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BMS-960

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BMS-960

PRECLINICAL

(S)-1-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic Acid

3-Piperidinecarboxylic acid, 1-[(2S)-2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-5-isoxazolyl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]-, (3S)-

(S)-1-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic Acid

CAS 1265321-86-5 FREE FORM

FREE FORM 528.48, C₂₆ H₂₃ F₃ N₄ O₅

CAS 1265323-40-7 HCL SALT

BASIC PATENT WO201117578, 2011, (US Patent 8399451)

Inventors	John L. Gilmore, James E. Sheppeck
Applicant	Bristol-Myers Squibb Company

Image result for Bristol-Myers Squibb Company

Sphingosine-1-phosphate (S1P) is the endogenous ligand for the sphingosine-1-phophate receptors (S1P_1–5) and triggers a number of cellular responses through their stimulation. S1P and its interaction with the S1P receptors play a significant role in a variety of biological processes including vascular stabilization, heart development, lymphocyte homing, and cancer angiogenesis. Agonism of S1P₁, especially, has been shown to play an important role in lymphocyte trafficking from the thymus and secondary lymphoid organs, inducing immunosuppression, which has been established as a novel mechanism of treatment for immune diseases and vascular diseases

Sphingosine-1 -phosphate (SlP) has been demonstrated to induce many cellular effects, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell and leukocyte chemotaxis, endothelial cell in vitro angiogenesis, and lymphocyte trafficking. SlP receptors are therefore good targets for a wide variety of therapeutic applications such as tumor growth inhibition, vascular disease, and autoimmune diseases. SlP signals cells in part via a set of G protein-coupled receptors named SlPi or SlPl, SlP₂ or S1P2, SlP₃ or S1P3, SlP₄ Or S1P4, and SlP₅ or S1P5 (formerly called EDG-I, EDG-5, EDG-3, EDG-6, and EDG-8, respectively).

SlP is important in the entire human body as it is also a major regulator of the vascular and immune systems. In the vascular system, SlP regulates angiogenesis, vascular stability, and permeability. In the immune system, SlP is recognized as a major regulator of trafficking of T- and B-cells. SlP interaction with its receptor SlPi is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Therefore, modulation of SlP receptors was shown to be critical for immunomodulation, and SlP receptor modulators are novel immunosuppressive agents.

The SlPi receptor is expressed in a number of tissues. It is the predominant family member expressed on lymphocytes and plays an important role in lymphocyte trafficking. Downregulation of the SlPi receptor disrupts lymphocyte migration and homing to various tissues. This results in sequestration of the lymphocytes in lymph organs thereby decreasing the number of circulating lymphocytes that are capable of migration to the affected tissues. Thus, development of an SlPi receptor agent that suppresses lymphocyte migration to the target sites associated with autoimmune and aberrant inflammatory processes could be efficacious in a number of autoimmune

Among the five SlP receptors, SlPi has a widespread distribution and is highly abundant on endothelial cells where it works in concert with SIP3 to regulate cell migration, differentiation, and barrier function. Inhibition of lymphocyte recirculation by non-selective SlP receptor modulation produces clinical immunosuppression preventing transplant rejection, but such modulation also results in transient bradycardia. Studies have shown that SlPi activity is significantly correlated with depletion of circulating lymphocytes. In contrast, Sl P3 receptor agonism is not required for efficacy. Instead, SIP3 activity plays a significant role in the observed acute toxicity of nonselective SlP receptor agonists, resulting in the undesirable cardiovascular effects, such as bradycardia and hypertension. (See, e.g., Hale et al, Bioorg. Med. Chem. Lett., 14:3501 (2004); Sanna et al., J. Biol. Chem., 279: 13839 (2004); Anliker et al., J. Biol. Chem., 279:20555 (2004); Mandala et al., J. Pharmacol. Exp. Ther., 309:758 (2004).)

An example of an SlPi agonist is FTY720. This immunosuppressive compound FTY720 (JPI 1080026-A) has been shown to reduce circulating lymphocytes in animals and humans, and to have disease modulating activity in animal models of organ rejection and immune disorders. The use of FTY720 in humans has been effective in reducing the rate of organ rejection in human renal transplantation and increasing the remission rates in relapsing remitting multiple sclerosis (see Brinkman et al., J. Biol. Chem., 277:21453 (2002); Mandala et al., Science, 296:346 (2002); Fujino et al., J.

Pharmacol. Exp. Ther., 305:45658 (2003); Brinkman et al, Am. J. Transplant., 4: 1019 (2004); Webb et al., J. Neuroimmunol, 153: 108 (2004); Morris et al., Eur. J. Immunol, 35:3570 (2005); Chiba, Pharmacology & Therapeutics, 108:308 (2005); Kahan et al., Transplantation, 76: 1079 (2003); and Kappos et al., N. Engl. J. Med., 335: 1124 (2006)). Subsequent to its discovery, it has been established that FTY720 is a prodrug, which is phosphorylated in vivo by sphingosine kinases to a more biologically active agent that has agonist activity at the SlPi, SIP3, SlP₄, and SIP5 receptors. It is this activity on the SlP family of receptors that is largely responsible for the pharmacological effects of FTY720 in animals and humans. [0007] Clinical studies have demonstrated that treatment with FTY720 results in bradycardia in the first 24 hours of treatment (Kappos et al, N. Engl. J. Med., 335: 1124 (2006)). The observed bradycardia is commonly thought to be due to agonism at the SIP₃ receptor. This conclusion is based on a number of cell based and animal experiments. These include the use of SIP3 knockout animals which, unlike wild type mice, do not demonstrate bradycardia following FTY720 administration and the use of SlPi selective compounds. (Hale et al., Bioorg. Med. Chem. Lett., 14:3501 (2004); Sanna et al., J. Biol. Chem., 279: 13839 (2004); and Koyrakh et al., Am. J. Transplant, 5:529 (2005)).

The following applications have described compounds as SlPi agonists: WO 03/061567 (U.S. Patent Publication No. 2005/0070506), WO 03/062248 (U.S. Patent No. 7,351,725), WO 03/062252 (U.S. Patent No. 7,479,504), WO 03/073986 (U.S. Patent No. 7,309,721), WO 03/105771, WO 05/058848, WO 05/000833, WO 05/082089 (U.S. Patent Publication No. 2007/0203100), WO 06/047195, WO 06/100633, WO 06/115188, WO 06/131336, WO 2007/024922, WO 07/109330, WO 07/116866, WO 08/023783 (U.S. Patent Publication No. 2008/0200535), WO 08/029370, WO 08/114157, WO 08/074820, WO 09/043889, WO 09/057079, and U.S. Patent No. 6,069,143. Also see Hale et al., J. Med. Chem., 47:6662 (2004).

There still remains a need for compounds useful as SlPi agonists and yet having selectivity over Sl P3.

Applicants have found potent compounds that have activity as SlPi agonists. Further, applicants have found compounds that have activity as SlPi agonists and are selective over SIP3. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

SYNTHESIS

(S)-1-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid, HCl (BMS-960). CAS 1265323-40-7

(S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid, HCl (BMS-960)

¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (br. s, 1H), 10.5 (br. s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.69–7.57 (m, 5H), 6.43 (br. s., 1H), 5.37 (d, J = 10.8 Hz, 1H), 3.89–3.60 (m, 2H), 3.50–2.82 (m, 6H), 2.14–1.99 (m, 1H), 1.97–1.75 (m, 1H), 1.63–1.35 (m, 1H);

¹³C NMR (101 MHz, CDCl₃) δ 172.8, 168.5, 164.0, 161.6, 155.4, 156.2, 131.2, 129.0, 128.9, 127.4, 127.2, 125.5, 124.3, 122.2, 111.6, 66.6. 63.0, 52.9, 52.2, 38.8, 25.0, 21.7;

¹⁹F NMR (376 MHz, DMSO-d₆) δ −54.16;

Anal. calcd for C₂₆H₂₃F₃N₄O₅·HCl: C, 54.71; H, 4.36; N, 9.80. Found: C, 54.76; H, 3.94; N, 9.76;

HRMS (ESI) m/e 529.17040 [(M + H)⁺, calcd for C₂₆ H₂₄ N₄ O₅ F₃ 529.16933].

