 (t, J=8.3 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.87 (t, J=9.1 Hz, 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=7.5 Hz, 3H). LC-MS m/z=381 [MH+H ₂ O] ⁺ ; RT [Analytical SFC method E]=3.402 min. [a] 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 using preparative SFC (prep. SFC method O) to obtain 4-(6'-methoxy-5'-propoxy-[3,3'-bipyridin]-5-yl)-1,2-oxaborolan-2- ol, enantiomer 1 (411 mg, 37%).

- 110 045319 ¹ H NMR (DMSO-66, 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). LC-MS m/z=347 [MH+H ₂ O] ⁺ ; RT [Analytical SFC method G]=4.231 min. [a] ²⁰ _D -27.2 (c=0.1,

EtOH).

Example 19: (R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylniridin-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 with using preparative SFC (prev. SFC method P) to obtain 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1, ( 66 mg, 36%). The material was recrystallized with EtOAc/heptane to give a crystalline solid. ^1H NMR (DMSO-b6, 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). LC-MS m/z=328 [MH] ⁺ ; RT [Analytical SFC method H]=1.768 min. [a] ²⁰ D-20.0 (c=0.4, EtOH).

Example 20: (S)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylniridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

Additional elution of the preparative SFC column (prev. SFC method P) described in example 19 provided 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol , enantiomer 2, (69 mg, 40%). ^1H NMR (DMSO-66, 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). LC-MS m/z=328 [MH] ⁺ ; RT [Analytical SFC method H]=2.168 min.

Example 21: 4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-Ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 53, 45 mg, 0.14 mmol) was further purified using a preparative SFC (prev. SFC 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%). ^1H NMR (DMSO-^, 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 (kv, 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). LC-MS m/z=328 [MH] ⁺ ; RT [Analytical SFC method I]=5.208 min.

Example 22: (-) 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(2-(4-Methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol (Example 54, 2.5 g, 7.28 mmol) was further purified with using preparative SFC (prev. SFC method Q) to obtain 4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (68 mg, 22%). ^1H NMR (CD3OD, 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 (w s, 1H), 4.07 (t, J=6.5 Hz, 2H), 4, 00 (w s, 1H), 3.91 (s, 2H), 3.41 (w s,

- 111 045319

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). LC-MS m/z=343 [MH] ⁺ ; RT [Analytical SFC method J]=3.148 min. [a] 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) was further purified using preparative SFC (prev. SFC method M) to obtain 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2 (100 mg, 18%). 1H NMR (DMSO-th 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). LC-MS m/z=397 [MH] ⁺ ; RT [Analytical SFC method E]=4.765 min. [a] 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 using preparative SFC (prep SFC Method R) to give 4-(6(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol, enantiomer 2 (6.4 mg, 34%). LC-MS m/z=315 [MH] ⁺ . RT [Analytical SFC method K]=3.23 min.

Example 25: 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol

A mixture of 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)prop-1-en-2-yl)- 5-(4-methoxy-3-propoxyphenyl)pyridine (preparation 8, 1.30 g, 2.41 mmol) in AcOH (10 ml) and water (5 ml) was stirred at approximately 50°C for approximately 1 hour. The mixture was concentrated and EtOH (10 ml) was added. The mixture was stirred at approximately 0°C for approximately 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 %). 1H NMR (DMSO-th 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). LC-MS 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 31, 140 mg, 0.25 mmol) was dissolved in AcOH (4.3 ml) and water (0.2 ml) and stirred at approximately 20°C for approximately 16 hours. The mixture concentrated and the residue was purified using preparative HPLC (prev. HPLC method B) to give 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol (60 mg , 70%). 1H NMR (DMSO-th 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=8.6 Hz, 1H), 4.02 (t, J=6.6 Hz, 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=7.0 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). LC-MS m/z=342 [MH] ⁺ .

Example 27: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol

- 112 045319

Mixture of 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol (Example 28, 50 mg, 0.15 mmol ) and Adam's catalyst (10.0 mg, 0.044 mmol) in EtOAc (1.5 ml) were hydrogenated at 20 psi at approximately 40°C for approximately 2 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated . The residue was purified using 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 )pyridin-2-yl)-3-methyl1,2-oxaborolan-2-ol (40 mg, 80%). 1H NMR ( _CDCl3 , 400 MHz): δ 7.73 (w s, 1H), 7.51-7.66 (m, 4H), 6.927.00 (m, 2H), 4.36 (d, J =3.1 Hz, 2H), 4.12 (t, J=6.8 Hz, 2H), 3.92 (s, 3H), 3.56 (w s, 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 ). LC-MS 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%) was prepared in a manner similar to Example 25, using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5 -(4-methoxy-3-propoxyphenyl)pyridine (receipt 32, 370 mg, 0.668 mmol). 1H NMR (DMSO-66, 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). LC-MS m/z=340 [MH] ⁺ .

Example 29: 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol

Into a solution of ethyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) )propanoate (preparation 33, 134 mg, 0.277 mmol) in THF (3.0 ml) at approximately 20°C was added LiBH ₄ (6.0 mg, 0.28 mmol), followed by the addition of water (0.10 ml) . The reaction mixture was stirred at approximately 20°C for approximately 3 hours. Another portion of LiBH ₄ (25 mg, 1.15 mmol) and water (0.2 ml) was added. The mixture was stirred at approximately 20°C for approximately 5 minutes. Another portion of LiBH ₄ (25 mg, 1.15 mmol) and water (0.3 ml) was added and stirred at approximately 20° C. for approximately 10 minutes. The mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered, concentrated and dissolved in THF (3 ml) and water (1 ml). The solution was treated with excess LiBH ₄ at approximately 20°C for approximately 3 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified using preparative HPLC (prev. HPLC method C) to give 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl1,2-oxaborolan-2-ol (46, 1 mg, 49%). 1H NMR (CD3OD, 500 MHz): δ 7.80 (w s, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H ), 7.62 (m, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 5.51 (s, 1H ), 4.29 (d, J=8.8 Hz, 1H), 4.07 - 4.16 (m, 3H), 3.92 (s, 3H), 3.47 (m, 1H), 3 .19 (m, 1H), 1.88 (m, 2H), 1.55 (d, J=16.1 Hz, 1H), 1.51 (s, 3H), 1.20 (d, J= 15.7 Hz, 1H), 1.10 (t, J=7.3 Hz, 3H). LC-MS 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 34, 160 mg, 0.29 mmol) in AcOH (6 ml) and water (1 ml) was stirred at approximately 70°C for approximately 21 hours. The mixture was concentrated, dissolved in MeCN (15 ml) and concentrated again. The mixture was purified using preparative HPLC (prev. HPLC method D) to give 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin4-yl)-5-methyl-1,2-oxaborolan-2-ol (10, 6 mg, 11%). 1H NMR (DMSO-66, 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

- 113 045319 (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). LC-MS m/z=343 [MH] ⁺ .

Example 31: 4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2ol

Turbo Grignard (0.5 mL, 1.3 M in THF) was stirred with anhydrous 1,4-dioxane (0.05 mL) at approximately 20° C. under N ₂ for approximately 30 minutes. to obtain a mixture that was used directly in the next procedure (reagent A). Into a solution of 3-(5-(iodomethyl)-2,2dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine (receipt 77, 120 mg, 0.25 mmol) Reagent A was added to THF (0.50 mL) under N2. The mixture was stirred at approximately 20°C for approximately 1 hour. Trimethyl borate (0.33 mL, 2.98 mmol) was added and stirred at approximately 20°C under atmosphere. N2 for approximately 1 hour. The cooled mixture was treated with HCl in IPA (5.5 M, 0.45 ml, 2.48 mmol) for approximately 1 hour. The mixture was diluted with 1 M HCl and washed with EtOAc. The EtOAc layer was extracted with 1M HCl (2x5 ml). The combined aqueous extracts were neutralized to pH 6-7 K ₃ PO ₄ . The aqueous extract was extracted with EtOAc (3x10 ml). The combined EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using preparative SFC (prev. SFC method S) to obtain 4-(hydroxymethyl)-4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ( 38 mg, 43%). 1H NMR (DMSO- _d6 , 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=8.6 Hz, 1H), 4.99 (m, 1H) , 4.39 (d, J=9.0 Hz, 1H), 4.00-4.13 (m, 4H), 3.82 (s, 3H), 3.47 (w s, 2H), 1 .77 (m, 2H), 1.28-1.38 (m, 1H), 1.14-1.22 (m, 1H), 0.96-1.08 (m, 3H). LC-MS 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 1, 1.0 g, 1.95 mmol) in AcOH (15 ml), THF (5 ml) and water (5 ml) was stirred at approximately 55°C for approximately 6 h. The mixture was concentrated and the residue was purified using preparative HPLC (prev. HPLC method E) to obtain 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (98 mg, 17%). 1H NMR (DMSOd 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). LC-MS m/z=300 [MH] ⁺ .

Example 3 3: 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 3, 3.80 g, 7.20 mmol) in AcOH (60 ml) and water (10 ml) was stirred at approximately 50°C for approximately 1 hour. The mixture was concentrated and the residue was purified using preparative HPLC (prev. HPLC method F) to give 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (810 mg, 34%). 1H NMR (DMSO- _d6 , 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). LC-MS m/z=314 [MH] ⁺ .

Example 34: 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

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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 5, 3.44 g, 6.35 mmol) in AcOH (60 ml) and water (10 ml) was stirred at approximately 50°C for approximately 1 hour. The mixture was concentrated and the residue was purified using preparative HPLC (prev. HPLC method d) to give 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.04 g, 49%). 1H NMR (DMSO-dg, 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). LC-MS 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 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 (receipt 9, 400 mg, 0.74 mmol) and purified using preparative HPLC (rep. HPLC method H). 1H NMR (DMSO-d6, 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). LC-MS 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 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 (receipt 10, 750 mg, 1.39 mmol) and purified using preparative HPLC (rep. HPLC method I). 1H NMR (DMSO-d ₆₄₀₀ 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). LC-MS m/z=326 [MH] ⁺ .

Example 37: 4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-Hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.5 g, 75%) was prepared in a manner similar to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-( 2-((tert-butyldimethylsilyl)oxy)ethoxy)-4methoxyphenyl)pyridine (preparation 11, 4.0 g, 6.1 mmol) and purified using preparative HPLC (prev. HPLC method J). ^1H NMR (DMSO- _d6 , 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). LC-MS m/z=330 [MH] ⁺ .

Example 38: 4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(3-Hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (2.5 g, 41%) was prepared in a manner similar to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-( 3-((tert-butyldimethylsilyl)oxy)propoxy)-4methoxyphenyl)pyridine (preparation 12, 12 g, 18.0 mmol) and purified using preparative

- 115 045319

VEZHKh (teacher VEZHKh method K). 1H 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). LC-MS m/z=344 [MH] ⁺ .

Example 3 9: 4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-Fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (122 mg, 29%) was prepared in a manner similar to Example 33 using 3- (1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2- fluoroethoxy)-4-methoxyphenyl)pyridine (receipt 13, 700 mg, 1.28 mmol) and purified using preparative HPLC (rep. HPLC method L). 1H 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), 7.307.37 (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). LC-MS m/z=332 [MH] ⁺ .

Example 40: 4-(3'-(3-fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(3'-(3-Fluoropropoxy)-4'-methoxy-[1,1'-biphenyl]-3-yl)-1,2-oxaborolan-2-ol was prepared in a manner similar to 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 (preparation 14). 1H NMR (DMSO-d ₆ , 400 MHz): δ 7.50 (w 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). LC-MS 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 was prepared (80 mg, 42%) in a manner similar to Example 33. using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2- (difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine (receipt 15, 300 mg, 0.519 mmol) and purified using preparative HPLC (rep. HPLC method M). 1H NMR (DMSO-d6, 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). LC-MS m/z=364 [MH] ⁺ .

Example 42: 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile

Into a solution of 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2carbonitrile (example 43, 500 mg, 1.43 mmol) in EtOAc (15 ml) was added PtO ₂ (16 mg, 72 μmol) under N ₂ atmosphere. The mixture was stirred under H ₂ (15 psi) at approximately 0° C. for approximately 2 hours. The mixture was filtered and concentrated. The residue was purified using preparative HPLC (prev. HPLC method N) to give 3'-(2-hydroxy-1,2-oxaborolan-4-yl)-4methoxy-3-propoxy-[1,1'-biphenyl]-2 -carbonitrile (284 mg, 55%). 1H 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 (kv, J=8.0 Hz, 1H). 1.07-1.11 (m, 1H), 1.01 (t, J=7.6 Hz, 3H). LC-MS m/z=352 [MH] ⁺ .

Example 43: 3'-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2carbonitrile

- 116 045319

Into a mixture of methyl 2-(2'-cyano-4'-methoxy-3'-propoxy-[1,1'-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl1,3 ,2-dioxaborolan-2-yl)acrylate (receipt 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 approximately 0°C. The mixture was stirred at approximately 20°C for approximately 1 hour. Water (150 ml) was added and the mixture was extracted with EtOAc (2x150 ml). The combined EtOAc extracts were washed with brine (150 ml), dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified using column chromatography (silica) and eluted with petroleum ether/EtOAc (10:1), then recrystallized with EtOH (30 ml) at approximately 0°C to give 3'-(2-hydroxy-2,5-dihydro -1,2oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1'-biphenyl]-2-carbonitrile (2.60 g, 26%). 1H NMR (DMSO- _d6 , 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). LC-MS 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 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 (receipt 16, 600 mg, 1.1 mmol) and purified using preparative HPLC (rep. HPLC method O). 1H NMR (DMSO- _d6 , 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), 3.453.56 (m, 2H), 1.39 ( t, J=6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LC-MS m/z=332 [MH] ⁺ .

Example 45: 4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (150 mg, 30%) was prepared in a manner similar to Example 33 using 3- (1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-chloro -5-ethoxy-4-methoxyphenyl)pyridine (receipt 17, 800 mg, 1.42 mmol) and purified using preparative HPLC (rep. HPLC method P). 1H NMR (DMSO- _d6 , 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), 3.443.57 (m, 1H), 1.39 ( t, J=6.9 Hz, 3H), 1.26-1.34 (m, 1H), 1.12-1.22 (m, 1H). LC-MS 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 Example 33 using 3- (1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(5-ethoxy-2 -fluoro-4-methoxyphenyl)pyridine (preparation 18, 2.0 g, 3.67 mmol) and purified using preparative HPLC (rep. HPLC method Q). ^1H NMR (DMSO-66, 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 (kv, 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). LC-MS m/z=332 [MH] ⁺ .

Example 47: 4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

- 117 045319

4-(5-(2-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (1.6 g, 65%) was prepared in a manner similar to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-chloro -5-ethoxy-4-methoxyphenyl)pyridine (preparation 19, 4.1 g, 7.30 mmol) and purified using preparative HPLC (rep. HPLC method R). 1H NMR (DMSO-Y6, 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=7.0 Hz, 2H), 3.81-3.85 (m, 4H), 3.47-3.55 (m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H ). LC-MS m/z=348 [MH] ⁺ .

Example 48: 4-(3-fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol

4-(3-Fluoro-5-methoxy-6-propoxy-[2,3'-bipyridin]-5'-yl)-1,2-oxaborolan-2-ol (780 mg, 49%) was prepared in a manner similar to example 33 using 5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3- fluoro-5-methoxy-6-propoxy-2,3'-bipyridine (preparation 22, 4.02 g, 7.14 mmol) and purified using preparative HPLC (rep. HPLC method S). ^1H NMR (DMSO-b 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). LC-MS 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%) was prepared in a manner similar to Example 33 using 3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-fluoro -4-methoxy-5-propoxyphenyl)pyridine (yield 20, 4.0 g, 7.1 mmol) and purified using preparative HPLC (rep. HPLC method T). 1H NMR (DMSO-Y6, 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). LC-MS m/z=347 [MH] ⁺ .

Example 50: 4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(4-(Difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (0.51 g, 31%) was prepared in a manner similar to Example 33 using 3- (1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-(difluoromethoxy) -3-propoxyphenyl)pyridine (preparation 21, 2.6 g, 4.50 mmol) and purified using preparative HPLC (rep. HPLC method U). ^1H NMR (DMSO-th ₆ , 400 MHz): δ 8.74 (d, J=2.1 Hz, 1H), 8.72 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.09 (t, J=74.5 Hz, 1H), 4.28 (t, J=8.3 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H), 3, 87 (t, J=9.1 Hz, 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=7.5 Hz, 3H). LC-MS 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 was prepared (720 mg, 25%)

- 118 045319 in a manner similar to example 33, using 5'-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan- 2-yl)-6-methoxy-5-propoxy-3,3'-bipyridine (preparation 23, 1.034 g, 1.9 mmol) and purified using preparative HPLC (prev. HPLC method V). 1H NMR (DMSO-a 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). LC-MS m/z=329 [MH] ⁺ .

Example 52: 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-Ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (182 mg, 43%) was prepared in a manner similar to Example 33 using 5-( 1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-(3-ethoxy-4- methoxyphenyl)-2-methylpyridine (yield 24, 700 mg, 1.29 mmol) and purified using preparative HPLC (rep. HPLC method W). 1H NMR (DMSO-d6, 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). LC-MS 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 Example 33 using 3 -(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy- 4-methoxyphenyl)-4-methylpyridine (preparation 35, 0.28 g, 0.51 mmol) and purified using preparative HPLC (rep. HPLC method X). ^1H NMR (DMSO-b 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 (kv, J=7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s, 3H), 3.633.71 (m, 1H), 2.22 ( s, 3H), 1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H). LC-MS 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 prepared in a manner similar to 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)pyrimidin4-yl)acetate (yield 28, 500 mg, 0.96 mmol) and purified using preparative HPLC (rep. HPLC method Y). 1H NMR (CD3OD, 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 (w s, 1H), 4.07 (t, J=6.5 Hz, 2H), 4.00 (w s, 1H), 3.91 (s, 2H), 3.41 (w s, 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). LC-MS m/z=343 [MH] ⁺ .

Example 55: 4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan2-ol

4-(2-(4-Methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol (582 mg, 36%) was prepared in a manner similar to Example 33 using 4-(1-((tert-butyldimethylsilyl)oxy)3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4- methoxy-3-propoxyphenyl)-6-(tri- 119 045319 fluoromethyl)pyrimidine (preparation 25, 2.5 g, 4.09 mmol) and purified using preparative

VEZHKH (prev. VEZHKH method Z). 1H 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 [MN] ⁺ .

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 Example 33 using 2-(1-( (tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine (receipt 26, 720 mg, 1.36 mmol) and purified using preparative HPLC (rep. HPLC method AA). 1H NMR (DMSO-Y6, 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). LC-MS 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 prepared in a similar manner Example 33 using 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 (preparation 29, 1.0 g, 1.5 mmol) and purified using preparative HPLC (rep. HPLC method BA ). 1H NMR (DMSO- _d6 , 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). LC-MS 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 Example 33 using 4-(1 -((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl) )thiazole (preparation 36, 1.42 g, 2.66 mmol) and purified using preparative HPLC (rep. HPLC method CA). 1H NMR (DMSO- _d6 , 400 MHz): δ 8.66 (w s, 1H), 7.42-7.46 (m, 2H), 7.30 (s, 1H), 7.05 (d , J=8.3 Hz, 1H), 4.24-4.28 (m, 1H), 4.09 (kV, J=7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.82 (s, 3H), 3.55-3.63 (m, 1H), 1.36 (t, J=7.0 Hz, 3H), 1.25-1.31 (m , 1H), 1.11-1.18 (m, 1H). LC-MS 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

(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol was added to hexylene glycol (1.0 g, 8.46 mmol) (Example 4, 0.051 g, 0.16 mmol) at approximately 20°C. The mixture was stirred until it became homogeneous to give (2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3yl)-3-(4,4,6-trimethyl-1,3,2- dioxaborinan-2-yl)propan-1-ol (5 wt.% solution in hexylene glycol) as a mixture of diastereomers (ratio 1:1). 1H NMR (DMSO-d ₆ , 400 MHz): δ 8.64 (d, J=2.2 Hz, 1H),

- 120 045319

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). LC-MS m/z=428

[MN] ⁺ .