PATENT

WO 2011017578

Example 14

(S)-l-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

Preparation 14A: (3S)-Ethyl l-(2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3- carboxylate

(14A)-isomer A (14A)-isomer B [00210] To a mixture of (S)-ethyl piperidine-3-carboxylate (1.3 g, 8.27 mmol) in toluene (50 mL) was added 4-(2-bromoacetyl)benzonitrile (2.4 g, 10.71 mmol). The reaction mixture was stirred overnight. LCMS indicated completion of reaction. MeOH (10 mL) was added to the mixture, followed by the portionwise addition of sodium borohydride (0.313 g, 8.27 mmol). After 1 hour, LCMS show complete reduction to the desired alcohol. The reaction was quenched with water. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO₄, filtered, concentrated, and purified on a silica gel cartridge using an EtOAc/hexanes gradient to yield 2.0 g of solid product. The product was separated by chiral HPLC (Berger SFC MGIII instrument equipped with a CHIRALCEL® OJ (25 x 3 cm, 5 μM). Temp: 30 ⁰C; Flow rate: 130 mL/min; Mobile phase: C(V(MeOH +

0.1%DEA) in 9: 1 ratio isocratic:

[00211] Peak 1 (Isomer A): RT = 2.9 min. for (S)-ethyl l-((S)-2-(4-cyanophenyl)-2- hydroxyethyl)piperidine-3-carboxylate (>99% d.e.). The absolute and relative stereochemistry of compound 14A-isomer A was assigned (S,S) by X-ray crystal structure (see Alternative Route data). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.63 (2 H, m, J=8.35 Hz), 7.49 (2 H, m, J=8.35 Hz), 4.77 (1 H, dd, J=10.55, 3.52 Hz), 4.17 (2 H, q, J=7.03 Hz), 3.13 (1 H, d, J=9.23 Hz), 2.53-2.67 (3 H, m), 2.44 (2 H, dd, J=18.68, 9.89 Hz), 2.35 (1 H, dd, J=12.74, 10.55 Hz), 1.87-2.01 (1 H, m), 1.71-1.82 (1 H, m), 1.52-1.70 (2 H, m), 1.28 (3 H, t, J=7.03 Hz).

[00212] Peak 2 (Isomer B): RT = 3.8 min for (S)-ethyl l-((R)-2-(4-cyanophenyl)-2- hydroxyethyl)piperidine-3-carboxylate (>99% d.e.). The absolute and relative stereochemistry of 14A-isomer B was assigned (S,R) based on the crystal structure of 14A-isomer A. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.63 (2 H, m, J=8.35 Hz), 7.49 (2 H, m, J=8.35 Hz), 4.79 (1 H, dd, J=10.55, 3.52 Hz), 4.16 (2 H, q, J=7.03 Hz), 2.69-2.91 (3 H, m), 2.60-2.68 (1 H, m), 2.56 (1 H, dd, J=12.30, 3.52 Hz), 2.36 (1 H, dd, J=12.52, 10.77 Hz), 2.25 (1 H, t, J=8.79 Hz), 1.65-1.90 (3 H, m), 1.52-1.64 (1 H, m, J=12.69, 8.49, 8.49, 4.17 Hz), 1.27 (3 H, t, J=7.25 Hz).

[00213] (S)-Ethyl l-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (14A-isomer A) was carried forward to make Example 14 and (S)-ethyl l-((R)-2-(4- cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (14A-isomer B) was carried forward to make Example 15.

Preparation 14B: (S)-Ethyl l-((S)-2-hydroxy-2-(4-((Z)-N’-hydroxycarbamimidoyl) phenyl)ethyl)piperidine-3 -carboxylate

[00214] To a mixture of ((S)-ethyl l-((S)-2-hydroxy-2-(4-((Z)-N’- hydroxycarbamimidoyl) phenyl)ethyl)piperidine-3 -carboxylate (14A-Isomer A) (58 mg, 0.192 mmol) and hydroxylamine hydrochloride (26.7 mg, 0.384 mmol) in 2-propanol (10 mL) was added sodium bicarbonate (64.5 mg, 0.767 mmol). The reaction mixture was heated at 85 ⁰C. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSO₄, filtered, and concentrated to yield 56 mg. MS (M+l) = 464. HPLC Peak RT = 1.50 minutes.

Preparation 14C: (S)-Ethyl l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate

[00215] 3-Phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, InM-G (214 mg, 0.78 mmol) was dissolved in acetonitrile (5.00 mL). DIEA (0.272 mL, 1.555 mmol) and (S)-ethyl- 1 -((S)-2-hydroxy-2-(4-((Z)-N’-hydroxycarbamimidoyl) phenyl)ethyl)- piperidine-3-carboxylate (261 mg, 0.778 mmol) were added. The reaction mixture was stirred for 2 hours, then IM TBAF in THF (0.778 mL, 0.778 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and purified by HPLC in three batches. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250 x 30mm); 25-100% CH₃CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were partitioned between EtOAc and saturated NaHCO₃ with back extracting aqueous layer once. The organic layer was dried with MgSO₄, filtered, and concentrated to give 155mg of (S)- ethyl l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxylate. ¹H NMR (400 MHz, MeOH-d₃) δ ppm 8.04 (2 H, d, J=8.13 Hz), 7.55-7.60 (2 H, m), 7.41-7.54 (5 H, m), 4.81 (1 H, ddd, J=8.35, 4.06, 3.84 Hz), 3.96-4.10 (2 H, m), 2.82-3.08 (1 H, m), 2.67-2.82 (1 H, m), 2.36- 2.61 (3 H, m), 2.08-2.33 (2 H, m), 1.73-1.87 (1 H, m, J=8.54, 8.54, 4.45, 4.17 Hz), 1.32- 1.70 (3 H, m), 1.09-1.19 (3 H, m). MS (m+l) = 557. HPLC Peak RT = 3.36 minutes. Purity = 99%.

Example 14: [00216] (S)-Ethyl l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5- yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (89 mg, 0.16 mmol) was heated at 50 ⁰C in 6N HCl (5 mL) in acetonitrile (5 mL). The reaction mixture was stirred overnight and then filtered and purified by HPLC. HPLC conditions:

PHENOMENEX® Luna C 18 5 micron column (250 x 30mm); 25-100% CH₃CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 36 mg of (S)-l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidine-3- carboxylic acid as a TFA salt. ¹H NMR (400 MHz, MeOH-d₃) δ ppm 8.23 (2 H, d, J=8.35 Hz), 7.65-7.74 (4 H, m), 7.54-7.65 (3 H, m), 5.29 (1 H, t, J=7.03 Hz), 4.00 (1 H, br. s.), 3.43-3.75 (1 H, m), 3.34-3.41 (2 H, m), 2.82-3.24 (2 H, m), 2.26 (1 H, d, J=I 1.86 Hz), 1.84-2.14 (2 H, m), 1.52-1.75 (1 H, m). MS (m+1) = 529. HPLC Peak RT = 3.24 minutes. Purity = 98%. Example 14-Alternate Synthesis Route 1

Preparation 14D (Alternate Synthesis Route 1): (S)-4-(Oxiran-2-yl)benzonitrile

[00217] To 800 mL of 0.2M, pH 6.0 sodium phosphate buffer in a 2 L flask equipped with an overhead stirrer was added D-glucose (38.6 g, 1.2 eq), β-nicotinamide adenine dinucleotide, free acid (1.6 g, mmol), glucose dehydrogenase (36 mg, 3.2 kU,

CODEXIS® GDH- 102, 90 U/mg), and enzyme KRED-NADH-110 (200 mg,

CODEXIS®, 25 U/mg). The vessels containing the reagents above were rinsed with 200 mL of fresh sodium phosphate buffer and added to the reaction which was stirred to dissolution and then heated to 40 ⁰C. To this mixture was added a solution of 2-bromo- 4′-cyanoacetophenone (40 g, 178.5 mmol) in 100 mL DMSO through an addition funnel in about 30 min. The container was rinsed with 20 mL DMSO and the rinse was added to the reactor. A pH of 5.5-6.0 was maintained by adding 1 M NaOH through a fresh addition funnel (total volume of 200 mL over 6h) after which HPLC showed complete consumption of the starting material. The reaction mixture was extracted with 800 mL MTBE x 2 and the combined extracts were washed with 300 mL of 25% brine. The crude alcohol was transferred to a 3L 3-neck flask and treated with solid NaOtBu (34.3 g, 357 mmol) stirring for 1 h and then additional NaOtBu (6.9 g, 357 mmol) and stirring for 30 min. The reaction mixture was filtered and the solution was washed with 300 mL 0.2 M pH 6.0 sodium phosphate buffer, brine, and then the solvent was removed in vacuo and the resulting white solid was dried in a vacuum oven to give (S)-4-(oxiran-2- yl)benzonitrile (23 g, 90% yield, 100% e.e.). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62 (2 H, d), 7.35 (2 H, d), 3.88 (1 H, dd), 3.18 (1 H, app t), 2.73 (1 H, dd) Purity = 99%.

[00218] Chiral HPLC was done on a CHIRALP AK® AD-RH 4.6x150mm (Daicel Chemical Industries Ltd.) column using gradient of solvent A (10 mM NH₄OAc in water/acetonitrile, 90: 10) and solvent B (10 mM NH₄OAc in water/acetonitrile, 10:90) with 70% to 90% in 40 min at a flow rate of 0.5 ml/min at ambient temperature. The detection employed UV at 235 nm. The retention times are as follows:

[00219] Peak 1 (Isomer A): RT = 16.7 min. for (S)-4-(oxiran-2-yl)benzonitrile

[00220] Peak 2 (Isomer B): RT = 14.0 min. for (R)-4-(oxiran-2-yl)benzonitrile Preparation of 14A-isomer A (Alternate Synthesis Route 1): (S)-Ethyl l-((S)-2-(4- cyanophenyl)-2 -hydroxy ethyl)piperidine-3-carboxylate

(14A)-isomer A

[00221] (S)-4-(Oxiran-2-yl)benzonitrile (10.00 g, 68.9 mmol), (S)-ethyl piperidine-3- carboxylate (10.83 g, 68.9 mmol) and iPrOH (100 mL) was charged into a round bottom flask under N₂. After heating at 55 ⁰C for 4 hours, 4-dimethylaminopyridine (1.683 g, 13.78 mmol) was then added. The reaction mixture was then heated to 50 ⁰C for an additional 12 hours. At this time HPLC indicated the starting material was completely converted to the desired product. The reaction mixture was then cooled to room temperature. EtOAc (120 ml) was added, followed by 100 ml of water. The organic layer was separated, extracted with EtOAc (2x 100 mL) and concentrated under vacuo to give a crude product. The crude product was recrystallized from EtOH/EtOAc/H₂O (3/2/2) (8ml/lg) to give a crystalline off-white solid 14A-alt (15 g, 72% yield, 99.6% e.e.). The absolute and relative stereochemistry was determined by single X-ray crystallography employing a wavelength of 1.54184 A. The crystalline material had an orthorhombic crystal system and unit cell parameters approximately equal to the following:

a = 5.57 A α = 90.0°

b = 9.7l A β = 90.0°

c = 30.04 A γ = 90.0°

Space group: P2₁2₁2₁

Molecules/asymmetric unit: 2

Volume/Number of molecules in the unit cell = 1625 A³

Density (calculated) = 1.236 g/cm³

Temperature 298 K.

Preparation 14E (Alternate Route 1): (S)-Ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2- (4-cyanophenyl)ethyl)piperidine-3-carboxylate

[00222] To a mixture of (S)-ethyl 1 -((S)-2-(4-cyanophenyl)-2-hydroxy ethyl) piperidine-3-carboxylate (17.0 g, 56.2 mmol) and DIPEA (17.68 ml, 101 mmol) in CH₂Cl₂ (187 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (16 ml, 69.6 mmol) slowly. The reaction was monitored with HPLC. The reaction completed in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted with DCM. The organic phase was combined and dried with Na₂SO₄. After concentration, the crude material was further purified on a silica gel cartridge (33Og silica, 10-30% EtOAc/hexanes gradient) to afford a purified product (S)- ethyl 1 -((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl) piperidine-3 – carboxylate (22.25 g, 53.4 mmol, 95 % yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.61 (2 H, d), 7.45 (2 H, d), 4.79 (1 H, m), 4.15 (2 H, m), 2.88 (1 H, m), 2.75 (1 H, m), 2.60 (1 H, dd), 2.48 (1 H, m), 2.40 (1 H, dd), 2.33 (1 H, tt), 2.12 (1 H, tt), 1.90 (1 H, m), 1.68 (1 H, dt), 1.52 (1 H, m), 1.48 (1 H, m), 1.27 (3 H, t), 0.89 (9 H, s), 0.08 (3 H, s), -0.07 (3 H, s).

Preparation 14F (Alternate Route 1): (S)-Ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2- (4-((Z)-N’-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate

[00223] (S)-Ethyl- 1 -((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl) piperidine-3-carboxylate (31.0 g, 74.4 mmol) was dissolved in EtOH (248 mL).

Hydroxylamine (50% aq) (6.84 ml, 112 mmol) was added and stirred at room temperature overnight. Then all volatiles were removed with ROTA VAPOR®. The residue was purified with on a silica gel cartridge (33Og silica, 0-50% EtOAc/hexanes gradient) to give (S)-ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N’- hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (31 g, 68.9 mmol, 93 % yield) as a white foam. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 (1 H, br s), 7.58 (2 H, d), 7.37 (2 H, d), 4.88 (2 H, br s), 4.81 (1 H, m), 4.13 (2 H, m), 2.96 (1 H, m), 2.82 (1 H, m), 2.61 (1 H, dd), 2.51 (1 H, m), 2.42 (1 H, dd), 2.32 (1 H, tt), 2.13 (1 H, dt), 1.91 (1 H, m), 1.66 (1 H, dt), 1.58 (1 H, m), 1.48 (1 H, m), 1.27 (3 H, t), 0.89 (9 H, s), 0.08 (3 H, s), -0.09 (3 H, s). Preparation 14G (Alternate Route 1): (S)-Ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2- (4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3- yl)phenyl)ethyl)piperidine-3-carboxylate

[00224] (S)-Ethyl- 1 -((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N’- hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (32.6g, 72.5 mmol) was dissolved in acetonitrile (145 ml) (anhydrous) and cooled to ~3 ⁰C with ice-bath. 3- phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl chloride (19.98 g, 72.5 mmol) was dissolved in 5OmL anhydrous acetonitrile and added dropwise. The internal temperature was kept below 10 ⁰C during addition. After addition, the reaction mixture was allowed to warm to room temperature. At 30 minutes, HPLC showed completion of the first reaction step. The reaction mixture was re-cooled to below 10 ⁰C. DIEA (18.99 ml, 109 mmol) was added slowly. After the addition, the reaction mixture was heated up to 55 ⁰C for 17 hr s. HPLC/LCMS showed completion of the reaction. The solvents were removed by ROTA VAPOR®. The residue was stirred in 25OmL 20% EtOAc/hexanes and the DIPEA HCl salt precipitated from solution and was removed via filtration. The filtrate was concentrated and purified using a silica gel cartridge (3X33Og silica, 0-50%

EtOAc/hexanes gradient). (S)-ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3- phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3- carboxylate (43g, 64.1 mmol, 88 % yield) was obtained a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (2 H, d), 7.68 (2 H, d), 7.57 (5 H, m), 4.85 (1 H, m), 4.14 (2 H, m), 2.95 (1 H, m), 2.82 (1 H, m), 2.64 (1 H, dd), 2.51 (1 H, m), 2.49 (1 H, dd), 2.35 (1 H, tt), 2.14 (1 H, dt), 1.91 (1 H, m), 1.66 (1 H, dt), 1.57 (1 H, m), 1.48 (1 H, m), 1.27 (3 H, t), 0.92 (9 H, s), 0.11 (3 H, s), -0.05 (3 H, s).

Example 14 (Alternate Route 1): (S)-l-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3- carboxylic acid

[00225] (S)-Ethyl l-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3- carboxylate (42g, 62.6 mmol) was dissolved in dioxane (150 ml) and treated with 6M HCl (150 ml). The reaction mixture was heated to 65 ⁰C for 6 hours (the reaction was monitored with HPLC, EtOH was distilled out to push the equilibrium forward). Dioxane was removed and the residue was redissolved in ACN/water and lyophilized separately to give crude (S)-l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid, HCl, (37g crude foamy solid). The crude solid (36 g, 63.7 mmol) was suspended in acetonitrile (720 mL) and heated to 60 ⁰C and water (14.4 mL) was added dropwise. A clear solution was obtained, which was cooled to room temperature and concentrated to a viscous oil, treated with ethyl acetate (1.44 L) with vigorously stirring, heated to 60 ⁰C, and cooled to room temperature. (S)-l-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxylic acid, HCl (28g, 49.3 mmol, 77 % yield) was collected and vacuum dried. Characterization of product by ¹H NMR and chiral HPLC matched Example 14 prepared in previous synthesis.

Preparation of Intermediate (14A)-isomer A-Alternate Route 2; 2-Steps: (S)-Ethyl 1- ((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate

(14A)-isomer A

Step 1 : Preparation (14D) (Alternate Route 2): (S)-Ethyl l-(2-(4-cyanophenyl)-2- oxoethyl)piperidine-3-carboxylate hydrobromide

(14D)-isomer A

[00226] To a solution of commercially available (S)-ethyl piperidine-3-carboxylate (10 g, 63.6 mmol) in 200 mL toluene was added 4-(2-bromoacetyl)benzonitrile (17g, 76 mmol). The reaction mixture was stirred overnight. The next day, the precipitated solid was collected by filtration and washed with ethyl acetate (x3) and dried under vacuum to give 15.2g of (S)-ethyl l-(2-(4-cyanophenyl)-2-oxoethyl)piperidine-3-carboxylate hydrobromide. MS (M+ 1) = 301. HPLC Peak RT = 1.51 minutes.