The following compounds, Examples 60-223, were prepared in a similar manner using the methods described above. Examples containing an asterisk (*) indicate the single enantiomer obtained by chiral purification. HPLC analytical methods are described for these examples, characterized by HPLC retention time (RT).

Example

Analytical data s, 1H), 7.46 (d, J= 7.8 Hz, 1H), 7.35 (t, J

J= 8.2 Hz, 1Н, 4.81-4.83 m, 1Н, 4.691Н, 7.70-7.75 m, ЗН, 7.62 dd, J = 2.0, oxaborolan-2-ol s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.57-7.66

7.3, 8.78 Hz, 1Н, 3.94-4.03 m, ЗН, 3.80 ol, enantiomer 1 ol, enantiomer 2

I] = 4.57 min.

I] = 4.98 min.

Structure and Name

4-(5-methoxy-6-propoxy-[2,3 bipyridin]-5-yl)-1,2-oxaborolan-24-(5-methoxy-6-propoxy-[2,3 bipyridin]-5-yl )-1,2-oxaborolane-24-(5-methoxy-6-propoxy-[2,3 bipyridin]-5-yl)-1,2-oxaborolane-24-(3-(2-fluoroethoxy)-4 - methoxy-[1,1 biphenyl 1-3-yl)-1,2-oxaborolan-2-ol

4-(4-(hydroxymethyl)-6-(4-methoxy-3 propoxyphenyl)pyridin-2-yl)-1.2H NMR (DMSO-Ob 400 MHz: δ 9.04 d, = 2.0 Hz, 1H , 8.71 s, 1H, 8.45 d, 4 =

2.0 Hz, 1H, 8.22 t, 4 = 2.2 Hz, 1H, 7.61 d, 4 = 7.8 Hz, 1H, 7.37 d, 4 = 8.3 Hz,

1Н, 4.36 t, 4 = 6.6 Hz, 2Н, 4.26-4.32 m, 1Н, 3.80-3.88 m, 4Н, 3.45-3.58 m,

1Н, 1.75-1.84 m, 2Н, 1.33 dd, 4 = 8.3,

16.1 Hz, 1H, 1.06-1.17 m, 1H, 1.00 t, = 7.3 Hz, ZN. LC-MS m/z = 329

H NMR (DMSO-R ₆₄₀₀ MHz): b 9.04 (d, = 2.0 Hz, 1H, 8.71 s, 1H, 8.45 d, 4 =

2.0 Hz, 1H, 8.22 t, 4 = 2.2 Hz, 1H, 7.61 d, 4 = 7.8 Hz, 1H, 7.37 d, 4 = 8.3 Hz,

1Н, 4.36 t, 4 = 6.6 Hz, 2Н, 4.26-4.32 m, 1Н, 3.80-3.88 m, 4Н, 3.45-3.58 m,

1Н, 1.75-1.84 m, 2Н, 1.33 dd, 4 = 8.3,

16.1 Hz, 1H, 1.06-1.17 m, 1H, 1.00 t, = 7.3 Hz, ZN). LC-MS m/z = 329

[MNG. RT [Analytical SFC Method

H NMR (DMSO-sU ₆₄₀₀ MHz): δ 9.04 (d, = 2.0 Hz, 1H, 8.71 s, 1H, 8.45 d, 4 =

2.0 Hz, 1H, 8.22 t, 4 = 2.2 Hz, 1H, 7.61 d, 4 = 7.8 Hz, 1H, 7.37 d, 4 = 8.3 Hz,

1Н, 4.36 t, 4 = 6.6 Hz, 2Н, 4.26-4.32 m, 1Н, 3.80-3.88 m, 4Н, 3.45-3.58 m,

1Н, 1.75-1.84 m, 2Н, 1.33 dd, 4 = 8.3,

16.1 Hz, 1H, 1.06-1.17 m, 1H, 1.00 t, = 7.3 Hz, ZN). LC-MS m/z = 329

[MN] ⁺ . RT [Analytical SFC Method

H NMR DMSO-sub, 400 MHz: δ 7.51 w = 7.8 Hz, 1H, 7.18-7.23 m, ZN, 7.06 d,

4.71 m, 1Н, 4.36-4.38 m, 1Н, 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). LC-MS m/z = 331 [MNG

H NMR DMSO-su ₆ , 400 MHz: δ 8.59 sh m, 2H, 7.11 s, 1H, 7.00-7.06 m, 1H,

5.41 (w s, 1H), 4.56 (s, 2H), 4.28 (dd, J =

S, ZN, 3.52-3.62 m, 1N, 1.70-1.82 m,

2H), 1.13-1.30 (m, 2H), 1.00 (t, J= 7.5

Hz, ZN). LC-MS m/z = 376 [MH+H ₂ O] ⁺

H NMR DMSO-su ₆ , 400 MHz: δ 8.59 s,

8.3 Hz, 1H), 7.10-7.20 (m, 1H), 7.03 (d, J

- 121 045319

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(5-(4-methoxy-3-(thiethan-3yloxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1 = 8.6 Hz, 1H), 4.90 (t, J = 5.9 Hz, 1H), 4.29 (t, J = 8.2 Hz, 1H), 3.99 (dd, 7 = 7.0, 8.9 Hz, 1H), 3.79 (s, ZN), 3.56-3.63 (m, 1H), 1.87-2.04 (m, 2H), 1.68-1.81 (m, 4H), 1.59 (w s, 2H ), 1.16-1.30 (m, 2H). LC-MS m/z = 372 [MH+H ₂ O] ⁺ .

LC-MS m/z = 354 [MH] ⁺ . RT [Analytical SFC Method V] = 3.60 min.

LC-MS m/z = 354 [M+H] ⁺ . RT [Analytical SFC Method V] = 3.93 min.

^1H NMR (DMSO-< ₇₆ , 400MHz): δ 8.72 (s, 1H), 8.70 (d, 7 = 2.0 Hz, 1H), 8.42 (d, 7 = 2.0 Hz, 1H), 7.92 (t, 7 = 2.0 Hz, 1H), 7.31 (dd, 7 = 2.3, 8.3 Hz, 1H), 7.22 (d, 7 = 2 .5 Hz, 1H), 7.09 (d, 7 = 8.5 Hz, 1H), 5.445.53 (m, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 3, 86 (t, 7 = 9.0 Hz, 1H), 3.81 (s, ZN), 3.47 (dd, 7 = 3.8, 7.8 Hz, 5H), 1.31 (dd, 7 = 8.3, 16.3 Hz, 1H), 1.11 1.19 (m, 1H). LC-MS m/z = 358 [MH] ⁺ .

^1H NMR (MeOD- _d3 , 400 MHz): δ 8.40 (d, 7 = 2.0 Hz, 1H), 8.31 (d, 7 = 2.5 Hz, 1H), 7.69 ( t, 7 = 2.0 Hz, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 4.06 (kv, 7 = 6.9 Hz, 2H), 3.83- 3.90 (m, 4H), 3.33-3.40 (m, 1H), 2.21 (s, ZN), 1.39 (t, 7 = 6.9 Hz, ZN), 1.16 -1.33 (m, 2H) LC-MS m/z = 328 [MH] ⁺ .

¹ H NMR (DMSO-7 ₆ , 400 MHz): δ 8.69 (w s, 1H), 8.31-8.49 (m, 2H), 7.66 (w s, 1H), 6.91 ( w s, 1H), 6.81 (w s, 1H), 4.27 (w s, 1H), 4.01 (d, 7 = 5.9 Hz, 2H), 3.73-3.90 ( m, 4N), 3.49 (w s, 1H), 2.18 (w s, ZN), 1.30 (w s, ZN), 0.99-1.16 (m, 2H). LCMS m/z = 346 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method L] = 2.67 min.

- 122 045319

4-(5-(5-ethoxy-4-methoxy-2methylphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

,ΟΗ

4-(5-(3-ethoxy-4-methoxyphenyl)1,2,4-thiadiazol-3-yl)-1,2oxaborolan-2-ol

4-(5-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(3'-isopropoxy-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

Ή NMR (DMSO-s/b, 400 MHz): δ 8.69 (w s, 1H), 8.31-8.49 (m, 2H), 7.66 (w s, 1H), 6.91 ( w s, 1H), 6.81 (w s, 1H), 4.27 (w s, 1H), 4.01 (d, J = 5.9 Hz, 2H), 3.73-3.90 ( m, 4N), 3.49 (w s, 1H), 2.18 (w s, ZN), 1.30 (w s, ZN), 0.99-1.16 (m, 2H). LCMS m/z = 327 [MN] ⁺ . RT [Analytical SFC Method L] = 2.91 min.

Ή NMR (DMSO-s/ 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, ZN), 3.85 (s, ZN), 3.76-3.83 (m, 1H), 1.231.43 (m, 5H). LC-MS m/z = 321.1 [MH] ⁺ .

Ή NMR (DMSO-s/b, 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 (kv, 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). LC-MS m/z = 332 [MH] ⁺ .

Ή NMR (DMSO-sHb, 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 (kv, 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). LC-MS m/z = 332 [MH] ⁺ . RT [Analytical SFC Method GA] = 6.58 min.

Ή NMR (DMSO-s/b, 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, ZN), 7.00-7.06 (m, 1H), 4.61-4.71 (m, 1H), 4.22-4.29 (m, 1H), 3.77-3.85 (m, ZN), 3.37-3.53 (m, 1H), 1.22-1.31 (m, 7H), 0.99-1 ,12 (m, ZN). LC-MS m/z = 327 [MH] ⁺ .

Ή NMR (DMSO-s/ ₆ , 400 MHz): δ 8.71 (s, 1 Η), 8.00 (dd, J = 2.0, 8.0 Hz, 1 Η), 7.96 (d, J= 2.0 Hz, 1 Η), 7.52 (s, 1 Η), 7.277.31 (m, 1Η), 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), 3.964.04 (m , 2H), 3.83 (s, ZN), 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, ZN). LC-MS m/z = 359 [MH] ⁺ . [a] ² % - 123 045319

3-propoxyphenyl)pyrimidin-4-yl)1,2-oxaborolan-2-ol, enantiomer 1

4-(3'-ethoxy-4'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(5-(4-methoxy-3((tetrahydr rotiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(4-methoxy-3((tetrahyde rotiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, diastereomer 1

4-(5-(4-methoxy-3((tetrahydr rotiophen-3yl)oxy)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, diastereomer 2

10.0 (c = 0.1, EtOH).

Ή NMR (DMCO-cfe, 400 MHz): δ 8.65 (s, 1H), 7.50 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.34 (t , 7 = 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, 7 = 8.1 Hz, 1H), 4.26 (t, 7 = 8.3 Hz, 1H), 4.10 (kv, 7 = 6.9 Hz, 2H), 3.77-3.84 (m, 4H), 3.42-3.49 (m, 1H), 1.35 (t, 7 = 7.0 Hz, ZN), 1.28 (dd, 7 = 8.2, 16.3 Hz, 1H), 1.08 (dd, 7= 10.0, 16.4 Hz, 1H). LC-MS m/z = 313 [MH] ⁺ . ^1H NMR (DMSO-s( ₆ , 400MHz): δ 8.73 (s, 1H), 8.70 (d, 7 = 2.0 Hz, 1H), 8.43 (d, 7 = 2.0 Hz, 1H), 7.93 (t, 7 = 2.0 Hz, 1H), 7.36 (d, 7 = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.10 (d, 7 = 8.0 Hz, 1H), 5.30 (w s, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 3.86 (t, 7 = 9.0 Hz, 1H), 3.81 (s, ZN), 3.46-3.55 (m, 1H), 3.13 (dd, 7 = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, ZN), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, 7 = 8.3 , 16.3 Hz, 1H), 1.14 (dd, 7= 10.3, 16.3 Hz, 1H) LC-MS m/z = 372 [MH] ⁺ .___________________________ ^1H NMR (DMSO-s /b, 400 MHz): δ 8.73 (s, 1H), 8.70 (d, 7 = 2.0 Hz, 1H), 8.43 (d, 7 = 2.0 Hz, 1H), 7, 93 (t, 7 = 2.0 Hz, 1H), 7.36 (d, 7 = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.10 (d, 7 = 8.0 Hz, 1H), 5.30 (w s, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 3.86 (t, 7 = 9.0 Hz, 1H) , 3.81 (s, ZN), 3.46-3.55 (m, 1H), 3.13 (dd, 7 = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, ZN), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, 7 = 8.3, 16.3 Hz, 1H ), 1.14 (dd, 7= 10.3, 16.3 Hz, 1H). LC-MS m/z = 372.3 [MH] ⁺ . RT [Analytical SFC Method EA] = 3.30 min. _______________ ^1H NMR (DMSO-sub, 400MHz): δ 8.73 (s, 1H), 8.70 (d, 7 = 2.0 Hz, 1H), 8.43 (d, 7 = 2.0 Hz , 1H), 7.93 (t, 7 = 2.0 Hz, 1H), 7.36 (d, 7 = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7 .10 (d, 7 = 8.0 Hz, 1H), 5.30 (w s, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 3.86 (t, 7 = 9 ,0 Hz, 1H), 3.81 (s, ZN), 3.46-3.55 (m, 1H), 3.13 (dd, 7 = 4.8, 11.8 Hz, 1H), 2 .85-3.00 (m, ZN), 2.27-2.34 (m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, 7 = 8.3, 16.3 Hz, 1H), 1.14 (dd, 7 = 10.3, 16.3 Hz, 1H). LC-MS m/z = 372.1 [MH] ⁺ . RT [Analytical SFC Method EA] = 4.18 min._______________ ¹ H NMR (DMSO-sub, 400 MHz): δ 8.71 (s, 1H), 8.54 (t, 7 = 2.0 Hz, 1H) , 8.48 (d, 7 = 2.0 Hz, 1H), 7.82 (d, 7 = 1.5 Hz, 1H), 7.26 (t, 7 = 8.7 Hz, 1H), 7 .01 (dd, 7 = 1.5, 8.8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, 7 =

- 124 045319

4-(5-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(6-(1-hydroxyethyl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, diastereomer 1

4-(5-(4-methoxy-3-propoxyphenyl)-4methylpyridin-3-yl)-1,2oxaborolan-2-ol

(+) 4-(5-(4-methoxy-3propoxyphenyl)-4-methylpyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1

6.6 Hz, 2H), 3.87 (s, ZN), 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, ZN). LC-MS m/z = 346 [MH] ⁺ .

Ή NMR (DMSO-s( 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, 4 = 1.5, 8, 8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.87 (s, ZH), 3.80-3, 86 (m, 1H), 3.44-3.57 (m, 1H), 1.63-1.72 (m, 2H), 1.31 (dd, 4 = 8.2, 16.3 Hz, 1H), 1.10 (dd, 4 = 10.3, 16.1 Hz, 1H), 0.98 (t, 4 = 7.3 Hz, ZN). LC-MS m/z = 372 [MH] ⁺ .RT [Analytical SFC Method E] = 4.76 min.___________________________ ¹ H NMR (DMSO-s( ₆ , 400 MHz): δ 8.68 (s, 1H), 8.00 (dd, 4 = 2.0 , 8.3 Hz, 1H), 7.97 (d, 4 = 2.0 Hz, 1H), 7.32 (s, 1H), 7.07 (d, 4 = 8.3 Hz, 1H), 5.57 (d, 4 = 4.9 Hz, 1H), 4.65-4.75 (m, 1H), 4.30 (dd, 4 = 7.3, 9.3 Hz, 1H), 3 .96-4.03 (m, ZN), 3.83 (s, ZN), 3.61 (s, 1H), 1.71-1.83 (m, 2H), 1.43 (d, J = 6.4 Hz, ZN), 1.27 (dd, 4 = 1.5, 8.3 Hz, 1H), 1.11-1.20 (m, 1H), 1.01 (t, 4= 7.6 Hz, 3N) LC-MS m/z = 391 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method E] = 4.07 min.

^1H NMR (DMSO-sub, 400MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.90 (d, 4 = 2.0 Hz, 1H), 6.84 (dd, 4 = 2.0, 8.3 Hz, 1H), 4.26 (dd, J = 7 ,3, 8.8 Hz, 1H), 3.89-3.97 (m, ZN), 3.80 (s, ZN), 3.67 (t, 4 = 8.1 Hz, 1H), 2 .21 (s, ZN), 1.68-1.77 (m, 2H), 1.33 (dd, 4 = 8.3, 16.1 Hz, 1H), 1.08 (dd, 4 = 8 ,6, 16.4 Hz, 1H), 0.97 (t, 4 = 7.3 Hz, ZN). LC-MS m/z = 342 [MH] ⁺ ._____________ ^1H NMR (DMSO-sub, 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, 4 = 2.0 Hz, 1H), 6.84 (dd, 4 = 2.0, 8.3 Hz, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 3.89-3.97 (m, ZN), 3.80 (s, ZN), 3.67 (t, 4 = 8.1 Hz, 1H), 2.21 (s, ZN), 1.68-1.77 (m, 2H), 1.33 (dd, 4 = 8.3, 16.1 Hz, 1H), 1.08 (dd, 4 = 8.6, 16.4 Hz, 1H), 0.97 (t, 4 = 7.3 Hz, ZN). LC-MS m/z = 342 [MH] ⁺ . [a] ² % +14.7 (c = 0.1, EtOH).

- 125 045319

6-(6-(2-hydroxy-1,2-oxaborolan-4yl)pyridin-2-yl)-3-methoxy-2propoxybenzonitrile

6-(6-(2-hydroxy-1,2-oxaborolan-4yl)pyridin-2-yl)-3-methoxy-2propoxybenzonitrile, enantiomer 2

4-(4'-methoxy-3'-propoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(4'-methoxy-3'-propoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2ol, enantiomer 1

4-(4'-methoxy-3'-propoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2ol, enantiomer 2

Ή NMR (DMSO-b ₆ , 400 MHz): δ 8.58 (s, 1H), 7.85 (t, 4 = 7.7 Hz, 1H), 7.60 (d, 4 = 7.8 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.447.49 (m, 1H), 7.32 (d, 4 = 7.6 Hz, 1H), 4.24-4.31 (m , 1H), 4.06-4.14 (m, ZN), 3.91 (s, ZN), 3.60-3.68 (m, 1H), 1.70-1.79 (m, 2H ), 1.20-1.37 (m, 2H), 1.02 (t, 4 = 7.5 Hz, ZN). LC-MS m/z = 353 [MH] ⁺ .