Step 2: Preparation of 14 A-isomer A (Alternate Route 2): (S)-Ethyl l-((S)-2-(4- cyanophenyl)-2-hydroxyethyl)piperidine-3 -carboxylate

[00227] Phosphate buffer (1100 mL, BF045, pH 7.0, 0. IM) was added into two liter jacketed glass reactor. The temperature of the reactor was adjusted to 20 ⁰C with the help of a circulator and the reaction mixture was stirred with a magnetic stirrer. Dithiothretol (185.2 mg, 1 mM), magnesium sulfate (288.9 mg, 2 mM), and D-glucose (11.343 g, 62.95 m moles) were added into the reactor. (5^*)-Ethyl l-(2-(4-cyanophenyl)-2-oxoethyl) piperidine-3 -carboxylate HBr salt (12 g, 31.47 m moles dissolved in 60 mL DMSO) was added into the reactor slowly with continuous stirring, β-nicotinamide adenine dinucleotide phosphate sodium salt (NADP), 918.47 mg, glucose dehydrogenase, 240 mg (total 18360 U, 76.5 U/mg, ~ 15U/mL, Amano Lot. GDHY1050601) and KRED-114, 1.2 g (CODEXIS® assay 7.8 U/mg of solid), were dissolved in 2.0 mL, 2.0 mL and 10 ml of the same buffer, respectively. Next, NADP, GDH and KRED-114 were added to the reactor in that order. The remaining 26 mL of same buffer was used to wash the NADP, GDH and KRED-114 containers and buffer was added into the same reactor. The starting pH of the reaction was 7.0 which decreased with the progress of the reaction and was maintained at pH 6.5 during the course of the reaction (used pH stat, maintained with IM NaOH). The reaction was run for 4.5 hours and immediately stopped and extracted with ethyl acetate. The ethyl acetate solution was evaporated under reduced pressure and weight of the dark brown residue was 12.14 g. The product was precipitated with dichloromethane and heptane to give 9 g of crude product which was further purified by dissolving it in minimum amount of dichloromethane and re-precipitating by the addition of excess amount of heptane to give 5.22 g. The process was repeated to give an additional 2.82 g of highly pure product for a total of 8.02 g of de > 99.5%.

[00228] Chiral HPLC was done on a CHIRALP AK® AD-RH 4.6x150mm (Daicel Chemical Industries Ltd.) column using gradient of solvent A (10 mM NH₄OAc in water/acetonitrile, 90: 10) and solvent B (IO mM NH₄OAc in water/acetonitrile, 10:90) with 70% to 90% in 40 min at a flow rate of 0.5 ml/min at ambient temperature. The detection was done by UV at 235 nm. The retention times are as follows: [00229] Peak 1 (14A-isomer A): RT = 20.7 min. for (S)-ethyl l-((S)-2-(4- cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate.

[00230] Peak 2 (14B-isomer B): RT = 30.4 min. for (S)-ethyl l-((R)-2-(4- cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate.

[00231] Compound 14A-isomer A prepared using this asymmetric method was unambiguously assigned since it was identical to the 14A-isomer A (by ¹H NMR and chiral HPLC retention time) that was prepared above and determined by X-ray crystallography. Synthesis of Example 14 from this material followed the same route as described above.

paper

Regioselective Epoxide Ring Opening for the Stereospecific Scale-Up Synthesis of BMS-960, A Potent and Selective Isoxazole-Containing S1P₁Receptor Agonist

Xiaoping Hou ^*^†

, Huiping Zhang^†, Bang-Chi Chen^†, Zhiwei Guo^‡, Amarjit Singh^‡, Animesh Goswami^‡, John L. Gilmore^†, James E. Sheppeck^†, Alaric J. Dyckman^†

, Percy H. Carter^†, and Arvind Mathur^†

^† Discovery Chemistry, Bristol-Myers Squibb, Princeton, New Jersey 08540, United States

^‡ Chemical & Synthetic Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00366

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00366

*E-mail: xiaoping.hou@bms.com.

This article presents a stereospecific scale-up synthesis of (S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (BMS-960), a potent and selective isoxazole-containing S1P₁ receptor agonist. The process highlights an enzymatic reduction of α-bromoketone toward the preparation of (S)-bromo alcohol, a key precursor of (S)-4-(oxiran-2-yl)benzonitrile. A regioselective and stereospecific epoxide ring-opening reaction was also optimized along with improvements to 1,2,4-oxadiazole formation, hydrolysis, and crystallization. The improved process was utilized to synthesize batches of BMS-960 for Ames testing and other toxicological studies.

PAPER

Journal of Medicinal Chemistry (2016), 59(13), 6248-6264.

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P₁)

Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543, United States

J. Med. Chem., 2016, 59 (13), pp 6248–6264

DOI: 10.1021/acs.jmedchem.6b00373

*Phone: 609-252-3153. E-mail: john.gilmore@bms.com.

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P₁ receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P₁ agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P₁ agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P₃ are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).

BASE

(S)-1-((S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic Acid (18a)

(S)-ethyl 1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (36%).

¹H NMR (400 MHz, MeOH-d₃) δ ppm 8.04 (2 H, d, J = 8.13 Hz), 7.55–7.60 (2 H, m), 7.41–7.54 (5 H, m), 4.81 (1 H, ddd, J = 8.35, 4.06, 3.84 Hz), 3.96–4.10 (2 H, m), 2.82–3.08 (1 H, m), 2.67–2.82 (1 H, m), 2.36–2.61 (3 H, m), 2.08–2.33 (2 H, m), 1.73–1.87 (1 H, m, J = 8.54, 8.54, 4.45, 4.17 Hz), 1.32–1.70 (3 H, m), 1.09–1.19 (3 H, m).

MS (M + H)⁺ at m/z 557. HPLC purity: 99%, t_r = 3.36 min (method B).

TFA salt

(S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid, TFA salt (18a, 61%) as a white solid.

¹H NMR (400 MHz, MeOH-d₃) δ ppm 8.23 (2 H, d, J = 8.35 Hz), 7.65–7.74 (4 H, m), 7.54–7.65 (3 H, m), 5.29 (1 H, t, J = 7.03 Hz), 4.00 (1 H, br s), 3.43–3.75 (1 H, m), 3.34–3.41 (2 H, m), 2.82–3.24 (2 H, m), 2.26 (1 H, d, J = 11.86 Hz), 1.84–2.14 (2 H, m), 1.52–1.75 (1 H, m).

MS (M + H)⁺ at m/z 529.

HPLC t_r = 3.27 min (method B). HPLC purity: 99.4%, t_r = 8.78 min (method E); 99.0%, t_r = 7.29 min (method F).

HCL SALT

This material was converted to the HCl salt for the following analyses: mp: 219.2 °C. Anal. Calcd for C₂₆H₂₃N₄O₅F₃·HCl: 0.14% water: C, 55.2; H, 4.31; N, 9.87; Cl, 6.25. Found: C, 55.39; H, 4.10; N, 9.88; Cl, 6.34. [α]_D²⁰ + 30.47 (c 0.336, MeOH). HPLC with chiral stationary phase (A linear gradient using CO₂ (solvent A) and IPA with 0.1% DEA (solvent B); t = 0 min, 30% B, t = 10 min, 55% B was employed on a Chiralcel AD-H 250 mm × 4.6 mm ID, 5 μm column; flow rate was 2.0 mL/min): t_r = 5.38 min with >99% ee.

References

Gilmore, J. L.; Sheppeck, J. E.; Watterson, S. H.; Haque, L.; Mukhopadhyay, P.; Tebben, A. J.; Galella, M. A.; Shen, D. R.; Yarde, M.; Cvijic, M. E.; Borowski, V.; Gillooly, K.; Taylor, T.; McIntyre, K. W.; Warrack, B.; Levesque, P. C.; Li, J. P.; Cornelius, G.; D’Arienzo, C.; Marino, A.; Balimane, P.; Salter-Cid, L.; Barrish, J. C.; Pitts, W. J.; Carter, P. H.; Xie, J.; Dyckman, A. J.Discovery and Structure Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-Phosphate (S1P₁) J. Med. Chem. 2016, 59, 6248– 6264, DOI: 10.1021/acs.jmedchem.6b00373

Gilmore, J. L.; Sheppeck, J. E. Preparation of 3-(4-(1-hydroxyethyl)phenyl)-1,2,4-oxadiazole derivatives as sphingosine-1-phosphate receptor agonists for the treatment of autoimmune disease and inflammation. PCT Int. Appl. 2011, WO 2011017578.

//////BMS-960, PRECLINICAL, BMS 960

Cl.O=C(O)[C@H]1CCCN(C1)C[C@@H](O)c2ccc(cc2)c3nc(on3)c5onc(c4ccccc4)c5C(F)(F)F

DNDI-VL-2098

December 19, 2016 9:22 am / Leave a comment

DNDI-VL-2098

CAS 681492-17-1

(R)-2-Methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole

Watch this post, will be updated………..

MF C₁₄ H₁₂ F₃ N₃ O_5,

_{MW 359.26}

Imidazo[2,1-b]oxazole, 2,3-dihydro-2-methyl-6-nitro-2-[[4-(trifluoromethoxy)phenoxy]methyl]-, (2R)-

Hidetsugu Tsubouchi, Hirofumi Sasaki, Hideaki Kuroda, Motohiro Itotani, Takeshi Hasegawa, Yoshikazu Haraguchi, Takeshi Kuroda, Takayuki Matsuzaki, Kuninori Tai, Makoto Komatsu, Makoto Matsumoto, Hiroyuki Hashizume, Tatsuo Tomishige, Yuji Seike, Masanori Kawasaki, Takumi Sumida, Shin Miyamura,
Applicant https://www.google.com/patents/WO2004033463A1?cl=en	Otsuka Pharmaceutical Co., Ltd.