Ή NMR (DMSO-b ₆ , 400 MHz): δ 8.58 (s, 1H), 7.85 (t, 4 = 7.7 Hz, 1H), 7.60 (d, 4 = 7.8 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.447.49 (m, 1H), 7.32 (d, 4 = 7.6 Hz, 1H), 4.24-4.31 (m , 1H), 4.06-4.14 (m, ZN), 3.91 (s, ZN), 3.60-3.68 (m, 1H), 1.70-1.79 (m, 2H ), 1.20-1.37 (m, 2H), 1.02 (t, 4 = 7.5 Hz, ZN). LC-MS m/z = 353.3 [MH] ⁺ . RT [Analytical SFC Method M] = 5.79 min.

1H NMR (DMSO-< ₄₆ , 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7 .22 (m, ZN), 7.02 (d, 4= 8.0 Hz, 1H), 4.26 (t, 4= 8.0 Hz, 1H), 4.01 (t, 4 = 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, 4 = 7.6 Hz, ZN). LC-MS m/z = 327 [MH] ⁺ .

1H NMR (DMSO-< ₄₆ , 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7 .22 (m, ZN), 7.02 (d, 4= 8.0 Hz, 1H), 4.26 (t, 4= 8.0 Hz, 1H), 4.01 (t, 4 = 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, 4 = 7.6 Hz, ZN). LC-MS m/z = 327 [MH] ⁺ . RT [Analytical SFC Method N] = 3.76 min._________________________________ 1H NMR (DMSO-< ₄₆ , 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m, 1H), 7.16-7.22 (m, ZN), 7.02 (d, 4= 8.0 Hz, 1H), 4.26 (t, 4= 8.0 Hz , 1H), 4.01 (t, 4 = 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, 4 = 7.6 Hz, ZN) . LC-MS m/z = 327 [MH] ⁺ . RT [Analytical SFC Method N] = 3.97 min.

^1H NMR (DMSO-ck, 400MHz): δ 8.66 (s, 1H), 7.62 (d, 4 = 7.0 Hz, 1H), 7.41 (s, 1H), 7.05- 7.10 (m, 1H), 4.26 (dd, 4 = 7.5, 8.5 Hz, 1H), 4.05 (kv, 4 = 6.9 Hz, 2H), 3.93 (dd , 4 = 7.5, 9.0 Hz, 1H), 3.83 (s, ZN), 3.57-3.66 (m, 1H), 1.34 (t, 4 = 7.0

- 126 045319

Hz, ZN), 1.25-1.32 (m, 1H), 1.12-1.20 (m, 1H). LC-MS m/z = 338 [MH] ⁺ .

4-(2-(5-ethoxy-2-fluoro-4methoxyphenyl)thiazol-4-yl)-1,2oxaborolan-2-ol

c-one (-) 4-(2-(5-ethoxy-2-fluoro-4methoxyphenyl)thiazol-4-yl)-1,2oxaborolan-2-ol enantiomer 2

4-(3-(4-(cyclopentyloxy)-5methoxypyrimidin-2-yl)phenyl)-1,2oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxy-2(trifluoromethyl)phenyl)pyridin-3yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxy-2(trifluoromethyl)phenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1

Ή NMR (DMSO-ck, 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, ZN), 3.57-3.66 (m, 1H), 1.34 (t, J = 7.0 Hz, ZN ), 1.25-1.32 (m, 1H), 1.12-1.20 (m, 1H). LC-MS m/z = 338 [MH] ⁺ . RT [Analytical SFC Method O] = 4.13 min. [a] ² % -37.9 (c = 0.1, EtOH).

Ή NMR (DMSO-s/b, 400 MHz): δ 8.67 (w s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 8.108.15 (m, 1H), 7.39-7.45 (m, 1H), 7.347.38 (m, 1H), 5.56-5.63 (m, 1H), 4.264.32 (m, 1H), 3.89 (s, ZN), 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 [MN] ⁺ .

Ή NMR (DMSO-ck, 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, ZN), 3.723.83 (m, 1H), 3.46-3.55 (m, 1H), 1.261.37 (m, 4H), 1.00-1.13 (m, 1H). LC-MS m/z = 382 [MH] ⁺ .

Ή NMR (DMSO-s/b, 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, ZN), 3.723 .83 (m, 1H), 3.46-3.55 (m, 1H), 1.261.37 (m, 4H), 1.00-1.13 (m, 1H). LC-MS m/z = 382 [MH] ⁺ . RT [Analytical SFC Method E] = 3.14 min.

H NMR (DMSO-f;, 400 MHz): δ 8.68- 127 045319

4-(5-(3,4-diethoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol

4-(5-(3,4-diethoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(3,4-diethoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol enantiomer 1

4-(5-(3-(cyclopentyloxy)-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

8.75 (m, 2H), 8.42 (d, 4 = 1.5 Hz, 1H), 7.93 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.23 (dd, 4 = 1.8, 8.3 Hz, 1H), 7.04 (d, 4 = 8.5 Hz, 1H), 4.27 (t, 4 = 8.3 Hz, 1H ), 4.13 (kv, 4 = 6.9 Hz, 2H), 4.06 (kv, 4 = 7.0 Hz, 2H), 3.86 (t, 4 = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, 4= 10.5, 16.1 Hz, 1H). LC-MS m/z = 328 [MH] ⁺ ._______________________ ¹ H NMR (DMSO-f>, 400 MHz): b 8.688.75 (m, 2H), 8.42 (d, 4 = 1.5 Hz, 1H ), 7.93 (s, 1H), 7.27 (d, 4 = 2.0 Hz, 1H), 7.23 (dd, 4 = 1.8, 8.3 Hz, 1H), 7.04 (d, 4 = 8.5 Hz, 1H), 4.27 (t, 4 = 8.3 Hz, 1H), 4.13 (kv, 4 = 6.9 Hz, 2H), 4.06 (kv , 4 = 7.0 Hz, 2H), 3.86 (t, 4 = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, 4= 10.5, 16.1 Hz, 1H). LC-MS m/z = 345 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method D] = 5.73 min._________________________________ ¹ H NMR (DMSO-s/b, 400 MHz): b 8.688.75 (m, 2H), 8.42 (d, 4 = 1.5 Hz, 1H), 7.93 (s, 1H), 7.27 (d, 4 = 2.0 Hz, 1H), 7.23 (dd, 4 = 1.8, 8.3 Hz, 1H), 7, 04 (d, 4 = 8.5 Hz, 1H), 4.27 (t, 4 = 8.3 Hz, 1H), 4.13 (kv, 4 = 6.9 Hz, 2H), 4.06 ( kv, 4 = 7.0 Hz, 2H), 3.86 (t, 4 = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m , 7H), 1.14 (dd, 4= 10.5, 16.1 Hz, 1H). LC-MS m/z = 328 [MN] ⁺ . RT [Analytical SFC Method D] = 5.37 min.___________ ¹ H NMR (DMSO-s/b, 400 MHz): b 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, 4 = 5.5 Hz, 1H), 4.28 (t, 4 = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.493.57 (m, 1H), 2, 39 (s, ZN), 1.87-1.96 (m, 2H), 1.75 (d, 4 = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1 .32 (dd, 4 = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H). LC-MS m/z = 370 [MN] ⁺ .

Ή NMR (DMSO-s/b, 400 MHz): b 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, 4= 5.5 Hz, 1H), 4.28 (t , 4 = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.493.57 (m, 1H), 2.39 (s, ZN), 1.87-1.96 ( m, 2H), 1.75 (d, 4 = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1.32 (dd, 4 = 8.3, 16.3 Hz , 1H), 1.10-1.19 (m, 1H). LC-MS m/z = 388 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method P] = 3.83 min.________________ ¹ H NMR (DMSO-s/b, 400 MHz): b 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, 4 = 5.5 Hz, 1H), 4.28 (t, 4 = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.493.57 (m, 1H), 2, 39 (s, ZN), 1.87-1.96 (m, 2H), 1.75 (d, 4 = 4.5 Hz, 4H), 1.56-1.66 (m, 2H), 1 .32 (dd, 4 = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H). LC-MS m/z = 388 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method P] = 4.17 min.

- 128 045319

4-(2-(4-methoxy-3-propoxyphenyl)-6(methoxymethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

(-) 4-(2-(4-methoxy-3-propoxyphenyl)6-(methoxymethyl)pyrimidin-4-yl)1,2-oxaborolan-2-ol, enantiomer 2

4-(5-(4-ethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(4-ethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

Ή NMR (DMSO-cfe, 400 MHz): δ 8.69 (w s, 1H), 7.99 (dd, J = 1.9, 8.4 Hz, 1H), 7.95 (d, 7 = 1 .8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, 7 = 8.8 Hz, 1H), 4.54 (s, 2H), 4.30 (dd, 7 = 7 ,5, 8.8 Hz, 1H), 3.96-4.03 (m, ZN), 3.83 (s, ZN), 3.58-3.65 (m, 1H), 3.43 ( s, ZN), 1.73-1.81 (m, 2H), 1.24-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.96-1, 06 (m, ZN). LC-MS m/z = 391 [MH+H ₂ O] ⁺ .

Ή NMR (DMSO-cfe, 400 MHz): δ 8.69 (w s, 1H), 7.99 (dd, 7 = 1.9, 8.4 Hz, 1H), 7.95 (d, 7 = 1 .8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, 7 = 8.8 Hz, 1H), 4.54 (s, 2H), 4.30 (dd, 7 = 7 ,5, 8.8 Hz, 1H), 3.96-4.03 (m, ZN), 3.83 (s, ZN), 3.58-3.65 (m, 1H), 3.43 ( s, ZN), 1.73-1.81 (m, 2H), 1.24-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.96-1, 06 (m, ZN). LC-MS m/z = 391 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method Q] = 3.25 min. [a] ² % -38.3 (c = 0.1, EUN).

Ή NMR (DMSO-sYe, 400 MHz): δ 8.71 (s, 1H), 8.70 (d, 7 = 1.5 Hz, 1H), 8.42 (d, 7 = 1.5 Hz, 1H ), 7.93 (t, 7 = 2.0 Hz, 1H), 7.28 (d, 7 = 2.0 Hz, 1H), 7.23 (dd, 7 = 2.0, 8.0 Hz , 1H), 7.03-7.07 (m, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 4.00-4.11 (m, 4H), 3.86 ( t, 7 = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, ZN), 1.27-1.37 (m, ZN), 1.ΙΟΙ .19 (m, 1H), 1.00 (t, 7 = 7.5 Hz, ZN). LC-MS m/z = 342 [MH] ⁺ .

Ή NMR (DMSO-s( ₆ , 400 MHz): δ 8.71 (s, 1H), 8.70 (d, 7 = 1.5 Hz, 1H), 8.42 (d, 7 = 1.5 Hz , 1H), 7.93 (t, 7 = 2.0 Hz, 1H), 7.28 (d, 7 = 2.0 Hz, 1H), 7.23 (dd, 7 = 2.0, 8, 0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 4.00-4.11 (m, 4H), 3, 86 (t, 7 = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, ZN), 1.27-1.37 (m, ZN), 1 ,ΙΟΙ,19 (m, 1H), 1.00 (t, 7 = 7.5 Hz, ZN) LC-MS m/z = 342 [MH] ⁺ .RT [Analytical SFC Method R] = 3.48 min_________________________________ ^1H NMR (DMSO-sub, 400MHz): δ 8.71 (s, 1H), 8.70 (d, 7 = 1.5 Hz, 1H), 8.42 (d, 7 = 1, 5 Hz, 1H), 7.93 (t, 7 = 2.0 Hz, 1H), 7.28 (d, 7 = 2.0 Hz, 1H), 7.23 (dd, 7 = 2.0, 8.0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 4.00-4.11 (m, 4H), 3.86 (t, 7 = 9.0 Hz, 1H), 3.45-3.55 (m, 1H), 1.701.80 (m, ZN), 1.27-1.37 (m, ZN) , 1.101.19 (m, 1H), 1.00 (t, 7 = 7.5 Hz, ZN).

- 129 045319

propoxyphene yl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1 LC-MS m/z = 342 [MH] ⁺ . RT [Analytical SFC Method R] = 2.25 min. 107 OH ^x °XX ⁰ then N 4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol ¹ H NMR (DMSO, 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), 7.257.29 (m, 1H), 7.02 (d, 4= 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). LC-MS m/z = 318 [MH] ⁺ . 108 HE ° oo N 4-(5-(2-fluoro-3,4- dimethoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 1 LC-MS m/z = 332 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method S] = 5.28 min. 109 HE o o Ν 4-(5-(2-fluoro-3,4- dimethoxyphenyl)pyridin-3-yl)-1,2- oxaborolan-2-ol, enantiomer 2 LC-MS m/z =318 [MH] ⁺ . RT [Analytical SFC Method S] = 5.35 min. 110 OH g-v T X G b 4-(4'-methoxy-3'-(pentyloxy)-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol LC-MS m/z = 355 [MN] ⁺ . 111 HE OO N L II J o (-) 4-(5-(2-fluoro-4-methoxy-5- propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1 ¹ H NMR (DMSO, 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, ZN), 3.87 (s, ZN), 3.82 (t, J = 8.7 Hz , 1H), 3.50-3.56 (m, 1H), 1.751.80 (m, 2H), 1.34 (dd, J= 8.2, 16.3 Hz, 1H), 1.01- 1.12 (m, 1H), 0.98 (t, J= 7.3 Hz, ZN). LC-MS m/z = 346 [MH] ⁺ . [a] ² % -17.7 (c = 0.15, EUN). 112 HE L II I o N 4-(5-(4-(methylthio)-3- propoxyphenyl)pyridin-3-yl)-1,2- ^1H NMR (DMSO, 400MHz): 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, 4 = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.46-3.57 (m, 1H), 2.41 (s, ZN), 1.71-1.82 (m, 2H), 1.27-1 .36 oxaborolan-2-ol (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, J = 7.5 Hz, ZN). LC-MS m/z = 344 [MH] ⁺ .

- 130 045319

4-(5-(4-(methylthio)-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(5-(4-(methylthio)-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(6-(4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol

4-(2'-fluoro-4'-methoxy-3'-propoxy[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol

3'-(2-hydroxy-1,2-oxaborolan-4-yl)4,5-dimethoxy-[1,1'-biphenyl]-3carbonitrile ^1H NMR (DMSO-c( ₆ , 400MHz): 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, 2 = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3 .46-3.57 (m, 1H), 2.41 (s, ZN), 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, ZN) LC-MS m/z = 343 [MH] ⁺ .

RT = 5.23 min._______________________ ¹ H NMR (DMSO-s( ₆ , 400 MHz): δ 8.74 (d, 2 = 2.5 Hz, 1H), 8.73 (s, 1H), 8.46 (d, 2 = 2.0 Hz, 1H), 7.98 (t, 2 = 2.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.26 (d, 2= 1.5 Hz, 1H), 7.22 (d, 2 = 8.0 Hz, 1H), 4.28 (t, 2 = 8.3 Hz, 1H), 4.11 (t, 2 = 6, 3 Hz, 2H), 3.87 (t, 2 = 9.0 Hz, 1H), 3.46-3.57 (m, 1H), 2.41 (s, ZN), 1.71-1, 82 (m, 2H), 1.27-1.36 (m, 1H), 1.11-1.20 (m, 1H), 1.03 (t, 2 = 7.5 Hz, ZN).LC -MS m/z = 343 [MN] ⁺ .

RT = 5.63 min._______________________ ¹ H NMR (DMSO-sub, 400 MHz): δ 9.06 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.73 (w s, 2H), 7.08 (d, 2 = 8.8 Hz, 1H), 4.30 (t, 2 = 8.2 Hz, 1H), 3.94-4.06 (m, ZN ), 3.83 (s, ZN), 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, 2 = 7.3 Hz, ZN). LC-MS m/z = 329 [MH] ⁺ .

^1H NMR (DMSO-sub 400 MHz): δ 8.65 (s, 1H), 7.36-7.40 (m, 2H), 7.26-7.32 (m, 2H), 7.16 (t, 2= 8.4 Hz, 1H), 6.97 (d, 2 = 8.8 Hz, 1H), 4.25 (t, 2= 8.0 Hz, 1H), 3.96 (t , 2= 4.2 Hz, 2H), 3.86 (s, ZN), 3.79 (t, 2= 8.8 Hz, 1H), 3.34-3.49 (m, 1H), 1.651 .71 (m, 2H), 1.26-1.28 (m, 1H), 1.021.08 (m, 1H), 0.98 (t, 2= 8.0 Hz, ZN). LC-MS m/z = 343 [MN]'.

^1H NMR (DMSO-sub, 400MHz): δ 7.47 (d, 2 = 8.8 Hz, 1H), 7.44 (s, 1H), 7.41 (d, 2 = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, 2 = 8.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.94 (s , ZN), 3.91 (s, ZN), 3.81 (t, 2= 8.8 Hz, 1H), 1.29 (dd, 2= 8.4, 16.2 Hz, 1H), 1 .08 (dd, 2= 10.0, 16.2 Hz, 1H). LC-MS m/z = 324 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 7.47 (d, 2 = 8.8 Hz, 1H), 7.44 (s, 1H), 7.41 (d, 2 =

- 131 045319

3-ethoxy-5-(5-(2-hydroxy-1,2oxaborolan-4-yl)pyridin-3-yl)-2methoxybenzonitrile

3-ethoxy-5-(5-(2-hydroxy-1,2oxaborolan-4-yl)pyridin-3-yl)-2methoxybenzonitrile, enantiomer 1

4-(3-(6-ethoxy-5-methoxyp irid and n-2yl)phenyl)-1,2-oxaborol-2(5H)-ol

4-(3-(6-ethoxy-5-methoxyp irid and n-2yl)phenyl)-1,2-oxaborolan-2-ol

4-(3-(4,5-dimethoxypyrimidin-2yl)phenyl)-1,2-oxaborolan-2-ol

4-(3-(4,5-dimethoxypyrimidin-2yl)phenyl)-1,2-oxaborolan-2-ol, enantiomer 1

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, ZN), 3.91 (s, ZN), 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). LC-MS m/z = 339 [MH] ⁺ .

Ή NMR (DMSO-s( 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, ZN), 3.91 (s, ZN), 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) LC-MS m/z = 339.1 [MH] ⁺ RT [Analytical SFC Method T] = 4.71 min.

Ή NMR (DMSO-cfe, 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 (kV, J = 7.2 Hz, 2H), 3.83 (s, ZN ), 1.39 (t, J = 6.8 Hz, ZN). LC-MS m/z = 312 [MH] ⁺ .

Ή NMR (DMSO-s( 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 (kv, J= 7.2 Hz, 2H), 4.27 (t, J= 8.0 Hz, 1H), 3.82 (m, 4H), 3.43-3.51 (m, 1H) 1.38 (t , J= 6.8 Hz, ZN), 1.30 (kv, J= 8.0 Hz, 1H), 1.03-1.10 (m, 1H). LC-MS m/z = 314 [MH ] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 8.67 (w 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, ZN), 3.90 (s, ZN), 1.32 (br dd, J = 8.4 , 16.2 Hz, 1 Η), 1.04 (br dd, J = 9.6, 16.1 Hz, 1H). LC-MS m/z = 317 [MH] ⁺ .

RT [Analytical SFC Method U] = 1.64 min.

- 132 045319

124

(+) 4-(2-(4-methoxy-3propoxyphenyl)-6(trifluoromethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1

125

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol

126

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

127

4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

128

(-) 4-(6-(4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

129 ^1H NMR (DMSO-s( ₆ , 400MHz): δ 8.72 (s, 1H), 8.03 (dd, 7= 2.0, 8.6 Hz, 1H), 7.95 (d, 7= 2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d, 7= 8.6 Hz, 1H), 4.32 (dd, 7= 7.4, 9.0 Hz, 1H), 3.98-4.09 (m, ZN), 3.86 (s, ZN), 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, 7 = 7.4 Hz, ZH). LC-MS m/ z = 397 [MH + H ₂ O] ⁺ [α] ² % +19.4 (c = 0.1, EUN).

^1H NMR (DMSO-sub, 400MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.70-7.73 (m, 2H ), 7.05-7.10 (m, 1H), 4.92 (t, 7 = 6.1 Hz, 1H), 4.31 (dd, 7 = 7.3, 9.3 Hz, 1H) , 3.99 (dd, 7 = 6.6, 9.0 Hz, 1H), 3.81 (s, ZN), 3.64-3.72 (m, 1H), 1.94 (d, 7 = 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). LC-MS m/z = 355 [MN] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.70-7.73 (m, 2H ), 7.05-7.10 (m, 1H), 4.92 (t, 7 = 6.1 Hz, 1H), 4.31 (dd, 7 = 7.3, 9.3 Hz, 1H) , 3.99 (dd, 7 = 6.6, 9.0 Hz, 1H), 3.81 (s, ZN), 3.64-3.72 (m, 1H), 1.94 (d, 7 = 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). LC-MS m/z = 355 [MN] ⁺ . RT [Analytical SFC Method C] = 7.2 min._________________________________ ¹ H NMR (DMSO-sub, 400 MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, ZH), 7, 64 (d, 7 = 8.3 Hz, 1H), 7.16 (dd, 7 = 2.8, 5.3 Hz, 1H), 7.04 (d, 7 = 8.3 Hz, 1H), 4.29 (t, 7 = 8.1 Hz, 1H), 3.94-4.05 (m, ZN), 3.81 (s, ZN), 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, 7 = 7, 5 Hz, ZN). LC-MS m/z = 346 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, ZH), 7.64 (d, 7 = 8.3 Hz, 1H), 7.16 (dd, 7 = 2.8, 5.3 Hz, 1H), 7.04 (d, 7 = 8.3 Hz, 1H), 4.29 (t, 7 = 8.1 Hz, 1H ), 3.94-4.05 (m, ZN), 3.81 (s, ZN), 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, 7 = 7.5 Hz, ZN). LC-MS m/z = 328 [MN] ⁺ . [a] ² % -39.5 (c = 3.8, EUR).

^1H NMR (DMSO-cfe, 400MHz): δ 7.71 (s, 1H), 7.62 (d, 7= 7.2 Hz, 1H), 7.51-7.53 (m, 1H), 7.44-7.48 (m, 1H), 7.21-7.24 (m,

- 133 045319

4-(3'-(cyclopentyloxy)-4'-methoxy[1,1'-biphenyl]-3-yl)-1,2-oxaborol2(5H)-ol

4-(3'-(cyclopentyloxy)-4'-methoxy[1,1'-biphenyl]-3-yl)-1,2oxaborolan-2-ol

4-(6-(3-(cyclopentyloxy)-4methoxyphenyl)-5-fluoropyridin-2yl)-1,2-oxaborolan-2-ol

4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)-6methoxypyrimidin-4-yl)-1,2oxaborolan-2-ol

2H), 7.04 (d, J= 8.0 Hz, 1H), 6.27 (s, 1H), 4.94-4.98 (m, ZN), 3.79 (s, ZN), 1.87-1.94 (m, 2H), 1.74-1.78 (m, 4H), 1.54-1.62 (m, 2H). LC-MS m/z = 351 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): 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, ZN ), 3.42-3.51 (m, 1H), 1.88-1.92 (m, 2H), 1.73-1.76 (m, 4H), 1.58 (m, 2H), 1.29 (kv, J = 8.0 Hz, 1H), 1.05-1.11 (m, 1H). LC-MS m/z = 353 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): 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, ZN), 3.58-3.66 (m, 1H), 1.92 (d, J = 6.5 Hz, 2H), 1.68-1.80 (m, 4H), 1.59 (w s, 2H), 1.23-1.31 (m, 1H), 1.12-1.20 (m, 1H). LC-MS m/z = 344 [MH] ⁺ .

Ή NMR (DMSO-s( ₆ , 400 MHz): δ 8.66 (w 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, ZN), 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 (w s, 2H), 1.20-1.29 (m, 1H), 1.091.18 (m, 1H) LC-MS m/z = 385 [MH] ⁺ .

Ή NMR (DMSO-s( 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 (kv, J = 7.1 Hz, 2H), 3.95-4.02 (m, ZN), 3.88 (s, 2H), 3.83 (s, ZN), 3.543.62 (m, 1H), 1.73-1.81 (m, 2H), 1.251.33 (m, 1H), 1.21 (t, J = 7.1 Hz, ZN), 1.12 -1.19 (m, 1H), 1.00 (t, J = 7.3 Hz, ZN) LC-MS m/z = 433 [MH+H ₂ O] ⁺ .

- 134 045319

Oxaborolan-4-yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4yl)acetate________________________ it

OH 2-(6-(2-hydroxy-1,2-oxaborolan-4yl)-2-(4-methoxy-3propoxyphenyl)pyrimidin-4yl)acetic acid

4-(5-fluoro-6-(4-m eto xy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol one

4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1 he

4-(6-(4-methoxy-3propoxyphenyl)pyridazin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

Ή 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= 6.5 Hz, 2H), 3.96-4.02 (m, 1H), 3.90 (s, ZN), 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, ZN). LC-MS m/z = 387 [MH] ⁺ .

Ή NMR (DMSO-s^, 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, ZN), 3.82 (s, ZN), 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, ZN). LC-MS m/z = 346 [MH] ⁺ .

LC-MS m/z = 342.3 [MH] ⁺ . RT [Analytical SFC Method V] = 6.90 min.

LC-MS m/z = 342.3 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method V] = 7.90 min.

- 135 045319

He

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

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

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

4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)-4-methylpyridin-3yl)-1,2-oxaborolan-2-ol

(-) 4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)-4-methylpyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 2

LC-MS m/z = 364.4 [MH] ⁺ . RT [Rev. HPLC Method C] = 2.30 min.

^1H NMR ( _CDCI3 , 400MHz): δ 8.72-8.92 (m, 1H), 8.50 (w s, 1H), 6.95-7.01 (m, 1H), 6.86 (dd, J = 2.3, 8.2 Hz, 1H), 6.516.83 (m, 2H), 4.48 (t, J = 8.2 Hz, 1H), 4.02-4.27 ( m, 4H), 3.94 (s, ZN), 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). LC-MS m/z = 364 [MH] ⁺ . RT [Analytical SFC Method W] = 3.95 min.

^1H NMR (CDCI3, 400MHz): δ 8.72-8.92 (m, 1H), 8.50 (w s, 1H), 6.95-7.01 (m, 1H), 6.86 ( dd, J = 2.3, 8.2 Hz, 1H), 6.516.83 (m, 2H), 4.48 (t, J = 8.2 Hz, 1H), 4.02-4.27 (m , 4H), 3.94 (s, ZN), 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). LC-MS m/z = 364 [MH] ⁺ . RT [Analytical SFC Method W] = 3.95 min.

^1H NMR (CD3OD, 400MHz): δ 8.40 (s, 1H), 8.16 (s, 1H), 6.91 (d, J= 11.0 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 4.04 (kv, J = 6.9 Hz, ZN), 3.89 (s, 4H), 3.64 (w s, 1H), 2.25 (d , J = 1.0 Hz, ZN), 1.39 (t, J = 7.0 Hz, ZN), 1.16-1.34 (m, 2H). LC-MS m/z = 346 [MH] ⁺ .

^1H NMR (DMSO-s/b, 400MHz): 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 (w s, 1H), 3.82 (s, ZN), 3.64-3.72 (m, 1H), 2.14 (s, ZN), 1.27- 1.38 (m, 4H), 0.98-1.12 (m, 1H). LC-MS m/z = 346 [MH] ⁺ . [a] ²⁰ _D -8.83 (c = 0.1, EUN).

^1H NMR (DMSO-s( ₆ , 400MHz): 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 (w s, 1H), 3.82 (s, ZN),

- 136 045319

4-(5-(5-ethoxy-2-fluoro-4methoxyphenyl)-4-methylpyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 1

4-(5-(3-ethoxy-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(5-(3-propoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol

(-) 4-(5-(3-propoxyphenyl)pyridin-3yl)-1,2-oxaborolan-2-ol, enantiomer 2

HE

IN

I O

4-(5-(4-methoxy-3-propoxyphenyl)1,2,4-thiadiazol-3-yl)-1,2oxaborolan-2-ol

3.64-3.72 (m, 1H), 2.14 (s, ZN), 1.27-1.38 (m, 4H), 0.98-1.12 (m, 1H). LC-MS m/z = 346.2 [MH] ⁺ . RT [Analytical SFC Method X] = 3.52 min.

Ή NMR (DMSO-s/b, 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 (w s, 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, ZN), 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). LC-MS m/z = 329 [MH] ⁺ .

Ή NMR (DMSO-s/b, 400 MHz): δ 8.678.79 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.37 -7.46 (m, 1H), 7.24-7.33 (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, ZN). LC-MS m/z = 298 [MH] ⁺ . __________________ ^1H NMR (DMSO-s(6, 400MHz): δ 8.678.79 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7 .37-7.46 (m, 1H), 7.24-7.33 (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, ZN) LC-MS m/z = 298 [MH] ⁺ .[a] ²⁰ D-25.7 (s = 0.1, EtOH).

Ή NMR (DMSO-s/b, 400 MHz): δ 8.70 (w s, 1H), 7.56-7.64 (m, 1H), 7.47 (d, J = 2.2 Hz, 1H ), 7.12 (d, J = 8.3 Hz, 1H), 4.294.35 (m, 1H), 4.12 (dd, J = 6.7, 9.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.85 (s, ZN), 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, ZN). LC-MS m/z = 335 [MH] ⁺ .

^1H NMR (DMSO-cfe, 400MHz): δ 8.70 (w s, 1H), 7.56-7.64 (m, 1H), 7.47 (d, J = 2.2 Hz, 1H) , 7.12 (d, J= 8.3 Hz, 1H), 4.294.35 (m, 1H), 4.12 (dd, J = 6.7, 9.2 Hz, 1H), 4.01 ( t, J = 6.5 Hz, 2H), 3.85 (s, ZN), 3.81 (t, 7 = 7.7 Hz, 1H), 1.72-1.81

- 137 045319

(-) 4-(5-(4-methoxy-3-propoxyphenyl)1,2,4-thiadiazol-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(5-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(2'-fluoro-4',5'-d imethoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

2-ethoxy-6-(6-(2-hydroxy-1,2oxaborolan-4-yl)pyridin-2-yl)-3methoxybenzonitrile

4-(3-(5,6-dimethoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol

6-(5-(2-hydroxy-1,2-oxaborolan-4yl)pyridin-3-yl)-2,3dimethoxybenzonitrile (m, 2H), 1.27-1.40 (m, 2H), 1, 00 (t, J = 7.5 Hz, ZN). LC-MS m/z = 335 [MH] ⁺ . [o] ²⁰ p -10.3 (s = 0.1, EUN)._____________ ¹ H NMR (DMSO-<7 ₆ , 400 MHz): δ 8.658.74 (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, ZN), 3.413.59 (m, 1H), 1.90 (d, J = 6.4 Hz, 2H), 1.66-1.80 (m, 4H), 1 .58 (w s, 2H), 1.29 (d, J = 8.3 Hz, 1H), 1.14 (dd, 7 = 10.4, 16.3 Hz, 1H). LC-MS m/z = 354 [MH] ⁺ .

^1H NMR (DMSO-( ₇₆ , 400 MHz): δ 8.66 (s, 1H), 7.33-7.44 (m, ZH), 7.26 (d, 7 = 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, 7= 16.0, 8.0 Hz, 1H), 1.05 (dd, 7= 16.0, 10.0 Hz, 1H), 1.02-1 .09 (m, 1H) LC-MS m/z = 317 [MH] ⁺ .

^1H NMR (DMSO-cfe, 400MHz): δ 8.58 (s, 1H), 7.85 (t, 7 = 7.7 Hz, 1H), 7.60 (d, 7 = 7.6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.50 (m, 1H), 7.33 (d, 7 = 7.8 Hz, 1H), 4.254.31 (m , 1H), 4.20 (kv, 7 = 7.1 Hz, 2H), 4.09 (t, 7 = 8.7 Hz, 1H), 3.91 (s, ZN), 3.60-3 .68 (m, 1H), 1.21-1.38 (m, 5H). LC-MS m/z = 339 [MH] ⁺ .

¹ H NMR (DMSO-sU ₆ , 400 MHz): δ 8.66 (s, 1H), 7.91 (s, 1H), 7.85 (d, 7= 8.0 Hz, 1H), 7, 51 (d, 7 = 8.4 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.24 (d, 7 = 7.6 Hz, 1H), 4.27 (t, 7 = 8.0 Hz, 1H), 3.97 (s, ZN), 3.80-3.82 (m, 4H), 3.43-3.52 (m, 1H), 1.27-1, 33 (m, 1H), 1.04-1.10 (m, 1H). LC-MS m/z = 300 [MN] ⁺ .

^1H NMR (DMSO-< ₇₆ , 400MHz): δ 8.72 (s, 1H), 8.57 (d, 7 = 2.0 Hz, 1H), 8.55 (d, 7 = 1.7 Hz, 1H), 7.93 (s, 1H), 7.51 (d, 7 = 8.6 Hz, 1H), 7.38 (d, 7 = 8.6 Hz, 1H), 4.28 ( t, 7 = 8.3 Hz, 1H), 3.95 (s, ZN), 3.92 (s, ZN), 3.84 (t, 7 = 9.0 Hz, 1H), 3.49- 3.57 (m, 1H), 1.32 (dd, 7 = 8.2, 16.3 Hz, 1H), 1.12 (dd, 7 = 10.4, 16.3 Hz, 1H). LC-MS m/z = 325 [MN] ⁺ .

- 138 045319

(-) 4-(2-(2-fluoro-4-methoxy-5propoxyphenyl)-6(hydroxymethyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(3-(5-methoxy-6-propoxypyridin2-yl)phenyl)-1,2-oxaborol-2(5H)-ol

4-(3-(5-methoxy-6-propoxypyridin2-yl)phenyl)-1,2-oxaborolan-2-ol

4-(3',4',5-trimethoxy-[1,1'-biphenyl]3-yl)-1,2-oxaborolan-2-ol

4-(6-(4-methoxy-3-propoxyphenyl)-4methylpyridin-2-yl)-1,2oxaborolan-2-ol

HE

^1H NMR (DMSO-s( ₆ , 400MHz): 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 , ZN), 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, 7 = 7.3 Hz, ZN) LC-MS m/z = 377 [MH] ⁺ . [o] ² % -11.9 (s = 0.1 , EYUN).

^1H NMR (DMSO-cfe, 400MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, 7= 7.2 Hz, 1H), 7.60 ( d, 7 = 8.0 Hz, 1H), 7.54 (d, 7 = 8.0 Hz, 1H), 7.48 (t, 7 = 7.6 Hz, 1H), 7.36 (d, 7= 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s, 2H), 4.37 (t, 7 = 6.8 Hz, 2H), 3.83 (s, ZN), 1.80 (kv, 7 = 6.8 Hz, 2H), 1.00 (t, 7 = 6.8 Hz, ZN). LC-MS m/z = 326 [MH] ⁺ .

^1H NMR (DMSO-cfe, 400MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, 7= 7.2 Hz, 1H), 7.60 ( d, 7 = 8.0 Hz, 1H), 7.54 (d, 7 = 8.0 Hz, 1H), 7.48 (t, 7 = 7.6 Hz, 1H), 7.36 (d, 7= 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s, 2H), 4.37 (t, 7 = 6.8 Hz, 2H), 3.83 (s, ZN), 1.80 (kv, 7 = 6.8 Hz, 2H), 1.00 (t, 7 = 6.8 Hz, ZN). LC-MS m/z = 328 [MN] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 8.65 (s, 1H), 7.12-7.22 (m, 2H), 7.09 (s, 1H), 6.95-7.05 (m, ZN), 6.79 (s, 1H), 4.24 (t, 7 = 8.2 Hz, 1H), 3.84 (s, ZN), 3.79 (d, 7 = 8, 0 Hz, 7H), 3.40-3.50 (m, 1H), 1.19-1.33 (m, 1H), 1.08 (dd, 7= 10.0, 16.1 Hz, 1H ), 1.01-1.13 (m, 1H). LC-MS m/z =329 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 8.58 (w s, 1H), 7.69 (d, 7= 1.5 Hz, 1H), 7.63 (d, 7 = 8.3 Hz , 1H), 7.59 (s, 1H), 7.02 (d, 7 = 8.3 Hz, 1H), 6.99 (s, 1H), 4.26 (t, 7 = 8.1 Hz , 1H), 4.00 (t, 7 = 6.6 Hz, 2H), 3.96 (dd, 7 = 6.8, 8.8 Hz, 1H), 3.80 (s, ZN), 3 .49-3.57 (m, 1H), 2.34 (s, ZN), 1.72-1.80 (m, 2H), 1.20-1.28 (m, 1H), 1.13 -1.20 (m, 1H), 1.00 (t, 7 = 7.3 Hz, ZN). LC-MS m/z = 342 [MH] ⁺ .