Hidetsugu Tsubouchi, Hirofumi Sasaki, Hideaki Kuroda, Motohiro Itotani, Takeshi Hasegawa, Yoshikazu Haraguchi, Takeshi Kuroda, Takayuki Matsuzaki, Kuninori Tai, Makoto Komatsu, Makoto Matsumoto, Hiroyuki Hashizume, Tatsuo Tomishige, Yuji Seike, Masanori Kawasaki, Takumi Sumida, Shin Miyamura,

Applicant

https://www.google.com/patents/WO2004033463A1?cl=en

Otsuka Pharmaceutical Co., Ltd.

Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan, and Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan

Image result for OTSUKA Hidetsugu Tsubouchi

(left to right) Hidetsugu Tsubouchi, Ph.D., Compliance & Ethics Department, manager; Hirofumi Sasaki, Medicinal Chemistry Research Laboratories, associate head and project OPC; Makoto Matsumoto, Ph.D, Pharmaceutical Business Division, senior director; Hiroyuki Hashizume, Pharmaceutical Marketing Headquarters, Product Planning and Management Group, product management manager; Masanori Kawasaki, TB Projects, associate director

Melting Point: 176-178 °C , Condition: Solvent ethyl acetate; isopropanol

Sasaki, Hirofumi; Journal of Medicinal Chemistry 2006, VOL 49(26), Pg 7854-7860

(2R)-2-Methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole

Mp: 169–171 °C; Org. Process Res. Dev., Article ASAP, DOI: 10.1021/acs.oprd.6b00331

HPLC (area %): 99.52%; HPLC (chiral): 99.8% (a/a);

¹H NMR (400 MHz, CDCl₃): δ 7.57 (s, 1H), 7.14–7.16 (d, 2H, J = 10.0 Hz), 6.83–6.86 (d, 2H, J = 7.2 Hz), 4.48–4.50 (d, 1H, J = 10.0 Hz), 4.22–4.24 (d, 1H, J = 10.0 Hz), 4.05–4.10 (t, 2H, J = 9.6 and 10.4 Hz), 1.79 (s, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 156.0, 155.8, 147.1, 143.5, 122.6, 115.5, 112.6, 122.6, 121.7, and 119.1 (J_C–F = 255.1 Hz), 116.6, 92.9, 71.8, 51.3, 23.0;

¹⁹F NMR (CDCl₃, 376 MHz): δ −58.4;

IR (KBr, cm^–1): 3155, 2996, 1607, 1456, 1281, 1106, 978, 921, 834,783, 708;

mass (m/z): 360.3 (M + 1)⁺;

[α]²⁵₅₈₉ = (+)8.445 (c 1.00 g/100 mL, CHCl₃).

Visceral leishmaniasis (VL), infamously known as kala-azar (black fever) in the Indian subcontinent, is the most lethal form of leishmaniasis and is caused by protozoan parasites. This deadly disease is the second largest parasitic killer in the world, surpassed only by malaria, with a worldwide distribution in Asia, East Africa, South America, and the Mediterranean region. In the search for effective treatments for visceral leishmaniasis, the Drugs for Neglected Diseases initiative (DNDi) recently evaluated fexinidazole a nitroimidazole being developed as a treatment for Human African Trypanosomiasis. Fexinidazole showed potential as a safe and effective oral drug for the treatment of visceral leishmaniasis and is now in clinical trials.

fexinidazole (1) and DNDI-VL-2098 (2).

Earlier, through an agreement with TB Alliance and in association with the ACSRC at the University of Auckland (NZ), DNDi screened about 70 other nitroimidazole analogues belonging to four chemical subclasses and investigated them for antileishmanial activity

Image result for DNDI-VL-2098

Paper

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01699

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

Andrew M. Thompson ^*^†, Patrick D. O’Connor^†, Adrian Blaser^†, Vanessa Yardley^‡, Louis Maes^§, Suman Gupta^∥, Delphine Launay^⊥, Denis Martin^⊥, Scott G. Franzblau^#, Baojie Wan^#, Yuehong Wang^#, Zhenkun Ma^¶, and William A. Denny^†

^† Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

^‡ Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom

^§ Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

^∥ Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, India

^⊥ Drugs for Neglected Diseases Initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland

^# Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States

^¶ Global Alliance for TB Drug Development, 40 Wall Street, New York 10005, United States

J. Med. Chem., 2016, 59 (6), pp 2530–2550

DOI: 10.1021/acs.jmedchem.5b01699

*Phone: (+649) 923-6145. Fax: (+649) 373-7502. E-mail: am.thompson@auckland.ac.nz.

Abstract

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.

Structures of various antileishmanial or antitubercular agents.

CLICK ON IMAGE

2-Methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1- b][1,3]oxazole (7).

Method A (Scheme 1B): Reaction of alcohol 88 with NaH, using procedure C, followed by chromatography of the product on silica gel, eluting with CH2Cl2, gave 71 (87%) as a pale yellow solid: mp (CH2Cl2/hexane) 122-124 C (lit.1 mp 126.8-127.9 C); 1 H NMR (CDCl3)  7.56 (s, 1 H), 7.16 (br d, J = 9.1 Hz, 2 H), 6.85 (br d, J = 9.2 Hz, 2 H), 4.48 (d, J = 10.2 Hz, 1 H), 4.23 (d, J = 10.1 Hz, 1 H), 4.09 (d, J = 10.1 Hz, 1 H), 4.05 (d, J = 10.2 Hz, 1 H), 1.79 (s, 3 H); 13C NMR (CDCl3)  156.3 (C-1’), 156.1 (C-7a), 147.4 (C- 6), 143.9 (q, JC-F = 2.1 Hz, C-4’), 122.8 (2 C, C-3’,5’), 120.7 (q, JC-F = 256.5 Hz, 4’-OCF3), 115.8 (2 C, C-2’,6’), 112.8 (C-5), 93.1 (C-2), 72.2 (2-CH2O), 51.6 (C-3), 23.3 (2-CH3). Anal. (C14H12F3N3O5) C, H, N.

Method B (Scheme 2B): Reaction of 2-bromo-1-[(2-methyloxiran-2-yl)methyl]-4-nitro-1Himidazole2 (98) with 4-(trifluoromethoxy)phenol (0.95 equiv) and NaH (1.2 equiv), using procedure I, followed by chromatography of the product on silica gel, eluting with 2:1 and 3:1 CH2Cl2/petroleum ether (foreruns) and then with 3:1 CH2Cl2/petroleum ether and CH2Cl2, S8 gave a crude product, which was crystallized from CH2Cl2/hexane (and the mother liquors further purified by chromatography on silica gel, eluting as before), to give 71 (55%) as a pale yellow solid (see data above). Method C (Scheme 2D): Reaction of 2-chloro-1-[(2-methyloxiran-2-yl)methyl]-4-nitro-1Himidazole1 (109) with 4-(trifluoromethoxy)phenol (1.0 equiv) and NaH, using procedure I, followed by chromatography of the product on silica gel, eluting with 1:1 and 3:2 CH2Cl2/petroleum ether (foreruns) and then with 3:1 CH2Cl2/petroleum ether and CH2Cl2, gave a crude product, which was crystallized from CH2Cl2/hexane (and the mother liquors further purified by chromatography on silica gel, eluting with 1:1 and 3:1 Et2O/petroleum ether and then with Et2O and CH2Cl2), to give 71 (51%) as a pale yellow solid (see data above).

Synthesis of 9 (Scheme 2A): (2R)-2-Methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo- [2,1-b][1,3]oxazole (9). Reaction of 2-chloro-1-{[(2R)-2-methyloxiran-2-yl]methyl}-4-nitro- 1H-imidazole3 (96) with 4-(trifluoromethoxy)phenol and NaH, using procedure H, gave 91,3 (36%) as a pale brown solid: mp 170-171 C (lit.1 mp 176.5-178 C); 1 H NMR (CDCl3)  7.56 (s, 1 H), 7.16 (br d, J = 8.8 Hz, 2 H), 6.85 (br d, J = 9.0 Hz, 2 H), 4.48 (d, J = 10.2 Hz, 1 H), 4.23 (d, J = 10.0 Hz, 1 H), 4.09 (d, J = 10.2 Hz, 1 H), 4.05 (d, J = 10.3 Hz, 1 H), 1.79 (s, 3 H); [α] 25 D 9.0 (c 1.002, CHCl3) [lit.1 [α] 28 D 7.67 (c 1.030, CHCl3)]. Anal. (C14H12F3N3O5) C, H, N. HPLC purity: 100%. Chiral HPLC (using a CHIRALPAK AD-H analytical column and eluting with 15% EtOH/hexane at 1 mL/min) determined that the ee of 9 was 98.7%.

Paper

Sasaki, Hirofumi; Journal of Medicinal Chemistry 2006, VOL 49(26), Pg 7854-7860

Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles

J. Med. Chem., 2006, 49 (26), pp 7854–7860

DOI: 10.1021/jm060957y

Abstract

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H₃₇Rv (MIC = 0.006 μg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure−activity relationships of these new compounds are presented.

(R)-2-Methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole (8). Mp 176−178 °C.

¹H NMR (CDCl₃) δ 1.79 (3H, s), 4.06 (1H, d, J = 6.8 Hz), 4.10 (1H, d, J = 6.8 Hz), 4.23 (1H, d, J = 10.1 Hz), 4.49 (1H, d, J = 10.1 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.56 (1H, s).