^1H NMR (DMSO-sub, 400MHz): δ 8.64 (s, 1H), 7.42-7.48 (m, 2H), 7.31 (s, 1H), 7.05 (d, 7 = 8.1 Hz, 1H), 4.26 (dd, 7 = 7.7, 8.7 Hz, 1H), 3.93 (dd, 7 = 7.6, 8.8 Hz, 1H), 3 .84 (s, ZN), 3.81 (s, ZN), 3.56-3.62 (m, 1H), 1.24-1.34 (m, 1H), 1.12-1.20 (m,

- 139 045319

4-(2-(3,4-dimethoxyphenyl)thiazol-4yl)-1,2-oxaborolan-2-ol 1H). LC-MS m/z = 306 [MH] ⁺ . 160 OH / g-V /G~\ s £ ζθ —o 4-(2-(3,4-dimethoxyphenyl)thiazol-4yl)-1,2-oxaborolan-2-ol, enantiomer 2 LC-MS m/z = 319.9 [MH] ⁺ . RT [Analytical SFC Method Y] = 5.76 min. 161 HE DHJ o' XI L/ 4-(3-(5,6-dimethoxypyridine-3- yl)phenyl)-1,2-oxaborolan-2-ol ^1H NMR (DMSO-ck, 400MHz): δ 7.98 (s, 1H), 7.55-7.57 (m, 1H), 7.50-7.52 (m, 2H), 7.39 -7.41 (m, 1H), 7.28-7.37 (m, 1H), 4.26 (t, 4 = 8.0 Hz, 1H), 3.89 (s, ZN), 3, 88 (s, ZN), 3.82 (t, 4 = 8.0 Hz, 1H), 3.32-3.79 (m, 1H), 1.28-1.32 (m, 1H), 1 .03-1.14 (m, 1H). LC-MS m/z = 300 [MN] ⁺ . 162 HE M AAy ° °; (U 4-(6-(2-fluoro-3,4- dimethoxyphenyl)pyridin-2-yl)-1,2- oxaborolan-2-ol ^1H NMR (DMSO-sub, 400 MHz): δ 8.59 (s, 1H), 7.78 (t, 4= 8.0 Hz, 1H), 7.67 (t, 4 = 8.8 Hz , 1H), 7.54-7.57 (m, 1H), 7.25 (d, 4 = 8.0 Hz, 1H), 7.02 (d, 4 = 9.2 Hz, 1H), 4 .26-4.30 (m, 1H), 4.01-4.97 (m, 1H), 3.88 (s, ZN), 3.82 (s, ZN), 3.323.65 (m, 1H ), 1.18-1.30 (m, 2H). LC-MS m/z = 318 [MH] ⁺ . 163 HE is a mustache N 4-(5-(3-ethoxy-2,6-d iforo-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol ^1H NMR (DMSO-< ₄₆ , 400MHz): δ 8.71 (s, 1H), 8.52 (d, 4 = 2.0 Hz, 1H), 8.46 (s, 1H), 7. 78 (s, 1H), 7.06 (d, 4 = 12.2 Hz, 1H), 4.28 (t, 4 = 8.3 Hz, 1H), 4.02 (kv, 4 = 7.3 Hz, 2H), 3.88 (s, ZN), 3.81 (t, 4 = 8.8 Hz, 1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LC-MS m/z = 350 [MN] ⁺ . 164 HE L II */ o ° MA N (-) 4-(5-(3-ethoxy-2,6-difluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1 ^1H NMR (DMSO-< ₄₆ , 400MHz): δ 8.71 (s, 1H), 8.52 (d, 4 = 2.0 Hz, 1H), 8.46 (s, 1H), 7. 78 (s, 1H), 7.06 (d, 4 = 12.2 Hz, 1H), 4.28 (t, 4 = 8.3 Hz, 1H), 4.02 (kv, 4 = 7.3 Hz, 2H), 3.88 (s, ZN), 3.81 (t, 4 = 8.8 Hz, 1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LC-MS m/z = 318 [MH] ⁺ . [a] ² % -20.6 (c = 0.22, EtOH). 165 HE M g*' JL II/o 4-(3'-(cyclopropylmethoxy)-4'- methoxy-[1,1'-biphenyl]-3-yl)-1,2-

- 140 045319 oxaborolan-2-ol

4-(3'-ethoxy-2'-fluoro-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2,4-dimethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

(-) 4-(5-(2,4-dimethoxy-3propoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(5-(4-methoxy-3-((tetrahydro-2Hthiopyran-4-yl)oxy)phenyl)pyridin3-yl)-1,2-oxaborolan-2-ol

4-(5-(4-methoxy-3-((tetrahydro-2Hthiopyran-4-yl)oxy)phenyl)pyridin3-yl)-1,2-oxaborolan-2-ol, enantiomer 1

¹ H NMR (DMSO-sU ₆ , 400 MHz): δ 7.367.39 (m, 2H), 7.31-7.32 (m, 1H), 7.27 (d, J = 7.6 Hz, 1H) , 7.15-7.19 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.25 (t, J = 8.0 Hz, 1H), 4.05 ( kv, J = 7.2 Hz, 2H), 3.85 (s, ZN), 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). LC-MS m/z =331 [MH] ⁺ .

^1H NMR (DMSO-cfe, 400MHz): δ 8.70 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H) , 4.25-4.32 (m, 1H), 3.90 (t, 7 = 6.5 Hz, 2H), 3.79-3.87 (m, 4H), 3.65 (s, ZN ), 3.45-3.54 (m, 1H), 1.65-1.76 (m, 2H), 1.32 (dd, 7= 8.2, 16.3 Hz, 1H), 1, 03-1.12 (m, 1H), 0.99 (t, 7 = 7.5 Hz, ZN). LC-MS m/z = 358 [MH] ⁺ .______________________ ^1H NMR (DMSO-cfe, 400 MHz): δ 8.70 (s, 1H), 8.47 (d, 7 = 2.0 Hz, 1H) , 8.42 (d, 7 = 2.0 Hz, 1H), 7.73 (t, 7 = 2.1 Hz, 1H), 7.09 (d, 7 = 8.8 Hz, 1H), 6 .91 (d, 7 = 8.6 Hz, 1H), 4.25-4.32 (m, 1H), 3.90 (t, 7 = 6.5 Hz, 2H), 3.79-3, 87 (m, 4H), 3.65 (s, ZN), 3.45-3.54 (m, 1H), 1.65-1.76 (m, 2H), 1.32 (dd, 7= 8.2, 16.3 Hz, 1H), 1.03-1.12 (m, 1H), 0.99 (t, 7 = 7.5 Hz, ZN). LC-MS m/z = 358 [MH] ⁺ . [o] ² % -18.8 (s = 0.1,

EUN).__________________________ ¹ H NMR (DMSO-<7 ₆ 400 MHz): δ 8.69 (w s, 1H), 8.42 (w s, 1H), 7.90 (w s, 1H), 7, 34 (s, 1H), 7.30 (d, 7 = 8.3 Hz, 1H), 7.09 (d, 7 = 8.3 Hz, 1H), 4.44-4.54 (m, 1H ), 4.27 (t, 7 = 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, 7= 10.3, 16.1 Hz, 1H).

LC-MS m/z = 386 [MH] ⁺ ._____________ ^1H NMR (DMSO-<7 ₆ 400 MHz): δ 8.69 (w s, 1H), 8.42 (w s, 1H), 7, 90 (w s, 1H), 7.34 (s, 1H), 7.30 (d, 7 = 8.3 Hz, 1H), 7.09 (d, 7 = 8.3 Hz, 1H), 4 .44-4.54 (m, 1H), 4.27 (t, 7 = 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, 7= 10.3, 16.1 Hz, 1H).

LC-MS m/z = 386 [MH] ⁺ . RT [Analytical SFC Method Z] = 5.20 min.__________________________________ ¹ H NMR (DMSO-ck, 400 MHz): δ 8.65 (s, 1H), 8.39 (s, 1H), 7.43 (s, 1H), 7.02 (d, 7 = 8.0 Hz, 1H), 6.90 (s, 1H), 6.84 (d, 7 = 8.3 Hz, 1H), 4.24 (t, 7 = 8.3 Hz, 1H), 4.03

- 141 045319

4-(5-(3-ethoxy-4-methoxyphenyl)-6ethylpyridin-3-yl)-1,2-oxaborolan2-ol

4-(3'-ethoxy-4'-(methylthio)-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-chloro-5-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(3-(4,5-dimethoxypyridin-2yl)phenyl)-1,2-oxaborolan-2-ol

4-(4-(3-(cyclopentyloxy)-4methoxyphenyl)-6methoxypyrimidin-2-yl)-1,2oxaborolan-2-ol (q, J = 6.8 Hz, 2H), 3.75-3.84 ( m, 4H), 3.39-3.52 (m, 1H), 2.69 (kv, J = 7.4 Hz, 2H), 1.21-1.37 (m, 4H), 1.00 -1.17 (m, 4H). LC-MS m/z = 342 [MH] ⁺ .

Ή NMR (DMSO-f;, 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, ZN), 1.36 (t, J = 7.0 Hz, ZN), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J= 10.1, 16.3 Hz, 1H). LC-MS m/z = 329 [MH] ⁺ .___________________________ ¹ H NMR (DMSO-cfe, 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, ZN), 3.83-3.91 (m, 1H), 3.81 (s, ZN), 3.44-3.57 (m, 1H), 1.39 (t, J= 6.9 Hz, ZN), 1.26-1.34 (m, 1H), 1.12-1.22 ( m, 1H). LC-MS m/z = 348 [MN] ⁺ . RT [Analytical SFC Method E] = 5.33 min.

^1H NMR (DMSO-sub, 400MHz): δ 8.65 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 4.27 ( t, J= 8.4 Hz, 1H), 3.95 (s, ZN), 3.89 (s, ZN), 3.82 (t, J= 8.4 Hz, 1H), 3.44- 3.53 (m, 1H), 1.30 (kv, J = 8.0 Hz, 1H), 1.08 (kv, J = 10.0 Hz, 1H). LC-MS m/z =300 [MH] ⁺ .__________________________________________ ¹ H NMR (DMSO-cfe, 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 (w s, 1H), 4.29 (t, J = 8.0 Hz, 1H), 4 .10 (dd, J = 6.0, 8.5 Hz, 1H), 3.94 (s, ZN), 3.81 (s, ZN), 3.553.63 (m, 14.2 Hz, 1H) , 1.93 (d, J = 5.5 Hz, 2H), 1.72 (w s, 4H), 1.58 (w s, 2H), 1.221.36 (m, 2H). LC-MS m/z = 385 [MN] ⁺ .

- 142 045319

4-(4-(3-(cyclopentyloxy)-4methoxyphenyl)-6methoxypyrimidin-2-yl)-1,2oxaborolan-2-ol, enantiomer 2 OH

N

3'-(2-hydroxy-1,2-oxaborolan-4-yl)3,4-d imethoxy-[1,1'-biphenyl]-2carbonitrile

4-(5-methoxy-4-propoxy-[2,3'bipyridin]-5'-yl)-1,2-oxaborolan-2ol

4-(5-methoxy-4-propoxy-[2,3'bipyridin]-5'-yl)-1,2-oxaborolan-2ol, enantiomer 1

4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1

Ή NMR (DMSO-cfe, 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 (w s, 1H), 4.29 (t, J = 8.0 Hz, 1H), 4.10 (dd, 7 = 6.0, 8.5 Hz , 1H), 3.94 (s, ZN), 3.81 (s, ZN), 3.553.63 (m, 14.2 Hz, 1H), 1.93 (d, 7 = 5.5 Hz, 2H ), 1.72 (w s, 4H), 1.58 (w s, 2H), 1.221.36 (m, 2H).

LC-MS m/z = 385 [MN] ⁺ . RT [Analytical SFC Method Z] = 2.79 min.

^1H NMR (DMSO-< ₇₆ , 400MHz): δ 7.197.53 (m, 7H) 4.22-4.31 (m, 1H), 3.94 (s, ZH), 3.91 (s, ZN), 3.79-3.83 (t, 7= 8.8 Hz, 1H), 3.42-3.53 (m, 1H), 1.26-1.32 (m, 1H), 1 .04-1.11 (m, 1H). LC-MS m/z = 322 [MH] ⁺ .

Ή NMR (DMSO-cfe, 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, ZN), 3.87 (w s, 1H), 3.39 (w s, 1H), 1.85-1.94 (m, 2H), 1.29 (d, J = 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, ZN). LC-MS m/z = 329 [MH] ⁺ .

Ή NMR (DMSO-cfe, 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, ZN), 3.87 (w s, 1H), 3.39 (w s, 1H), 1.85-1.94 (m, 2H), 1.29 (d, J= 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, ZN). LC-MS m/z = 329 [MH] ⁺ . RT [Analytical SFC Method G] = 4.36 min.

Ή NMR (DMSO-cfe, 400 MHz): δ 8.73 (s, 1H), 7.61-7.67 (m, ZN), 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, ZN), 3.463.54 (m, 1H), 1.72-1.81 (m, 2H), 1.32 (dd, J= 8.3, 16.1 Hz, 1H), 1.09 (dd, J= 9.5 , 16.4 Hz, 1H), 0.98-1.03 (m, ZN). LC-MS m/z = 358 [MH] ⁺ . RT [Analytical SFC Method L] = 3.58 min.

^1H NMR (DMSO-< ₇₆ , 400MHz): 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, 7 = 7.6, 9.0 Hz, 1H), 4.12 (dd, J = 6 ,6, 9.0 Hz, 1H), 3.97-3.99 (m, 1H), 3.76- 143 045319

(-) 4-(5-(3-cyclopropoxy-4methoxyphenyl)-1,2,4-thiadiazol-3yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(4'-ethoxy-3'-methoxy-[1,1 biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(3'-isobutoxy-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

3.88 (m, 4H), 1.25-1.43 (m, 2H), 0.770.86 (m, 2H), 0.67-0.74 (m, 2H). LC-MS m/z = 333 [MH] ⁺ . [a] ² % -12.7 (c = 0.1, EUN).

^1H NMR (DMSO-cfe, 400MHz): δ 7.50 (w s, 1H), 7.46 (d, 7= 7.8 Hz, 1H), 7.35 (t, 7 = 7.8 Hz, 1H), 7.14-7.22 (m, ZN), 7.01 (d, 7= 8.2 Hz, 1H), 4.26 (t, 7= 7.8 Hz, 1H), 4, 04 (kv, 7= 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). LC-MS m/z = 313 [MH] ⁺ .

^1H NMR (DMSO-de, 400MHz): δ 7.447.56 (m, 2H), 7.32-7.39 (m, 1H), 7.157.24 (m, ZN), 7.00-7.04 (m, 1H), 4.15 (t, 7 = 10.5 Hz, 1H), 4.02-4.06 (m, 1H), 3.793.84 (m, 5H), 3.43-3, 51 (m, 1H), 1.992.09 (m, 1H), 1.22-1.32 (m, 1H), 1.051.11 (m, 1H), 0.98-1.01 (m, 6H) . LC-MS m/z = 359 [MH+H ₂ O] ⁺ .

4-(3'-cyclobutoxy-4'-methoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(2-(3-ethoxy-4-methoxyphenyl)-6methoxypyrimidin-4-yl)-1,2oxaborolan-2-ol

(-) 4-(2-(3-ethoxy-4-methoxyphenyl)-6methoxypyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

Ή NMR (DMSO-s( 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, 7 = 7.3 Hz, 1H), 7.16 (dd, 7 = 2.1, 8.4 Hz, 1H), 6.99-7.05 (m, 2H), 4.75-4.83 (m, 1H), 4.26 (t, 7 = 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, 7 = 8.2, 16.3 Hz, 1H), 1.05-1.12 (m, 1H), 1.03 (d, 7 = 6, 8 Hz, 1H) LC-MS m/z = 339 [MH] ⁺ ._________ ^1H NMR (DMSO-de, 400 MHz): δ 8.67 (s, 1H), 7.99 (dd, 7 = 2 ,0, 8.5 Hz, 1H), 7.96 (d, 7 = 2.0 Hz, 1H), 7.06 (d, 7 = 8.5 Hz, 1H), 6.64 (s, 1H ), 4.26 (dd, 7 = 7.3, 8.8 Hz, 1H), 4.10 (kv, 7 = 6.9 Hz, 2H), 4.00 (s, ZN), 3.95 (dd, 7 = 6.0, 9.0 Hz, 1H), 3.83 (s, ZN), 3.48-3.54 (m, 1H), 1.37 (t, 7 = 7.0 Hz, ZN), 1.21-1.27 (m, 1H), 1.111.18 (m, 1H). LC-MS m/z =345 [MH] ⁺ .

Ή NMR (flMCO-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, 7 = 6.9 Hz, 2H), 4.00 (s, ZN), 3.95 (dd, J = 6.0, 9.0 Hz, 1H), 3.83 (s, ZN), 3.48-3.54 (m, 1H), 1.37 (t, J = 7.0 Hz, ZN), 1.21-1.27 (m, 1H), 1.111, 18 (m, 1H). LC-MS m/z = 345 [MH] ⁺ . [a] ² % -37.4 (c = 0.1, EUN).

- 144 045319

He

4-(5-(4-ethoxy-3methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

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

4-(5-(3-ethoxy-4-methoxyphenyl)-4methylpyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(5-(3-isopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

He

N

3-ethoxy-3'-(2-hydroxy-1,2oxaborolan-4-yl)-4-methoxy-[1, Tbiphenyl]-2-carbonitrile_________

HE

N

3-ethoxy-3'-(2-hydroxy-1,2oxaborolan-4-yl)-4-methoxy-[1, T ¹ H NMR (DMSO-cfe, 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 .3 Hz, 1H), 4.05 (kv, J = 7.2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H), 1 .27-1.37 (m, 4H), 1.10-1.19 (m, 1H). LC-MS m/z = 314 [MH] ⁺ .___________________________ ^1H NMR (DMSO-cfe, 400 MHz): b 8.73 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H) , 8.42 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7 .21-7.25 (m, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.05 (kV, J = 7 .2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H), 1.27-1.37 (m, 4H), 1.10- 1.19 (m, 1H). LC-MS m/z = 314 [MH] ⁺ . RT [Analytical SFC Method AA] = 3.61 min._______________ ¹ H NMR (DMSO-s( 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 (kv, J= 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s, ZN) , 3.63-3.71 (m, 1H), 2.22 (s, ZN), 1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H).LC -MS m/z = 328 [MH] ⁺ .RT [Analytical SFC Method E] = 5.71 min.__________________________________ ¹ H NMR (DMSO-cfe, 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, ZN), 3.47-3.55 (m, 1H), 1.26-1.35 (m , 7H), 1.10-1.18 (m, 1H). LC-MS m/z = 328 [MH] ⁺ . RT [Analytical SFC Method BA] = 5.69 min._______________ ¹ H NMR (DMSO- cfe, 400 MHz): δ 7.317.46 (m, ZN), 7.33-7.36 (m, 2H), 7.27 (d, J= 8.8 Hz, 1H), 4.18-4, 28 (m, ZN), 3.90 (s, ZN), 3.81 (t, J = 8.8 Hz, 1H), 3.453.52 (m, 1H), 1.26-1.34 (m , 4H), 1.081.11 (m, 1H). LC-MS m/z = 338 [MH] ⁺ .

RT [Analytical SFC Method CA] = 3.14 min.

- 145 045319

biphenyl]-2-carbonitrile, enantiomer 2__________

4-(5-(3-cyclopropoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1

HE

(-) 4-(2-(3-ethoxy-4methoxyphenyl)thiazol-4-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(6-(2-hydroxyethoxy)-2-(4-methoxy3-propoxyphenyl)pyrimidin-4-yl)1,2-oxaborolan-2-ol

(-) 4-(6-(2-hydroxyethoxy)-2-(4methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1

Ή NMR (DMSO-a ₆ , 400 MHz): δ 8.698.72 (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, ZN), 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). LC-MS m/z = 326 [MH] ⁺ . RT [Analytical SFC Method D] = 5.38 min.__________________________ ¹ H NMR (DMSO-a ₆ , 400 MHz): δ 8.66 (w s, 1 H), 7.42-7.46 (m, 2 H), 7.30 (s, 1H), 7.05 (d, J= 8.3 Hz, 1H), 4.24-4.28 (m, 1H), 4.09 (kv, J= 7.0 Hz , 2H), 3.90-3.95 (m, 1H), 3.82 (s, ZN), 3.55-3.63 (m, 1H), 1.36 (t, J= 7.0 Hz, ZN), 1.25-1.31 (m, 1H), 1.11-1.18 (m, 1H). LC-MS m/z = 320 [MN] ⁺ . RT [Analytical SFC Method DA] = 4.47 min. [a] ² % -17.4 (c = 0.1, EtOH).

^1H NMR (DMSO-a 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, ZN), 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, ZN). LC-MS m/z = 406 [MH+H ₂ O] ⁺ .

Ή NMR (DMSO-sub, 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, ZN), 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, ZN). LC-MS m/z = 406 [MH+H ₂ O] ⁺ . [a] ² % -38.9 (c = 0.1, EtOH).