MS (DI) m/z 359 (M⁺). Anal. (C₁₄H₁₂F₃N₃O₅) C, H, N.

PAPER

A process suitable for kilogram-scale synthesis of (2R)-2-methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole (DNDI-VL-2098, 2), a preclinical drug candidate for the treatment of visceral leishmaniasis, is described. The four-step synthesis of the target compound involves the Sharpless asymmetric epoxidation of 2-methyl-2-propen-1-ol, 8. Identification of a suitable synthetic route using retrosynthetic analysis and development of a scalable process to access several kilograms of 2 are illustrated. The process was simplified by employing in situ synthesis of some intermediates, reducing safety hazards, and eliminating the need for column chromatography. The improved reactions were carried out on the kilogram scale to produce 2 in good yield, high optical purity, and high quality.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00331

Development of a Scalable Process for the Synthesis of DNDI-VL-2098: A Potential Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis

Vijay S. Satam, Srinivasa Rao Pedada, Pasumpon Kamaraj, Nakita Antao, Apoorva Singh, Rama Mohan Hindupur, and Hari N. Pati ^*

Process Chemistry Division, Advinus Therapeutics Ltd., 21 & 22, Phase II, Peenya Industrial Area, Bangalore 560058, Karnataka, India

Andrew M. Thompson ,

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

Delphine Launay and Denis Martin

Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00331

*Process Chemistry Division, Advinus Therapeutics Ltd., 21 & 22, Phase II, Peenya Industrial Area, Bangalore -560058, Karnataka, India. E-mail: hari.pati@advinus.com. Tel. No.: (+91)9900212096.

Hiroyuki Fujiki, Ph.D, New Drug Research Division, Biology and Translational Research Unit, senior research scientist; Yoshitaka Yamamura, Pharmaceutical Business Division, senior director; Youichi Yabuuchi, Ph.D, Otsuka Pharmaceutical Factory, Inc., corporate adviser; Hidenori Ogawa, Ph.D, Medicinal Chemistry Research Laboratories

/////////////preclinical, DNDI-VL-2098, 681492-17-1, Visceral Leishmaniasis

CEP 33779

December 7, 2016 11:03 am / Leave a comment

CEP-33779, CEP33779
CAS 1257704-57-6
Chemical Formula: C24H26N6O2S
Molecular Weight: 462.57
Elemental Analysis: C, 62.32; H, 5.67; N, 18.17; O, 6.92; S, 6.93

N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

PRECLINICAL Treatment of Rheumatoid Arthritis, Agents for Colorectal Cancer Therapy Systemic Lupus Erythematosus,

Jak2 Inhibitors

Image result for teva logo

Matthew A. Curry, Bruce D. Dorsey, Benjamin J. Dugan, Diane E. Gingrich, Eugen F. Mesaros, Karen L. Milkiewicz,
Applicant	Cephalon, Inc.

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States

Image result for Cephalon, Inc.

Matt Curry

Matthew A. Curry

Bruce Dorsey

Image result for Cephalon, Inc. Benjamin J. Dugan

Benjamin Dugan

Benjamin J. Dugan received a B.S. degree in Chemistry from the University of Delaware in 1993 under the tutelage of the late Dr. Cynthia McClure. He began his career at FMC Corporation in the agricultural products division. In 2006, he moved to Cephalon, Inc., acquired by Teva Pharmaceutical Industries Ltd. in 2011, and engaged in oncology research focused on small molecule, ATP competitive, kinase inhibitors culminating with the discovery of CEP-33779. He is currently a Research Scientist focused on the development of novel, bioactive small molecules for treatment of central nervous system disorders.

Cephalon Inc.

Malvern, United States

Image result for Cephalon, Inc. Diane E. Gingrich

Members of the Cephalon research team that discovered CEP-5214 and CEP-7055 include (from left) Hudkins, Thelma S. Angeles, Bruce A. Ruggeri, and Diane E. Gingrich. CEPHALON PHOTO

Eugen F. Mesaros

Cephalon Inc.

Malvern, United States

Image result for cephalon Karen L. Milkiewicz

Karen Milkiewicz

Lupus (systemic lupus erythematosus, SLE) is a chronic autoimmune disease characterized by the presence of activated T and B cells, autoantibodies and chronic inflammation that attacks various parts of the body including the joints, skin, kidneys, CNS, cardiac tissue and blood vessels. In severe cases, antibodies are deposited in the cells (glomeruli) of the kidneys, leading to inflammation and possibly kidney failure, a condition known as lupus nephritis.

Although the cause of lupus remains unknown, manifestations of the disease have been linked to genetic polymorphisms, environmental toxins and pathogens (Morel;

Fairhurst, Wandstrat et al. 2006). In addition, gender, hormonal influences and cytokine dysregulation have been tightly linked to the development of lupus (Aringer and Smolen 2004; Smith-Bouvier, Divekar et al. 2008). Lupus affects nine times as many women as men. It may occur at any age, but appears most often in people between the ages of 10 and 50 years. African Americans and Asians are affected more often than people from other races.

There is no cure for lupus. Current treatments for lupus are aimed at controlling symptoms and are limited to toxic and immunosuppressive agents with severe side-effects such as high dose glucocorticoids and/or hydroxchloroquine. Severe disease (e.g., patients that have signs of renal involvement) require more aggressive drugs including

mycophenolate mofetil (MMF), azathioprine (AZA) and/or cyclophosphamide (CTX) (Bertsias and Boumpas 2008). CTX, AZA and MMF are very toxic and

immunosuppressive, and only 50% of treated patients enter complete remission, with relapse rates up to 30% over a 2-year period.

Memory B cells, and more important, long-lived plasma cells (LL-PCs) which differentiate from memory B cells, are key cell types involved in lupus (Neubert, Meister et al. 2008; Sanz and Lee 2010). Long-lived plasma cells synthesize and secrete large quantities of high-affinity isotype switched antibodies (Meister, Schubert et al. 2007;

Muller, Dieker et al. 2008). Circulating antinuclear antibodies (ANAs) increase the chances of antibody depositing onto self tissues, forming immune-complexes and eventually leading to tissue destruction, epitope spreading and involvement of other organ systems. LL-PCs are commonly found to be chemo- and radio-resistant, over expressing various heat shock proteins and drug pumps (Obeng, Carlson et al. 2006; Neubert, Meister et al. 2008). In addition, LL-PCs primarily reside in the bone marrow where they are protected from current lupus therapies such as cyclophosphamide and glucocorticoids.

A need exists for new treatments for lupus, including lupus nephritis. A need particularly exists for lupus treatments that can target and reduce LL-PCs.

CEP-33779 is a highly selective, orally active, small-molecule inhibitor of JAK2. CEP-33779 induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. Tumor regression correlated with inhibition of STAT3 and NF-κB (RelA/p65) activation in a CEP-33779 dose-dependent manner. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.

{[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine} (1)

LC/MS: (M+H⁺)⁺ = 463.2;

¹H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 6.8 Hz, 2H), 8.06 (d, J = 6.8 Hz, 2H), 7.96 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.17 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.6 Hz 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).

CEP-33779 Diglycolate Salt

¹H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.43 (d, J = 6.7 Hz, 2H), 8.06 (d, J = 6.7 Hz, 2H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.18 (d, J = 6.7 Hz, 1H), 7.11 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.89 (s, 4H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).

DSC: Endotherm onset at 153.0 °C; Peak at 155.8 °C.

PATENT

WO 2010141796

https://www.google.com/patents/WO2010141796A3?cl=en

Example 35 [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-

1 -yl)-phenyl]-amine

35 a) l-(3-Bromo-phenyl)-4-methyl-piperazine was prepared from l-(3-bromo-phenyl)- piperazine (1.33 g, 5.52 mmol) in a manner analogous to Step 32a. The reaction product was isolated as a pale yellow oil (1.4 g, 100%). ¹H NMR (400 MHz, CDCl₃, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, IH), 7.04 (dd, J=2.1, 2.1 Hz, IH), 6.95 (ddd, J=I. S, 1.7, 0.7 Hz, IH), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, IH), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+. 35b) [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl- piperazin-l-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and l-(3-bromo-phenyl)-4- methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.072 g, 60%).

MP = 232-234 ⁰C.

¹H NMR (400 MHz, CDCl₃, δ, ppm): 8.49 (d, J=I 2 Hz, IH), 8.25 (d, J=I .5 Hz, 2H), 8.08 (d, J=I .9 Hz, 2H), 7.65 (d, J=I .1 Hz, IH), 7.38 (s, IH), 7.27-7.20 (m, IH), 7.04-6.95 (m, 2H), 6.84 (s, IH), 6.60 (d, J=8.0 Hz, IH), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H).

MS = 463 (MH)+.