Ή NMR (DMSO-a _6,400 MHz): δ 8.59 (s, 1H), 7.73-7.75 (m, ZN), 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, 1N), 3.84 (s, ZN), 3.80 (s, ZN), 3.57- 146 045319

4-(6-(3,4-dimethoxyphenyl)pyridin2-yl)-1,2-oxaborolan-2-ol

4-(4-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyrimidin-2-yl)-1,2oxaborolan-2-ol

4-(6-(3-ethoxy-2-fluoro-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

4-(1-(4-methoxy-3-propoxyphenyl)1 H-pyrazol-3-yl)-1,2-oxaborolan-2ol

4-(5-(3-methoxy-4(methylthio)phenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(2-(hydroxymethyl)-6-(4-methoxy-3propoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol

3.60 (m, 1H), 1.15-1.29 (m, 2H). LC-MS m/z = 298 [MH]'.________________________ ¹ H NMR (DMSO-s ( ₆₄₀₀ MHz): δ 8.71 (w s, 1H), 7.70-7.81 (m, ZN) , 7.53 (d, J = 8.0 Hz, 1H), 7.07-7.14 (m, 1H), 5.71 (w s, 1H), 4.55 (d, J = 5, 5 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 3.95-4.11 (m, 2H), 3.81-3.88 (m, 4H), 1, 71-1.83 (m, 2H), 1.27 (d, J = 8.0 Hz, 1H), 0.96-1.05 (m, 4H) LC-MS m/z = 359 [MH ] ⁺ .

^1H NMR (DMSO-cfe 400 MHz): δ 8.60 (w 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= 7.0 Hz, 2H), 3.96-4.02 (m, 1H), 3.87 (s, ZN), 3.61 (td, J = 8.0, 15.8 Hz, 1H), 1.13-1.32 (m, 5H). LC-MS m/z = 332 [MH] ⁺ .

^1H NMR (DMSO-cfe 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, ZN), 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, ZN). LC-MS m/z =317 [MH] ⁺ ._________ ^1H NMR (DMSO-cfe 400 MHz): δ 8.60 (w 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 = 7.0 Hz, 2H), 3.96-4.02 ( m, 1H), 3.87 (s, 2H), 3.57-3.65 (m, 1H), 1.13-1.33 (m, 5H). LC-MS m/z = 316 [MH] ⁺ .

^1H NMR (DMSO-cfe 400 MHz): δ 8.74 (s, 1H), 7.61-7.69 (m, ZH), 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, ZN), 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, ZN). LC-MS m/z = 358 [MH] ⁺ .

^1H NMR (DMSO- _su6 , 400MHz): δ 8.61 (w 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 (kv, J= 7.1 Hz, 2H), 3.97 (dd, J = 6 ,6, 8.8 Hz, 1H), 3.57-3.64 (m, 1H),

- 147 045319

4-(6-(3-ethoxy-4(methylthio)phenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

4-(6-(3-ethoxy-4(methylthio)phenyl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

(+) 4-(5-(3-ethoxy-4-methoxyphenyl)4,6-dimethylpyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(3'-methoxy-4'-(methylthio)-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(3',4'-dimethoxy-5-methyl-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

(+) 4-(3-fluoro-5-methoxy-6-propoxy[2,3'-bipyridin]-5'-yl)-1,2oxaborolan-2-ol, enantiomer 2

2.42 (s, ZN), 1.38 (t, J = 7.0 Hz, ZN), 1.22-1.31 (m, 1H), 1.14-1.22 (m, 1H) . LC-MS m/z = 330 [MN] ⁺ .

RT [Analytical SFC Method Y] = 7.70 min.

^1H NMR (DMSO-cfe 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 (ddd, J = 2.0, 4.2, 8.1 Hz, 1H), 4.22 (dd, J= 7.3, 8.8 Hz, 1H), 3.96-4.01 (m, 2H), 3.84-3.92 (m, 1H), 3.80 (s, ZN ), 3.54-3.62 (m, 1H), 2.13 (s, ZN), 1.97 (s, ZN), 1.25-1.34 (m, 4H), 0.99- 1.09 (m, 1H). LC-MS m/z = 342 [MH] ⁺ . [a] ²⁰ _D +9.6 (s = 0.1, EUN)._________________________ ¹ H NMR (DMSO-cfe 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, ZN), 3.82 (t, J = 8.9 Hz, 1H), 3.44-3.52 (m, 1H), 2.41 (s, ZN), 1.29 (dd, J= 8.2, 16.3 Hz, 1H), 1.09 (dd, J = 10.3, 16.1 Hz, 1H). LC-MS m/z = 315 [MH] ⁺ ._______________________ ¹ H NMR (DMSO-cfe, 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, ZN), 1.24-1.30 (m, 1H), 1.04-1.11 (m, 1H). LC-MS m/z 313 [MH] ⁺ .

^1H NMR (DMSO-s( ₆ , 400MHz): δ 8.89 (s, 1H), 8.73 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8, 09 (s, 1H), 7.49 (d, J = 12.0 Hz, 1H), 4.28-4.33 (m, ZN), 3.87 (s, ZN), 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, ZN) LC-MS m/z = 347 [MH] ⁺ [a] ² % +20, 4 (c= 0.1, EUN).

^1H NMR (DMSO-s/b 400 MHz): δ 8.66 (w s, 1H), 7.35-7.40 (m, 2H), 7.26-7.34 (m, 2H), 7.18 (t, J= 8.4 Hz, 1H), 6.95-7.00

- 148 045319

4-(2'-fluoro-3',4'-d imethoxy-[1,1'biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol

4-(2-(3-(cyclopentyloxy)-4methoxyphenyl)pyridin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

(m, 1 Η), 4.22-4.28 (m, 1 Η), 3.86 (s, ZN), 3.77-3.84 (m, 4Η), 3.41-3.52 (m, 1 Η), 1.29 (kv, J = 8.0 Hz, 1H), 1.04 (kv, 8.0 Hz, 1H). LC-MS m/z = 317 [MH] ⁺ .

Ή NMR (DMSO-<7 ₆ , 400 MHz): b 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), 4.874.94 (m, 1H), 4.24-4.31 (m, 1H), 3.84 (t, J = 9 .0 Hz, 1H), 3.79 (s, ZN), 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, 7 = 10.0, 16.4 Hz, 1H). LC-MS m/z = 354 [MH] ⁺ .__________ ^1H NMR (DMSO-cfe, 400 MHz): δ 8.72 (s, 1H), 8.50 (d, 7 = 5.4 Hz, 1H) , 7.77 (s, 1H), 7.66 (d, 7 = 2.0 Hz, 1H), 7.62 (dd, 7 = 2.2, 8.6 Hz, 1H), 7.18 ( dd, 7 = 1.2, 5.1 Hz, 1H), 7.03 (d, 7 = 8.3 Hz, 1H), 4.874.94 (m, 1H), 4.24-4.31 (m , 1H), 3.84 (t, 7 = 9.0 Hz, 1H), 3.79 (s, ZN), 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, 7 = 8.3, 16.1 Hz, 1H) , 1.10 (dd, 7= 10.0, 16.4 Hz, 1H). LC-MS m/z = 354 [MH] ⁺ . RT [Analytical SFC Method EA] = 4.27 min.__________________________________ ¹ H NMR (DMSO-<7 ₆ 400 MHz): δ 8.71 (d, 7 = 5.1 Hz, 1H), 8.69 (s, 1H), 8.00 (dd, 7 = 1.8, 8.4 Hz, 1H), 7.96 (d, 7 = 1.7 Hz, 1H), 7.26 (d, 7 = 4.9 Hz, 1H), 7.08 (d, 7 = 8.3 Hz, 1H), 4.30 (dd, 7 = 7.5, 8.9 Hz, 1H), 3.97-4.02 (m , ZN), 3.83 (s, ZN), 3.55-3.63 (m, 1N), 1.73-1.82 (m, 2N), 1.25-1.33 (m, 1N ), 1.13-1.20 (m, 1H), 1.01 (t, 7 = 7.5 Hz, ZN). LC-MS m/z = 329 [MH] ⁺ . __________________ ^1H NMR (DMSO-dg 400 MHz): δ 8.61 (s, 1H), 7.75-7.80 (m, 1H), 7.66 (t, 7 = 8.8 Hz, 1H) , 7.55 (dd, 7 = 1.8, 7.7 Hz, 1H), 7.24 (d, 7 = 7.6 Hz, 1H), 6.99-7.04 (m, 1H), 4.27 (dd, 7 = 7.8, 8.6 Hz, 1H), 3.924.02 (m, ZN), 3.86 (s, ZN), 3.57-3.65 (m, 1H) , 1.63-1.72 (m, 2H), 1.14-1.31 (m, 2H), 0.98 (t, 7 = 7.3 Hz, ZN). LC-MS m/z = 346 [MH] ⁺ .

^1H NMR (DMSO-cfe, 400MHz): δ 8.75 (d, 7 = 2.0 Hz, 1H), 8.71 (s, 1H), 8.47 (d, 7 = 1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd, 7 = 2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, 7 = 8 ,3 Hz, 1H), 4.21 (kv, 7 = 6.9 Hz, 2H), 3.82-3.90 (m, ZN), 3.45-3.56 (m, 2H),

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4-(5-(3-ethoxy-5-fluoro-4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol

ABOUT

4-(6-(2-fluoro-4-methoxy-3propoxyphenyl)pyrazin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(5-(4-ethoxy-2-fluoro-3methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol

4-(6'-methoxy-2-methyl-5'-propoxy[3,3'-bipyridin]-5-yl)-1,2oxaborolan-2-ol

(-) 4-(6'-methoxy-2-methyl-5'-propoxy[3,3'-bipyridin]-5-yl)-1,2oxaborolan-2-ol, enantiomer 1

1.39 (t, 2= 6.9 Hz, ZN), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LC-MS m/z = 349 [MH+H ₂ O] ⁺ . RT [Analytical SFC Method D] = 4.59 min.

Ή NMR (DMSO-cfe 400 MHz): b 8.81 (d, 2 = 2.4 Hz, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.67 (t , 2 = 8.8 Hz, 1H), 7.07 (d, 2 = 7.8 Hz, 1H), 4.31 (t, 2 = 8.3 Hz, 1H), 3.94-4.06 (m, ZN), 3.89 (s, ZN), 3.67-3.75 (m, 1N), 1.64-1.73 (m, 2N), 1.27-1.36 (m , 1H), 1.15-1.25 (m, 1H), 0.98 (t, 2= 7.3 Hz, ZN). LC-MS m/z = 347 [MH] ⁺ .

Ή NMR (DMSO-<2 ₆ 400 MHz): b 8.81 (d, 2 = 2.4 Hz, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.67 (t, 2 = 8.8 Hz, 1H), 7.07 (d, 2 = 7.8 Hz, 1H), 4.31 (t, 2 = 8.3 Hz, 1H), 3.94-4 .06 (m, ZN), 3.89 (s, ZN), 3.67-3.75 (m, 1N), 1.64-1.73 (m, 2N), 1.27-1.36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t, 2= 7.3 Hz, ZN). LC-MS m/z = 347 [MH] ⁺ . RT [Analytical SFC Method C] = 4.40 min._________________________________ ¹ H NMR (DMSO-<2 ₆ 400 MHz): b 8.72 (s, 1H), 8.54 (t, 2 = 2.0 Hz, 1H), 8.48 (d, 2 = 2.5 Hz, 1H), 7.82 (d, 2 = 1.5 Hz, 1H), 7.24 (t, 2 = 8.8 Hz, 1H) , 6.98-7.02 (m, 1H), 4.25-4.31 (m, 1H), 4.14 (kv, 2 = 6.9 Hz, 2H), 3.81-3.87 (m, 4H), 3.46-3.56 (m, 1H), 1.38 (t, 2 = 6.8 Hz, ZN), 1.32 (dd, 2 = 8.3, 16.3 Hz, 1H), 1.10 (dd, 2= 10.0, 16.1 Hz, 1H). LC-MS m/z = 332 [MH] ⁺ .

Ή NMR (flMCO- _d6 , 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, ZN), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H), 2.41 (s, ZN), 1.721.77 (m, 2H) , 1.26-1.30 (m, 1H), 1.071.11 (m, 1H), 0.96-1.00 (m, ZN). LC-MS m/z = 343 [MH] ⁺ .

Ή NMR (flMCO-d ₆ , 400 MHz): b 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, ZN), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H), 2.41 (s, ZN), 1.721.77 (m, 2H) , 1.26-1.30 (m, 1H), 1.071.11 (m, 1H), 0.96-1.00 (m, ZN). LC-MS m/z = 343 [MH] ⁺ . RT [Analytical

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ABOUT

4-(6-(3-ethoxy-4-methoxyphenyl)-4(trifluoromethyl)pyridin-2-yl)-1,2oxaborolan-2-ol

4-(5-(3,4-dimethoxyphenyl)pyridin3-yl)-1,2-oxaborolan-2-ol, enantiomer 2

4-(6-ethoxy-2-(3-ethoxy-4methoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol

4-(6-ethoxy-2-(3-ethoxy-4methoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 1

SFC Method Z] = 2.28 min. [a] ² % -16.2 (s = 0.1, EUN)._________________________ ¹ H NMR (MeOD-cG, 400 MHz): δ 7.85 (s, 1H), 7.76 (d, 4 = 2 .0 Hz, 1H), 7.67 (dd, 4 = 2.0, 8.3 Hz, 1H), 7.39 (s, 1H), 7.06 (d, 4 = 8.8 Hz, 1H ), 4.17 (sq, 4 = 7.2 Hz, ZN), 4.02 (w s, 1H), 3.89 (s, ZN), 3.57 (w s, 1H), 1.45 (t, 4 = 7.1 Hz, ZN), 1.33-1.41 (m, 1H), 1.24-1.32 (m, 1H). LC-MS m/z 382 [MH] ⁺ .

Ή NMR (DMSO-<4 ₆ , 400 MHz): δ 8.72 (d, 4= 2.8 Hz, 2H), 8.43 (d, 4= 2.0 Hz, 1H), 7.95 (t , 4 = 2.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.06 (d, 4 = 8.4 Hz, 2H), 4.28 (t, 4 = 4, 28 Hz, 1H), 3.84-3.88 (m, 4H), 3.80 (s, ZN), 3.46-3.54 (m, 1H), 1.28-1.34 (m , 1H), 1.12-1.18 (m, 1H). LC-MS m/z = 300 [MN] ⁺ . RT [Analytical SFC Method FA] = 6.04 min.

Ή NMR (DMSO-<4 ₆ , 400 MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, 4 = 8.5 Hz, 1H) , 6.59 (s, 1H), 4.47 (kv, 4 = 6.9 Hz, 2H), 4.25 (t, 4 = 8.0 Hz, 1H), 4.09 (kv, 4 = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, ZN), 3.48 (w s, 1H), 1.36 (t, 4 = 7, 0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m, 1H). LC-MS m/z [Analytical SFC Method FA] = 359 [MH] ⁺ .

Ή NMR (DMSO-cfe, 400 MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, 4 = 8.5 Hz, 1H), 6 .59 (s, 1H), 4.47 (kv, 4 = 6.9 Hz, 2H), 4.25 (t, 4 = 8.0 Hz, 1H), 4.09 (kv, 4 = 6, 9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, ZN), 3.48 (w s, 1H), 1.36 (t, 4 = 7.0 Hz , 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m, 1H). LC-MS m/z = 359 [MH] ⁺ . RT [Analytical SFC Method D] = 2.97 min.

Ή NMR (DMSO-<4 ₆ , 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, 4 = 2.0, 8.5 Hz, 1H), 7.947.97 (m, 1H) , 7.06 (d, 4 = 8.5 Hz, 1H), 6.63 (s, 1H), 4.26 (dd, 4 = 7.5, 9.0 Hz, 1H), 3.97- 4.03 (m, 5H), 3.94 (dd, 4 = 6.0, 9.0 Hz, 1H), 3.82 (s, ZN), 3.50 (d, 4 = 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, 4 = 7.5 Hz, ZN). LC-MS m/z = 359 [MH] ⁺ .

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propoxyphene yl)pyrimidin-4-yl)-1,2oxaborolan-2-ol__________________

(-) 4-(6-methoxy-2-(4-methoxy-3propoxyphenyl)pyrimidin-4-yl)-1,2oxaborolan-2-ol, enantiomer 2

2-(cyclopentyloxy)-6-(6-(2hydroxy-1,2-oxaborolan-4yl)pyridin-2-yl)-3methoxybenzonitrile

4-(2-(3,4-dimethoxyphenyl)pyridin4-yl)-1,2-oxaborol-2(5H)-ol

(+) 4- (5- (3- (2-hydro xyethoxy) -4methoxyphenyl)pyridin-3-yl)-1,2oxaborolan-2-ol, enantiomer 2

4-(5-(3-ethoxy-4methoxyphenyl)pyridin-3-yl)-1,2oxaborol-2(5H)-ol

4-(3-fluoro-6- (4-m is xi-3-

Ή NMR (DMSO-s/ ₆ , 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.5 Hz, 1H), 7.947.97 (m, 1H) , 7.06 (d, 7 = 8.5 Hz, 1H), 6.63 (s, 1H), 4.26 (dd, 7 = 7.5, 9.0 Hz, 1H), 3.97- 4.03 (m, 5H), 3.94 (dd, 7 = 6.0, 9.0 Hz, 1H), 3.82 (s, ZN), 3.50 (d, 7 = 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, 7 = 7.5 Hz, ZN). LC-MS m/z = 359 [MH] ⁺ . [o] ²⁰ _d -16.9 (c = 0.1, EUN).

Ή NMR (DMSO-<7 ₆ , 400 MHz): δ 8.57 (s, 1H), 7.81-7.88 (m, 1H), 7.59 (d, 7 = 7.8 Hz, 1H) , 7.49-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.32 (d, 7 = 7.6 Hz, 1H), 5.11 (t, 7 = 5.1 Hz, 1H), 4.27 (t, 7 = 8.3 Hz, 1H), 4.08 (t, 7 = 8.7 Hz, 1H), 3.91 (s, ZN), 3.593.68 (m, 1H), 1.79-1.93 (m, 4H), 1.681.76 (m, 2H), 1.54-1.63 (m, 2H), 1.281.36 (m, 1H), 1.21-1.28 (m, 1H). LC-MS m/z = 379 [MH] ⁺ .

^1H NMR (DMSO-s/ ₆₄₀₀ MHz): δ = 8.85 (s, 1H), 8.65 (d, 7= 5.2 Hz, 1H), 7.97 (s, 1H), 7 .73-7.74 (m, 2H), 7.43 (d, 7 = 4.8 Hz, 1H), 7.06 (d, 7 = 4.8 Hz, 1H), 6.58 (s, 1H), 5.00 (d, 7= 1.6 Hz, 1H), 3.86 (m, ZN), 3.82 (s, ZN). LC-MS m/z = 298 [MH] ⁺ .

1H NMR (CD ₃ OD, 400 MHz): δ 8.60 (w s, 1H), 8.37 (w s, 1H), 7.93 (s, 1H), 7.227.30 (m, 2H), 7 .10 (d, J = 8.3 Hz, 1H), 4.16 (t, J = 4.6 Hz, 2H), 4.08 (w s, 1H), 3.83-3.95 (m , 6H), 3.34-3.42 (m, 1H), 1.25-1.39 (m, 2H). LC-MS m/z = 330 [MN] ⁺ . [o] ² % +31.9 (c = 0.1, EUN).

Ή NMR (DMSO-s/ ₆ , 400 MHz): δ 8.85 (d, 7 = 2.0 Hz, 1H), 8.77 (s, 1H), 8.73 (d, 7 = 2.0 Hz , 1H), 8.13 (s, 1H), 7.31-7.33 (m, 2H), 7.07 (d, 7= 8.0 Hz, 1H), 6.45 (s, 1H) , 5.01 (s, 2H), 4.14 (kv, 7 = 6.8 Hz, 2H), 3.81 (s, ZN), 1.36 (kv, 7 = 6.8 Hz, ZN) . LC-MS m/z = 312 [MH] ⁺ .

Ή NMR (DMSO-s/ ₆ , 400 MHz): δ 8.64 (w s, 1H), 7.84 (dd, 7 = 3.4, 8.8 Hz, 1H), 7.67 (t, 7 = 4.6 Hz, 2H), 7.60 (dd, 7 = 1.5, 8.3 Hz, 1H), 7.03 (d, 7 = 8.8 Hz, 1H), 4.27 (t , 7 = 7.8 Hz, 1H), 3.98-4.07 (m, ZN), 3.85 (d, 7 = 6.8 Hz, 1H), 3.81 (s, ZN), 1 .72-1.80 (m, 2H), 1.22-1.27 (m, 2H), 1.00 (t, 7 = 7.3 Hz, ZN). LC-MS m/z = 346 [MH] ⁺ . RT [Analytical SFC

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231

232

233 propoxyphene yl)pyridin-2-yl)-1,2oxaborolan-2-ol, enantiomer 1

(-) 4-(5-methoxy-2'-methyl-6-propoxy[2,3'-bipyridin]-5'-yl)-1,2oxaborolan-2-ol, enantiomer 1

4-(3',4'-dimethoxy-[1,1'-biphenyl]-3yl)-1,2-oxaborolan-2-ol

4-(6-(3-ethoxy-4methoxyphenyl)pyridin-2-yl)-1,2oxaborolan-2-ol

Method G] = 3.25 min.

^1H NMR (flMCO- _d6 , 400MHz): δ 8.67 (s, 1H), 8.34 (s, 1H), 7.65 (s, 1H), 7.37 (d, J = 8, 1 Hz, 1H), 7.13 (d, J= 8.1 Hz, 1H), 4.21-4.28 (m, ZN), 3.76-3.85 (m, 4H), 3, 41-3.50 (m, 1H), 2.52 (s, ZN), 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, ZN). LC-MS m/z = 343 [MH] ⁺ . [a] ² % -20.1 (c = 0.1, EUN).

^1H NMR (DMSO-cfe, 400MHz): δ 7.51 (s, 1H), 7.45 (br d, J = 7.6 Hz, 1H), 7.347.35 (m, 1H), 7.16 -7.23 (m, ZN), 7.02 (d, J= 8.0 Hz, 1H), 4.22-4.28 (m, 1H), 3.84 (s, ZN), 3, 81 (s, 1H), 3.79 (s, 3N), 3.423.51 (m, 1H), 1.25-1.31 (m, 1H), 1.051.12 (m, 1H). LC-MS m/z = 299 [MH] ⁺ . ^1H NMR (DMSO-s/b 400 MHz): δ 8.57 (s, 1H), 7.61-7.70 (m, ZH), 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, ZN), 3.56-3.58 (m, 1H), 1.33 (t, J= 7.0 Hz, ZN), 1.16-1.24 (m, 2H). LC-MS m/z = 314 [MH] ⁺ .

X-ray analysis of a single crystal 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 using single crystal X-ray diffraction analysis. X-ray diffraction data of the single crystal were collected on a Bruker D8 Quest diffractometer at room temperature. Data collection consisted of omega and fiscans. The structure was determined by internal phasing using the SHELX software suite in the P21 space group of the monoclinic system. The structure was then optimized using full matrix least squares. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on oxygen were determined from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and carriers were allowed to jump onto their atoms. The final refinement included isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). The Hooft parameter is shown as 0.02 with an Esd of 0.003, and the Parson parameter is shown as 0.02 with an Esd of 0.003. The final R-index was 4.5%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 1 is the resulting X-ray structure (ORTEP graphic) of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3). Crystal structure data are given in table. 3.

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Table 3. Crystal data and structure refinement for example 3 Empirical formula C ₁₇ H ₂₀ V N O ₄ Mass according to formula 313.15 Temperature 296(2) K Wavelength 1.54178 A Crystal system Monoclinic Space group _P2d Unit cell parameters a= 11.0798(5) A a= 90°. b = 13.1083(6) A β= 99.346(2)°. c = 11.2398(6) A γ = 90°. Volume 1610.77(13) A ³ Z 4

Density(calculated) 1.291 mg/ ^m3 Absorption coefficient F(000) 0.738 mm'1 664 Crystal size Theta band for data acquisition Index Ranges Collected reflections Independent reflections Occupancy to theta = 67.679° Absorption correction Refinement method 0.360x0.220x0.140 mm ³ from 3.986 to 70.310° -13<=h<=l3, -1b<=k<=15, -13<=1<=12 29459 6084 [R(int) = 0.0304 ] 99.9% Empirical Least Squares in Full Matrix Approximation F^ Data/constraints/parameters Consistency criterion on F^ Final R indices [1>2 sigma(1)] R-indices (all data) Absolute structure parameter Extinction coefficient 6084 /3/426 1.132 R1 = 0.0446, wR2 = 0.1005 R1 =0.0452, wR2 = 0.1013 0.02(3) 0.125(4) Largest diff. peak and pit 0.307 and -0.371 e.A' ³

X-ray analysis of a single crystal of crystalline (R) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (example 4).

The crystal structure of Example 4 was determined using single crystal X-ray diffraction analysis. X-ray diffraction data of the single crystal were collected on a Bruker D8 Venture diffractometer at a temperature of -150°C. Data collection consisted of omega and fiscans. The structure was determined by internal phasing using the SHELX software suite in the P21 space group of the monoclinic system. The structure was then optimized using full matrix least squares. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on oxygen were determined from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and carriers were allowed to jump onto their atoms. The final refinement included isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). The Hooft parameter is presented as 0.08 with an Esd of 0.003, and the Parson parameter is presented as 0.15 with an Esd of 0.002. The final R-index was 4.6%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 2 is the resulting X-ray structure (ORTEP graphic) of crystalline (R)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4). Crystal structure data are given in table. 4.

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Table 4. Crystal data and structure refinement for example 4

Empirical formula C ₁₈ H ₂₂ V N O ₄ Mass according to formula 327.17 Temperature 123(2) K Wavelength 1.54178 A Crystal system Monoclinic Space group Ρ2ι Unit cell parameters a = 10.7077(14) A a = 90°. b = 13.4140(17) A β= 110.396(5)°. c = 13.0151(16) A γ = 90°. Volume 1752.2(4) A ³ Z 4 Density (calculated) 1.240 mg/ ^m3 Absorption coefficient 0.699 mm' ¹ F(000) 696 Crystal size 0.240x0.160x0.120 mm ³ Theta band for data acquisition from 3.623 to 72.240° Index Ranges -12<=h<=13, -16<=k<=16, -16<=1<=16 Collected Reflections 63647 Independent reflections 6737 [R(int) = 0.0312] Occupancy to theta = 67.679° 98.8% Absorption adjustment Empirical Clarification method Least squares in full matrix approximation F ² Data/Limitations/Options 6737 /3/443 Consistency criterion on F ² 1,044 Final R indices [1>2sigma(1)] R1 = 0.0457, wR2 = 0.1282 R-indexes (all data) R1 =0.0477, wR2 = 0.1311 Absolute structure parameter 0.08(3) Extinction coefficient not determined Largest diff. peak and pit 0.279 and -0.203 e.A- ³

X-ray analysis of a single crystal of crystalline (S) 4-(5-(4-methoxy-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (example 5).

The crystal structure of Example 5 was also determined using single crystal X-ray diffraction analysis. X-ray diffraction data of the single crystal were collected on a Bruker D8 Quest diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by internal phasing using the SHELX software suite in the P2 ₁ space group of the monoclinic system. The structure was then optimized using full matrix least squares. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on oxygen were determined from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and carriers were allowed to jump onto their atoms. The final refinement included isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). The Hooft parameter is represented as 0.01 with an Esd of 0.007, and the Parson parameter is presented as 0.01 with an Esd of 0.006. The final R-index was 4.8%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 3 is the resulting X-ray structure (ORTEP graphic) of crystalline (S)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5). Crystal structure data are given in table. 5.

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Table 5. Crystal data and structure refinement for Example 5

Empirical formula Mass according to formula Temperature Wavelength Crystal system Space group Unit cell parameters Ci in H22 V N O4 327.17 296(2) K 1.54178 A Monoclinic Ρ2ι a = 10.6918(4) A a = 90°. b= 13.4115(4) Α β= 110.311(2)°. с = 13.0161(4) Α γ = 90°. Volume 1750.37(10) A ³ Z 4 Density (calculated) 1.242 mg/ ^m3 Absorption coefficient F(000) 0.700 mm'1 696 Crystal size Theta band for data acquisition Index Ranges Collected reflections Independent reflections Occupancy to theta = 67.679° Absorption correction Refinement method 0.260x0.220x0.140 mm ³ from 3.621 to 70.234° -12<=h<=13, -16<=k<=16, -15<=1<=15 16854 6536 [R(int) = 0.0328 ] 99.3% Empirical Least squares in full matrix approximation F ² Data/constraints/parameters Consistency criterion on F ² Final R indices [1>2sigma(1)] R-indices (all data) Absolute structure parameter Extinction coefficient X-ray analysis of a single crystal 6536 /3/446 1.065 R1 = 0.0478, wR2 = 0.1176 R1 =0.0512, wR2 = 0.1220 0.01(7) 0.0385(19) 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 using single crystal X-ray diffraction analysis. X-ray diffraction data of the single crystal were collected on a Bruker D8 Quest diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by internal phasing using the SHELX software suite in the P2 ₁ space group of the monoclinic system. The structure was then optimized using full matrix least squares. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on oxygen were determined from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and carriers were allowed to jump onto their atoms. The final refinement included isotropic substitution parameters for all hydrogen atoms. Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). The Hooft parameter is presented as 0.06 with an Esd of 0.004, and the Parson parameter is presented as 0.06 with an Esd of 0.003. The final R-index was 4.0%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 4 is the resulting X-ray structure (ORTEP graphic) of crystalline (R) 4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (example 19). Crystal structure data are presented in table. 6.

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Table 6. Crystal data and structure refinement for Example 19 Largest diff. peak and pit 0.236 and -0.273 e.A ^-3 Empirical formula C36 H44 B ₂ N ₂ O ₈ Mass according to formula 654.35 Temperature 296(2) K Wavelength 1.54178 A Crystal system Monoclinic Space group Ρ2ι Unit cell parameters a = 11.2655(18) A a= 90°. b = 12.903(2) A β= 111.269(5)°. c = 12.959(2) A γ = 90°. Volume 1755.4(5) A ³ Z 2

Density(calculated) 1.238 mg/ ^m3 Absorption coefficient F(000) 0.698 mm'1 696 Crystal size Theta band for data acquisition Index Ranges Collected reflections Independent reflections Occupancy to theta = 67.679° Absorption correction Refinement method 0.420x0.360x0.120 mm ³ from 3.660 to 72.747° -1 z<=i<=13, -15<=k<=15, -15<=1<=16 53020 6907 [R(int) = 0, 0361] 100.0% Empirical Least squares in full matrix approximation F ² Data/constraints/parameters Consistency criterion on F ² Final R indices [1>2sigma(1)] R-indices (all data) Absolute structure parameter Extinction coefficient 6907 /3/446 1.055 R1 = 0.0396, wR2 = 0.1023 R1 =0.0414, wR2 = 0.1043 0.06(4) 0.0261(13) Largest diff. peak and pit 0.230 and -0.298 e.A-3

X-ray powder diffraction analysis.

The crystal structures of Examples 3, 4, 5, 10 and 19 were analyzed using powder x-ray diffraction (PXRD).

For Example 4, powder X-ray diffraction analysis was performed using a Bruker AXS D8 ADVANCE diffractometer equipped with a Cu radiation source (K-α average). The system is equipped with Soller 2.5 axial slots on the primary circuit. The secondary circuit uses Soller 2.5 axial slits and motorized slits. Diffracted radiation was detected by a Lynx Eye XE detector. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a theta-theta goniometer at Cu wavelengths from 3.0 to 40.0 degrees 2-theta, using a step size of 0.037 degrees and a step time of 10 s per stage. Samples were obtained by placing them in a low-background sample holder (Bruker catalog number: C79298A3244B261) and rotating during collection. Data were collected using Bruker DIFFRAC Plus software. The analysis was carried out using EVA diffract plus software. The PXRD data file was not processed before peak searching. By applying the peak finding algorithm in EVA software, peaks selected with a threshold value of 1 and a width of 0.3 were used for preliminary peak assignment. To ensure reliability, adjustments were made manually; the result of the automatic assignment was checked visually and the peak positions were adjusted according to the maximum of the peak. In general, peaks with relative intensities >3% were selected. Peaks that were not resolved or were consistent with noise were not selected. The typical error associated with peak position from PXRD, as specified in the USP, is within ±0.2° 2-Theta (USP-941).

For Examples 3, 5, 10 and 19, powder X-ray diffraction analysis was carried out using

- 157 045319 using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source (K-α average value). The system is equipped with Soller 2.5 axial slots on the primary circuit. The secondary circuit uses Soller 2.5 axial slits and motorized slits. Diffracted radiation was detected by a Lynx Eye XE detector. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a theta-2theta goniometer at Cu wavelengths from 3.0 to 43.0 degrees 2-Theta, using a step size of 0.020 degrees and a step time of 3 s per stage. Samples were obtained by placing them in a low-background sample holder, rotating them during collection. Data were collected using Bruker DIFFRAC Plus software. The analysis was carried out using EVA diffract plus software. The PXRD data file was not processed before peak searching. By applying the peak finding algorithm in EVA software, peaks selected with a threshold value of 1 and a width of 0.3 were used for preliminary peak assignment. To ensure reliability, adjustments were made manually; the result of automatic assignment was checked visually and the position of the peaks was adjusted according to the maximum of the peak. In general, peaks with relative intensities >3% were selected. Peaks that were not resolved or were consistent with noise were not selected. Typical error associated with peak position from PXRD is specified in the USP to be within ±0.2° of 2-Theta (USP-941).

As a qualified crystallographer will appreciate, the relative intensities of the various peaks shown in the tables and figures below may vary due to a number of factors, such as the orientation effects of the crystals in the X-ray beam or the purity of the substance being analyzed or the degree of crystallinity of the sample. The peak positions will remain largely as determined. A skilled crystallographer will also appreciate that measurements using different wavelengths will result in different shifts according to the Bragg equation nλ,=2d sin θ. Such further PXRD models of the crystalline materials of the present invention and as such are within the scope of this information.

Fig. 5 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 3) and Table. 7 shows PXRD peaks.

Fig. 6 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 4) and Table. 8 shows PXRD peaks.

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Table 8. PXRD data for example 4

Angle (2-Theta), Relative G degrees 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

Fig. 7 is the resulting powder X-ray diffraction pattern of crystalline (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 5) and Tab. 9 shows PXRD peaks.

Table 9. PXRD data for example 5

Angle (2-Theta) Degrees Relative 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 z, z 39.0 3.1 39.6 3.3 41.4 3.9

Fig. 8 is the resulting powder X-ray diffraction pattern of crystalline (-) 4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolane-2 -ola (example 10) and table. 10 shows PXRD peaks.

Table 10. PXRD data for example 10

Angle 2-Theta (G degrees) 8.9 12.0 12.3 12.8 13.7 13.9 14.2 14.5 15.9 17.6 17.8 19.2 19.4 19.6 20.4 21.4 22.0 22.3 22.5 22.9 23.1 24.2 25.7 27.3 27.5 28.5 28.8 29.6 30.7 33.7 35.6 40.3 40.9

Relative intensity % 12.7 18.0 14.5 100.0 5.6 20.6 13.2 3.7 5.8 14.4 31.5 21.6 16.5 17.2 59.3 13.9 16.3 17.4 15.1 32.3 31.4 14.5 44.2 3.7 6.3 11.7 7.0 5.2 12.9 3.9 9.9 3.7 5.4

Fig. 9 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol (Example 19) and table 11 shows PXRD peaks.

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Table 11. PXRD data for

Angle 2-Theta (G degrees) Relative 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

Examples of drugs.

An embodiment of the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention for treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% w/w . up to approximately 15% w/w. solvent and (c) ointment base. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention for treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% by weight ./wt. up to approximately 15% w/w. solvent and (c) petroleum jelly. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention for treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% by weight ./wt. up to approximately 15% w/w. solvent, (c) ointment, (d) antioxidant, (e) stabilizer, (f) emulsifying agent and (e) thickening agent. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention for treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% by weight ./wt. up to approximately 15% w/w. solvent, (c) ointment, (d) antiok

- 161 045319 sedentant, (f) emulsifying agent and (f) thickening agent. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention for treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 5% by weight ./wt. up to approximately 15% w/w. solvent, (c) petrolatum, (d) antioxidant, (e) emulsifying agent and (f) thickening agent. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 8% by weight ./wt. up to approximately 10% w/w. propylene or hexylene glycol, (c) from about 75% wt./wt. up to approximately 80% w/w. white petrolatum, (d) from about 8% w/w. to about 10% glyceride mixture, (e) about 4% to about 6% paraffin wax, and (f) about 0.05% to 0.5% butylated hydroxytoluene. In one embodiment, the present invention provides a topical pharmaceutical preparation containing: (a) an active agent of the invention treating an inflammatory disease, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (b) from about 8% by weight ./wt. up to approximately 10% w/w. hexylene glycol, (c) from about 75% wt./wt. up to approximately 80% w/w. white petrolatum, (d) from about 8% w/w. to about 10% glyceride mixture, (e) about 4% to about 6% paraffin wax, and (f) about 0.05% to 0.5% butylated hydroxytoluene.

In one embodiment, the present invention provides a topical pharmaceutical preparation 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-3propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, or a pharmaceutically acceptable salt thereof, a hydrate thereof , or solvate. In another embodiment, the active agent is (S)-4-(5-(4methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, or a pharmaceutically acceptable salt thereof, a hydrate thereof , 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 thereof, 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 pharmaceutical grade thereof an acceptable salt, its hydrate, or solvate.

In another embodiment, the active agent is (-)-4-(5-(2-(difluoromethyl)-3ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another embodiment, the present invention provides a topical pharmaceutical preparation containing the 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 a salt, hydrate, or solvate thereof. In another embodiment, the present invention provides a combination of an active agent and another active agent, wherein the second active agent is suitable for the treatment of inflammatory disorders such as atopic dermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus, allergies, fibromyalgia, healing wounds and inflammation resulting from surgical complications. The combination may consist of mixing or co-formulating two active ingredients. Alternatively, the combination may be packaged in a dispenser in which one active agent is in one chamber and the other active ingredient is in a second chamber, but after dosing, the two active agents are simultaneously delivered together such that administration of the combination can occur in a single application. Alternatively, the active agents may be administered separately with a second active agent, wherein the second active agent may be administered orally or topically.