PATENT

WO 2012078504

PATENT

WO 2012078574

https://google.com/patents/WO2012078574A2?cl=da

COMPOUND A is a JAK2 inhibitor with the chemical name [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine. COMPOUND A has the following structure:

COMPOUND A

COMPOUND A was prepared in a manner analogous to the five-step method described below (see Example 35 of International Application No. PCT/US10/37363):

Step 1 : To a solution of 1-(3-bromo-phenyl)-piperazine (about 1 g) and acetic acid (about 0.4 mL) in methanol (about 25 mL) is added 37% formaldehyde in water/methanol (about 56.7:37:6.3, water:formaldehyde:methanol; about 5 mL). The mixture is stirred at room temperature for about 18 hours. The suspension is cooled to about 5°C in an ice/water bath and sodium cyanoborohydride (about 5 g) is added in small portions. The mixture is stirred and warmed to room temperature for about 18 hours. The mixture is slowly poured into saturated aqueous ammonium chloride (about 200 mL) and stirred for about 1 hour. The mixture is extracted with dichloromethane (3 x about 75 mL). The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The material is placed under high vacuum for about 18 hours to yield 1-(3-bromo-phenyl)-4-methyl-piperazine as a pale yellow oil (about 1 g). ¹H NMR (400 MHz, CDCl₃, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+.

Step 2: To a solution of 3-bromo-pyridin-2-ylamine (about 10 g) in 1,4-dioxane (about 100 mL) is added dropwise ethoxycarbonyl isothiocyanate (about 7 mL). The mixture is stirred under an atmosphere of nitrogen for about 18 hours. The volatiles are evaporated to yield a waxy solid. The recovered material is triturated with hexane (about 250 mL). N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea is isolated and used without further purification. ¹H NMR (400 MHz, (D₃C)₂SO, δ, ppm): 11.46 (s, 1H), 11.43 (s, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (dd, J=8.0, 4.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). MS = 215 (MH)+.

Step 3: To a stirred suspension of hydroxylamine hydrochloride (about 17 g) and Ν,Ν-diisopropylethylamine (about 26 mL) in a mixture of methanol (about 70 mL) and

ethanol (about 70 mL) is added N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea. The mixture is stirred for about 2 hours at room temperature then heated to about 60°C for about 18 hours. The suspension is cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as an off-white solid (about 8 g). ¹H NMR (400 MHz, (D₃C)₂SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS = 213, 215 (MH)+.

Step 4: An oven dried tube is charged with palladium acetate (about 0.2 g) and triphenylphosphine (about 0.6 g). The tube is evacuated under high vacuum and backflushed under a stream of nitrogen for about 5 minutes. A suitable solvent such as

1,4-dioxane (about 10 mL) is added and the mixture is stirred under nitrogen for a suitable time (e.g., for about 10 minutes). 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 0.75 g), (4-methylsulfonylphenyl)boronic acid (about 1 g), a suitable solvent, such as N,N-dimethylformamide (about 10 mL) and a suitable base, such as about 1.5 M of sodium carbonate in water (about 10 mL) are added. The mixture is stirred for about 2 minutes at room temperature under nitrogen then the tube is sealed and heated at about 80°C for about 18 hours. The mixture is transferred to a round bottom flask and the volatiles are evaporated under reduced pressure. The product is isolated in a suitable manner. For example, water (about 100 mL) may be added and the mixture stirred. The solid may then be collected by filtration, and optionally rinsed with water, air dried, triturated with ether/dichloromethane (about 4: 1; about 10 mL), filtered and rinsed with ether. 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as a tan solid (about 0.6 g). MP = 236-239 °C. ¹H NMR (400 MHz, (D₃C)₂SO, δ, ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J= 7.3 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS = 289 (MH)+.

Step 5: To an oven dried tube is added palladium acetate (about 10 mg) and 2,2′-bis-dicyclohexylphosphanyl-biphenyl (about 30 mg), 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 75 mg), 1-(3-bromo-phenyl)-4-methyl-piperazine (about 80 mg), a suitable base, such as cesium carbonate (about 270 mg) and a suitable solvent, such as 1,4-dioxane (about 5 mL). The tube is evacuated and backflushed with nitrogen three times. The tube is sealed and heated at about 80°C for about 72 hours. The mixture is cooled to room temperature and the product isolated in a suitable manner.

For example, the cooled mixture may be diluted with dichloromethane (about 10 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material may then be purified, e.g., via chromatography, e.g., utilizing an ISCO automated purification apparatus (e.g., amine modified silica gel column 5%→100% ethyl acetate in hexanes). [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (i.e., COMPOUND A) is isolated as a yellow solid (about 0.07 g). MP = 232-234 °C. ¹H NMR (400 MHz, CDCl₃, δ, ppm): 8.49 (d, J=7.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS = 463 (MH)+.

PATENT

WO 2015089153

https://www.google.com/patents/WO2015089153A1?cl=un

This disclosure relates to a l,2,4 riazolo[l,5a]pyridine derivative, [8-(4 methanesulfonyl-phenyl)-[ 1 ,2,4]triazoio[1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin- 1 -yl phenyl] -amine, re g structure:

or a pharmaceutical salt thereof, and its use in the treatment of multiple sclerosis.

Compound A is a potent, orally active, small molecule inhibitor of JA 2. See, e.g..International Application No. PCT/USlO/37363, U.S. Patent Nos. 8,501,936 and ,633,173, and U.S. Published Patent Application Nos. 2013/0267535 and 2014/0024655, each of which is incorporated by reference herein. Compound A can be prepared, for example, using methods analogous to Example 35 of International Application No.PCT/US 10/37363.

PAPER

A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-a]pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of CEP-33779

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States

J. Med. Chem., 2012, 55 (11), pp 5243–5254

DOI: 10.1021/jm300248q

Publication Date (Web): May 10, 2012

*Phone: 610-738-6733. Fax: 610-738-6643. E-Mail: bdugan@cephalon.com.

http://pubs.acs.org/doi/full/10.1021/jm300248q

Abstract

Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure–activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.

[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (29)

¹H NMR (CDCl₃) δ 8.49 (dd, J = 6.6, 1.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 7.5, 0.9 Hz, 1H), 7.39–7.36 (m, 1H), 7.23 (t, J = 8.2 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.97 (dd, J = 7.8, 1.4 Hz, 1H), 6.88 (s, 1H), 6.60 (dd, J = 8.3, 1.8 Hz, 1H), 3.30–3.25 (m, 4H), 3.10 (s, 3H), 2.63–2.58 (m, 4H), 2.38 (s, 3H).

¹³C NMR (CDCl₃) δ 162.65, 152.28, 148.87, 141.00, 140.91, 140.05, 129.64, 129.29, 128.18, 127.85, 127.76, 124.77, 112.03, 109.40, 108.59, 104.80, 55.19, 49.02, 46.19, 44.59;

mp 208–211 °C.

High resolution mass spectrum (ESI+) m/z 463.1925 [(M + H)⁺calcd for C₂₄H₂₆N₆O₂S: 463.1916]. HPLC: 95 A%.

PAPER

An Improved Synthesis of the Free Base and Diglycolate Salt of CEP-33779; A Janus Kinase 2 Inhibitor

Daniel V. Levy, Joseph A. Sclafani ^*, and Roger P. Bakale

Chemical Process Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00311

Publication Date (Web): November 30, 2016

*E-mail: Joseph.Sclafani@tevapharm.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00311

Abstract

CEP-33779 is a triazole that has been reported to show highly selective inhibition of Janus kinase 2 (JAK2). An efficient process to form CEP-33779 will be presented that uses multiple palladium couplings to provide the drug substance in a convergent manner. The existing medicinal chemistry route was modified to avoid chromatographic purification, improve safety, and utilize palladium ligands which are available in quantities amenable to scale-up. Challenges faced during the development of the new process included optimization of conditions for Buchwald–Hartwig and Suzuki couplings, control of homocoupled impurities and removal of residual palladium. In addition, a screen of conditions to form a diglycolate salt of the parent compound are also presented.

REFERENCES

1: Dugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, Dobrzanski P, Serdikoff C, Jan M, Angeles TS, Albom MS, Mason JL, Aimone LD, Meyer SL, Huang Z, Wells-Knecht KJ, Ator MA, Ruggeri BA, Dorsey BD. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem. 2012 Jun 14;55(11):5243-54. doi: 10.1021/jm300248q. Epub 2012 May 18. PubMed PMID: 22594690.

2: Tagoe C, Putterman C. JAK2 inhibition in murine systemic lupus erythematosus. Immunotherapy. 2012 Apr;4(4):369-72. doi: 10.2217/imt.12.20. PubMed PMID: 22512630.

3: Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O’Kane TM, Ruggeri BA, Dobrzanski P. Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther. 2012 Apr;11(4):984-93. doi: 10.1158/1535-7163.MCT-11-0951. Epub 2012 Feb 14. PubMed PMID: 22334590.

4: Lu LD, Stump KL, Wallace NH, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Mason JL, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J Immunol. 2011 Oct 1;187(7):3840-53. doi: 10.4049/jimmunol.1101228. Epub 2011 Aug 31. PubMed PMID: 21880982.

5: Stump KL, Lu LD, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis. Arthritis Res Ther. 2011 Apr 21;13(2):R68. doi: 10.1186/ar3329. PubMed PMID: 21510883; PubMed Central PMCID: PMC3132063.