In another embodiment, the present invention provides the active agent described herein, or a salt, hydrate, or solvate thereof, in a topical preparation containing 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% wt./wt. to approximately 15.0% w/w. In another embodiment, the solvent is present at a concentration of from about 6.0% w/w. to approximately 12.0% w/w. In another embodiment, the solvent is present at a concentration of from about 7.0% wt./wt. to approximately 11.0% w/w.

In another embodiment, the solvent is present at a concentration of from about 8.0% wt./wt. to approximately 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 preparation containing an ointment base. In another embodiment, the ointment base is white petroleum jelly. In another embodiment, the ointment base is petrolatum, petrolatum, yellow petrolatum, yellow soft paraffin, yellow petrolatum, white 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 the topical pharmaceutical preparation will depend on the amounts of other components. In another embodiment, the ointment base is present in a sufficient quantitative concentration. In another embodiment, the ointment base is present in a concentration of from about 65% wt./wt. up to approximately 85% w/w. In another embodiment, the base is present in a concentration of from about 70% wt./wt. up to approximately 80% w/w. In another embodiment, the base is present in a concentration of from about 75% wt./wt. up to approximately 80% w/w.

In another embodiment, the present invention provides an active agent described herein, or a salt, hydrate, or solvate thereof, in a topical preparation that further contains an antioxidant. In another embodiment, the antioxidant is butylated hydroxytoluene, ascorbic acid, ascorbic palmitate, butylated hydroxyanosole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl galate, thiodipropionic acid , dilaurylthiodipropionate, tert-butylhydroquinone, 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% wt./wt. to approximately 1% w/w. In another embodiment, the antioxidant is present at a concentration of from about 0.01% wt./wt. to approximately 0.5% w/w. In another embodiment, the antioxidant is present at a concentration of from about 0.05% wt./wt. to approximately 0.5% w/w. In another embodiment, the antioxidant is present at a concentration of from about 0.075% w/w. to approximately 0.2% w/w.

In another embodiment, the topical pharmaceutical preparation 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, wherein 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 contains a monoglyceride and a diglyceride and at the same time from about 40% wt./wt. up to approximately 55% w/w. The glyceride mixture is a monoglyceride. In another embodiment, the emulsifying agent is a glyceride mixture, wherein the glyceride mixture contains a monoglyceride, a diglyceride and a triglyceride and at the same time from about 40% wt./wt. up to approximately 55% w/w. The glyceride mixture is a monoglyceride. In another embodiment, the monoglyceride is selected from the group consisting of glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, or combinations thereof. In another embodiment, the monoglyceride is a long chain monoglyceryl ester of a saturated or unsaturated fatty acid. In one embodiment, the monoglyceride is an alpha monoglyceride. In an advantageous embodiment, the diglyceride is a long chain diglyceryl ester of a saturated or unsaturated fatty acid. In another embodiment, the glyceride mixture is present at a concentration of from about 3.0% wt./wt. to approximately 10.0% w/w. In another embodiment, the glyceride mixture is present at a concentration of from about 5.0% wt./wt. to approximately 10.0% w/w. In another embodiment, the glyceride mixture is present from about 6.0% wt./wt. to approximately 8.0% w/w.

In another embodiment, the topical pharmaceutical preparation further comprises a thickening agent. In another embodiment, the thickening agent is a wax. In another embodiment, the thickening agent is a wax, and the wax is selected from the group consisting of beeswax, paraffin wax and spermaceti wax. In another embodiment, the thickening agent is paraffin wax. In another embodiment, the thickening agent is present at a concentration of from about 3.0% wt./wt. to approximately 7.0% w/w. In an advantageous embodiment, the thickening

- 163 045319 the agent is present in a concentration of approximately 4.0% w/w. to approximately 6.0% w/w.

In another embodiment, the thickening agent is present in a concentration of about

4.5% w/w to approximately 5.5% w/w.

In another embodiment, the topical pharmaceutical preparation 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 ethylenediaminetetraacetic acid salt thereof, 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 approximately 0.0450% w/w.

A topical formulation for a compound of the present invention includes excipients providing at least one of the following functionality: a solvent; base; dispersing agent; emulsifying agent; thickening agent; rheology modification agent; stabilizing agent; and antioxidant. For example, acceptable topical ointment preparations for Example 4 include, but are not limited to, the preparations shown in table. 12, 13, 15 and 16. In addition to ointment preparations given in table. 12 and 13, other topical preparations suitable for the compounds of the present invention include, but are not limited to, creams, lotions, gels, solutions, suspensions, foams and sprays. Table 12

Amount (% w/w) Example 4 0.001 - 1 0.001 - 1 0.001 - 1 0.001 - 1 I 0.001 -1 I 0.001 - 1 Propylene glycol 2-9 Hexylene glycol Tran su go lol 2-9 Diisopropyl adipate 2 - 20 PEG400 Propylene carbonate 2-9 White Vaseline qs qs qs qs qs qs Mono- and diglycerides 0-7 0-7 0-7 0-7 0-7 0-7 Span 60 0-2 0-2 0-2 0-2 0-2 0-2 Span 40 0-2 0-2 0-2 0-2 0-2 0-2 Phospholipid 0-10 0-10 0-10 0-10 0-10 0-10 (lecithin) Butylated hydroxytoluene 0-0.1 0-0.1 0-0.1 0-0.1 0-0.1 0-0.1 Butylated hydroxyanisole 0-0.1 0-0.1 0-0.1 0-0.1 0-0.1 0-0.1 Paraffin wax 0-5 0-5 0-5 0-5 0-5 0-5 Total (%) 100.0 100.0 100.0 100.0 100.0 100.0

qs or sufficient quantity means sufficient quantity to obtain total=100%.

Preparations for topical use were prepared as those containing example 4, which were studied regarding skin permeability and maximum penetration of example 4, shown in table. 13.

Table 13

Amount (% w/w) Example 4 1 0.1 0.01 0 White 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 wax, 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 penetration assay or Franz cell assay was used to demonstrate the ability of the drugs listed in Table. 13 to ensure penetration of Example 4 through the stratum corneum barrier and motility through the epidermis and dermis by measuring penetration. The formulations exhibited concentration-dependent penetration through the skin (Table 14) and can contain 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.

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Table 14. Cumulative Amount Penetrated and Maximum Penetration for Example 4

Example 4 Preparations from Table 13 N* Average value, total for 24 hours, (ng) Std. error, total for 24 hours (ng) Average value, Max. passage, (ng/cm ² /h.) Std. error, Max. passage, (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

Table 15

Amount (% w/w) Example 4 0.001 -1 0.001 - 1 0.001 - 1 0.001 - 1 Medium chain triglycerides* 2-20 Crodamol GTCC 2-20 Crodamol GMCC 2-20 Triacetin 2-10 White Vaseline qs qs qs qs Mono- and diglycerides 0-7 0-7 0-7 0-7 Span 60 0-2 0-2 0-2 0-2 Span 40 0-2 0-2 0-2 0-2 Phospholipid (lecithin) 0- 10 0-10 0-10 0-10 Butylated hydroxytoluene 0-0.1 0-0.1 0-0.1 0-0.1 Butylated hydroxyanisole 0-0.1 0-0.1 0-0.1 0-0.1 Paraffin wax 0-5 0-5 0-5 0-5 Total (%) 100.0 100.0 100.0 100.0

*Medium chain triglycerides contain two or three fatty acids that have an aliphatic tail of 6-12 carbon atoms.

Table 16. Example 4. Ointment preparations for topical use

Component milligram/gram (mg/g) milligram/gram (mg/g) milligram/gram (mg/g) Example 4 0.100 0.300 0.600 Hexylene glycol 90,000 90,000 90,000 White Vaseline 788,900 788,700 788,400 Mono- and diglycerides 70,000 70,000 70,000 Paraffin wax 50,000 50,000 50,000 Butylated hydroxytoluene (BHT) 1,000 1,000 1,000 Total 1000,000 1000,000 1000,000

Biological analyses.

PDE4 SPA assay.

Phosphodiesterase (PDE) activity is determined by measuring the effect of the test agent on the activity of the PDE4B enzyme in a scintillation proximity assay (SPA). At the time of analysis, 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 various concentrations of the test compound. After ~10 min at room temperature (RT; ~21°C), the assay is initiated by adding 20 µl of a mixture of ^3H -labeled (adenosine 3',5'-cyclic phosphate, ammonium salt, [ ^2.8-3H ]; Perkin Elmer) and unlabeled cAMP. Final assay conditions are approximately 81.6 pM PDE4B in 50 mM Tris pH 7.5, 1.3 mM MgCl2, 0.004% Brij 35, 1 µM ³ H-labeled/unlabeled cAMP (1425 dpm/pmol) and the final test concentration indicated compounds (approximately 10 μM to 9.5 pM by 4-fold dilution). The final concentration of DMSO in the assay is approximately 2.0. After 30 min at room temperature, the assay is stopped 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 sit for at least 2 hours and the plate is then counted on a MicroBeta2 (Perkin Elmer). Concentrations and resulting effect values for the test compound are plotted and the compound concentration required for 50% effect (IC50) is determined using a four-parameter logistic dose response equation (E-WorkBook, ID Business Solutions Ltd.) and are shown in Table . 17.

Cytokine assays.

Cytokine inhibitory activity is determined by measuring the effect of the test agent on the release of the cytokines IL-4, IL-13, and IFNy from human peripheral blood mononuclear cells (PBMCs) stimulated with the T cell mitogen phytohemagglutinin-L (PHA-L). At the time of analysis, human PBMCs (Astarte Biologics) are removed from cryopreservation, quickly 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 250xg for 5 minutes. The resulting cell pellet is resuspended in assay medium to a concentration of approximately 5 x 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 assay medium and added to the wells of the assay plate in a volume of 25 μL. After ∼10 min at room temperature (∼21°C), cells are stimulated by adding 25 μl of PHA-L (14 μg/ml; Millipore) and the assay plate is placed in an incubator at 37°C in a humidified 5% carbon dioxide environment. The final assay conditions are approximately 250,000 human PBMCs per well in assay medium containing 3.5 μg/ml PHA-L and the specified final concentration of test compound (approximately 10 μM to 9.5 pM by 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 x g for 5 minutes. A portion of the resulting cell supernatant is then used to determine the amount of IL-4, IL-13, and IFNy in each well. Cytokine measurements are performed using human IL-4, IL-13, or IFNy HTRF assay kits (CisBio) according to the manufacturer's assay protocol. Concentrations and resulting effect values for the test compound are plotted and the compound concentration required for 50% effect (IC ₅₀ ) is determined using a four-parameter logistic dose response equation (E-WorkBook, ID Business Solutions Ltd.) and is shown in table 17.

Table 17

Example number PDE4B2 IC50 nM IL13 IC50 nM IL4 IC50 nM IFNy IC50 nM 1 3.16 284 14.34 2.98 2 0.67 1346 210.39 2.73 3 1.14 165 3.54 0.70 4 0.50 135 4.11 1.06 5 0.93 2394 36.33 4.04 6 1.05 283 17.58 0.72 7 0.97 289 7.76 0.71 8 2.42 25 0.76 1.20 9 1.26 265 3.63 1.87 10 6.92 438 2.39 1.62 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

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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

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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

- 168 045319

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

- 169 045319

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 major isoform of PDE4 in neutrophils and monocytes, and the PDE4B2 variant is the major subtype found in these cells associated with inflammation. Interferon gamma (IFNy), interleukin 4 (IL4), and interleukin 13 (IL13) are cytokines that are primarily produced by 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. Inhibiting the release of these inflammatory cytokines will modulate the inflammatory response.

It is understood that the preliminary detailed description and accompanying examples are illustrative only and should not be construed as limiting the scope of the invention, which is defined by the claims which are appended. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including, without limitation, changes that relate to chemical structures, substitutes, derivatives, intermediates, syntheses, preparations and/or methods of using the invention, may be made without departing from the spirit and scope of this invention.

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.

Powder X-ray diffraction analysis was carried out using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-α average value). The slit divergence was set to 15 mm constant radiation. Diffracted radiation was detected using a PSD-Lynx Eye detector, with the PSD detector opening set to 2.99 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a theta-theta goniometer at Cu wavelengths from 3.0 to 40.0 degrees 2-theta using a step size of 0.01 degrees and a step time of 1.0 s. The anti-scatter screen was set at a fixed distance of 1.5 mm. Samples were rotated at 15 rpm during collection. Samples were obtained by placing them in a silicon low-background sample holder and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed using EVA diffract plus software.

Data analysis was carried out using EVA diffract plus software (ver.

- 170 045319 this 4.2.1). The PXRD data file was not processed before peak searching. Using the peak finding algorithm in EVA software, peaks selected from a threshold of 1 were used for preliminary peak assignment. To ensure reliability, adjustments were made manually; the result of automatic assignment was checked visually and the position of the peaks was adjusted according to the maximum of the peak. In general, peaks with relative intensities >3% were selected. Peaks that were not resolved or were consistent with noise were not selected. The typical error associated with the peak position of a crystalline material from PXRD specified in the USP is within ±0.2° of 2-Theta (USP-941).

Table 18. List of PXRD peaks for (4-methoxy-3-propoxyphenyl)boronic acid

- 171 045319

Table 19. List of PXRD peaks for 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine

Angle 2-Theta ⁰ Relative intensity % 5.5 100 11.0 5.1 16.4 4.4 21.2 6.6 22.1 78.7 25.2 11.1 25.3 10.7 26.1 11.6 26.2 6.8 27.7 22 30.0 16.0 30.1 7.1 30.9 15.9 33.3 14.2 33.4 7.1 39.1 7.7 39.2 3.8

Table 20. List of PXRD peaks for 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

Angle 2-Theta° Relative intensity % 5.5 34.3 7.7 43.6 9.4 8.6 11.0 19.7 13.4 100.0 15.3 32.2 15.6 2.6 16.3 95.0 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

- 172 -

Claims (14)

CLAIM 1. Compound of formula (IA) or formula (IB) or a pharmaceutically acceptable salt thereof, wherein B represents boron; A ₁ and A2 are independently O or S; R1, R2 and R5 independently represent H, deuterium, (C ₁ -C _{6 )} alkoxy, (C ₁ -C ₆ )alkoxy-b _{1_13} , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-b ₁ _ ₁₃ , cyano, halogen or halogen(C1-C ₆ )alkyl; R3 and R4 are independently (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl _{- b1_13} , ( _C3 - _C8 )cycloalkyl, halogen( _C1 - _C6 )alkyl or hydroxy(C ₁ -C ₆ )alkyl; R ₆ , R ₇ and R ₉ are independently, H, deuterium, (C ₁ -C _{6 )} alkyl, (C ₁ -C ₆ )alkyl-b _{1_13} or halogen(C1-C ₆ )alkyl; and p represents 0. 2. Compound according to claim 1 of formula (IA) Rn OH ³ Λ Λ ^Re Г ⁰ θ)ρ r ₅ II J r<^nr ₉ Formula (IA) or a pharmaceutically acceptable salt thereof, wherein B represents boron; A ₁ and A ₂ are independently O or S; R1, _R2 and R5 are independently H, deuterium, (C1- _C6 )alkoxy, ( _C1 - _C6 )alkoxy- _{b1_13} , (C1- _C6 )alkyl, ( _C1 - _{C6 )} alkyl-b ₁ _ ₁₃ , cyano, halogen or halogen(C1-C ₆ )alkyl, R3 and _R4 are independently (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl _{-b1_13 ,} ( _C3 - _C8 )cycloalkyl, halogen(C1- _C6 )alkyl or hydroxy(C1 -C ₆ )alkyl; R6, R7 and _R9 are independently, H, deuterium, (C1- _{C6 )} alkyl, ( _C1 - _C6 )alkyl- _{b1_13} or halogen(C1- _C6 )alkyl; and p represents 0. 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A1 and A2 represent O; R1, R2 and R5 are independently H, cyano, halogen or halogen(C1- _C6 )alkyl; R3 and R4 are independently (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halogen(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 )alkyl or halogen(C1 -C ₆ )alkyl; and p represents 0. 4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A1 and A2 represent O; R1, R2 and R5 represent H; R3 and R4 are independently (C1- _C6 )alkyl, ( _C3 - _C8 )cycloalkyl, halogen(C1- _C6 )alkyl or hydroxy( _C1 - _C6 )alkyl; R ₆ , R ₇ and R ₉ are independently H or (C1-C ₆ )alkyl; and p represents 0. 5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A ₁ and A ₂ represent O; R1, R2 and _R5 represent H; R3 and R4 are independently (C1- _C6 )alkyl; R6, R7 and _R9 are independently H or (C1- _C6 )alkyl; and p represents 0. 6. Compound according to claim 1 of formula (IB) - 173 045319 Formula (IB) or a pharmaceutically acceptable salt thereof, wherein B represents boron; A ₁ and A2 are independently O or S; R1, R2 and _R5 are independently H, deuterium, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )alkoxy- _d1-13 , (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl-b _1-13 , cyano, halogen or halogen(C1-C ₆ )alkyl, R ₃ and R4 are independently (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 , (C ₃ -C ₈ )cycloalkyl, halogen(C1-C ₆ )alkyl or hydroxy( C1- _C6 )alkyl; R ₆ , R 7 and R ₉ are independently, H, deuterium, (C 1 -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-d _1-13 or halogen(C 1 -C ₆ )alkyl; and p represents 0. 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A1 and A2 represent O; R ₁ , R 2 and R ₅ are independently H, cyano, halogen, or halogen(C1-C ₆ )alkyl; R ₃ and R ₄ are independently (C1- _C6 )alkyl, ( _C3 - _C8 )cycloalkyl, halogen(C1- _C6 )alkyl or hydroxy(C1- _C6 )alkyl; R ₆ , R 7 and R ₉ are independently H, (C 1 -C ₆ )alkyl or halogen(C 1 -C ₆ )alkyl; and p represents 0. 8. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A ₁ and A ₂ represent O; R ₁ , R 2 and R ₅ represent H; _R3 and R4 are independently (C1- _C6 )alkyl, ( _C3 - _C8 )cycloalkyl, halogen(C1- _C6 )alkyl or hydroxy(C1- _C6 )alkyl; R ₆ , R 7 and R ₉ are independently H or (C 1 -C ₆ )alkyl; and p represents 0. 9. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein B represents boron; A1 and A2 represent O; R1, R2 and _R5 represent H; R ₃ and R4 represent (C1-C ₆ )alkyl; R6, R7 and _R9 are independently H or (C1- _C6 )alkyl; and p represents 0. 10. Compound (R)-4-(5-(4-methoxy-3-n-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol structure or a pharmaceutically acceptable salt thereof. 11. Crystalline form of (K)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan2-ol, having a powder X-ray diffraction pattern containing diffraction peaks 11.0±0 ,2, 22.9±0.2 and 25.1±0.2 degrees two theta. 12. The crystalline form according to claim 11, having a powder X-ray diffraction pattern additionally containing diffraction peaks of 11.4±0.2, 18.8±0.2 and 26.4±0.2 degrees two theta. 13. Compound (S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol structure or a pharmaceutically acceptable salt thereof. 14. Crystalline form of (8)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan2-ol having an X-ray powder diffraction pattern containing diffraction peaks - 174 -