/////////////CEP-33779, CEP33779, CEP 33779, 1257704-57-6, PRECLINICAL, TEVA, Rheumatoid Arthritis, Colorectal Cancer Therapy, Systemic Lupus Erythematosus,

Jak2 Inhibitors

O=S(C1=CC=C(C2=CC=CN3C2=NC(NC4=CC=CC(N5CCN(C)CC5)=C4)=N3)C=C1)(C)=O

str0

Enzalutamide

October 30, 2016 2:18 am / Leave a comment

4-(6-chloro-1-oxo-3-thioxo-9,9a-dihydro-1H-imidazo[1,5-a]indol-2(3H)-yl)-2-(trifluoromethyl)-benzonitrile

Drug Name：: Enzalutamide
Research Code：: MDV-3100
Trade Name：: Xtandi^®
MOA：: Androgen receptor inhibitor
Indication：: Prostate cancer
Status：: Approved
Company：: Medivation (Originator) , Astellas
Sales：: $2,100.8 Million (Y2015);
$1,247.3 Million (Y2014);
$546 Million (Y2013);
$148.8 Million (Y2012);
ATC Code：: L01

Approved Countries or AreaUpdate Date：2015-07-29

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2012-08-31	Marketing approval	Xtandi	Prostate cancer	Capsule, Liquid filled	40 mg	Astellas	Priority

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2013-06-21	Marketing approval	Xtandi	Prostate cancer	Capsule	40 mg	Astellas

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2014-03-24	Marketing approval	Xtandi	Prostate cancer	Capsule	40 mg	Astellas

WILL BE UPDATED………

Enzalutamide was approved by the U.S. Food and Drug Administration (FDA) on August 31, 2012, then approved by European Medicine Agency (EMA) on June 21, 2013, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 24, 2014. It was developed by Medivation and Astellas and marketed as Xtandi^® by Astellas.

Enzalutamide is an androgen receptor inhibitor that decreases proliferation and induces death of prostate cancer cells. It is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

Xtandi^® is available as capsule for oral use, containing 40 mg of free Enzalutamide, and the recommended doe is 160 mg once daily.

Prostate cancer, one of the most malignant tumors worldwide, is the second leading cause of cancer deaths among men in America . Although androgen deprivation therapy (ADT) has been proved to be effective initially, the tumor will eventually progress and develop into the lethal castration resistant prostate cancer (CRPC) . The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and plays a critical role in the progression of normal prostate cells. However, overexpression of AR was found in most CRPC, which is essential for CRPC to adapt to the low levels of androgens. As AR contributes significantly to the resistance to castration, it has been recognized as an attractive target for the treatment of CRPC

Reagents and conditions: (i) HNO3 , H2SO4 , -5 oC, 3 h; (ii) SOCl2 , MeOH, reflux, 12 h; (iii) H2 , Pd/C, MeOH, rt, 12 h; (iv) (CH3CO)2O, TEA, 50 oC, 6 h; (v) H2 , Pd/C, MeOH, rt, 12 h; (vi) acetone, HCl (6 mol/L), -10 oC, 0.5 h, NaNO2 , H2O, -10 oC, 1 h, CuCl/CuBr/KI, 0 oC, 3 h; (vii) HCl, 50 oC, 3 h; (viii) SOCl2 , MeOH, reflux, 12 h; (ix) 2, DMF, TEA, 60 oC, 1 h.

4-(6-chloro-1-oxo-3-thioxo-9,9a-dihydro-1H-imidazo[1,5-a]indol-2(3H)-yl)-2-(trifluoromethyl)-benzonitrile (48c). It was obtained as a yellow solid

m.p. 220-222 oC;

1H-NMR (300 MHz，DMSO-d6): δ 8.40 (d, J = 8.1 Hz, 1H, Ar-H), 8.19 (s, 1H, Ar-H), 8.02-7.92 (m, 2H, Ar-H), 7.49-7.46 (m, 1H, Ar-H), 7.34-7.32 (m, 1H, Ar-H), 5.56 (t, J = 9.6 Hz, 1H, -CH-), 3.58 (d, J = 9.6 Hz, 2H, -CH2-) ppm;

13C-NMR (75 MHz, DMSO-d6): δ 184.1, 172.1, 142.3, 138.5, 136.8, 134.7, 131.9, 131.5, 128.0, 126.1 (q, J = 267.9 Hz, CF3), 117.2, 115.4, 66.9, 39.9 ppm;

IR (KBr): 3094, 2232, 1763, 1607, 1499, 1270, 1136, 1052, 998, 786 cm-1;

HRMS (ESI): m/z, calculated for C18H9ClF3N3OS 408.0180 (M + H)+ , found 408.0173.

Paper

A series of indoline thiohydantoin derivatives were synthesized and evaluated in vitro.The most potent compound 48c shows comparable ability with enzalutamide in proliferation inhibition of LNCaP cells.Compound 48c has less cytotoxic to AR-negative cells compared with Enzalutamide.

The bicalutamide-resistant mechanism was clarified and overcome by compound 48c.

Abstract

A novel scaffold of indoline thiohydantoin was discovered as potent androgen receptor (AR) antagonist through rational drug designation. Several compounds showed good biological profiles in AR binding and higher selective toxicity than enzalutamide toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient). In addition, the docking studies supported the rationalization of the biological evaluation. Among these compounds, the representative compound 48c exhibited the strongest inhibitory effect on LNCaP growth and also acted as a competitive AR antagonist. Further preliminary mechanism study confirmed that 48c exerted its AR antagonistic activity through impairing AR nuclear translocation. All these results indicated that the novel scaffold compounds demonstrated AR antagonistic behaviour and promising candidates for future development were identified.

Graphical abstract

European Journal of Medicinal Chemistry

Available online 22 October 2016

Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer

Minzan Zuo ¹,

Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
zhiyuli@cpu.edu.cn

http://www.sciencedirect.com/science/article/pii/S0223523416309114

http://dx.doi.org/10.1016/j.ejmech.2016.10.049

Paper

Chinese Chemical Letters

Volume 28, Issue 2, February 2017, Pages 426-430

An improved and practical route for the synthesis of enzalutamide and potential impurities study

https://doi.org/10.1016/j.cclet.2016.09.007

SYN 1

. WO2006124118A1.

2. WO2007127010A2 / US8110594B2.

3. J. Med. Chem. 2010, 53, 2779-2796.

4. WO2013087004A1 / US20140371284A1.

SYN 2

WO2011106570A1 / US20130190507A1.

2. WO2014041487A2.

3. CN103980141A.

4. CN104016924A.

SYN 3

WO2011106570A1 / US20130190507A1.

SYN 4

CN103910679A.

2. Fine Chem. Intermed. 2012, 42, 34-36.

CHINA PATENTS

////////Prostate cancer, Androgen receptor, Antagonist, Indoline thiohydantoin derivatives, indoline thiohydantoin derivatives, enzalutamide, antiproliferative agents, prostate cancer

c1c(cc(c(c1)C#N)C(F)(F)F)N2C(C3Cc4ccc(cc4N3C2=S)Cl)=O

BMS-852927

October 24, 2016 11:16 am / 1 Comment on BMS-852927

BMS-852927

CAS 256918-39-4

609.51 MW

C₂₉ H₂₈ Cl₂ F₂ N₂ O₄ S MF

2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

1H-Imidazole-4-methanol, 2-[1-(2,6-dichlorophenyl)-1-methylethyl]-1-[3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)[1,1′-biphenyl]-4-yl]-α,α-dimethyl-

Treat metabolic syndrome

Brett Busch, Ph.D.

https://www.linkedin.com/in/brettbbusch

Exelixis

Brett B. Busch, William C. Stevens, Jr., Ellen K. Kick, Haiying Zhang, Venkataiah Bollu,Richard Martin, Raju Mohan
Applicant	Exelixis, Inc.

Brett B. Busch, William C. Stevens, JR., Ellen K. Kick, Haiying Zhang, Venkataiah Bollu,Richard Martin, Raju Mohan
	Bristol-Myers Squibb Company, Exelixis Patent Company Llc

Originator Exelixis
Developer Bristol-Myers Squibb
Class Antihyperlipidaemics; Small molecules
Mechanism of Action Liver X receptor modulators

Discontinued Atherosclerosis; Hypercholesterolaemia

Most Recent Events

04 Jun 2014 BMS 852927 is still in phase I trials for atherosclerosis and in preclinical development for hypecholesterolaemia in USA
02 Aug 2013 Bristol-Myers Squibb terminates the planned phase I trial for Hypercholesterolaemia in Germany, Canada and Switzerland (NCT01651273)
06 Jul 2012 Bristol-Myers Squibb plans a phase I trial for Hypercholesterolaemia in Germany, Canada and Switzerland (NCT01651273)

1H-NMR (DMSO-d6, 400 MHz) δ 7.94 (m, 2H), 7.63 (dd, 1H, J = 11.29, 1.51 Hz), 7.34 (d, 1H, J = 9.54
Hz), 7.14 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 5.58 (t, 1H, J = 5.27 Hz), 4.96 (d, 2H, J = 4.27 Hz), 4.70
(s, 1H), 3.46 (s, 3H), 1.96 (s, 6H), 1.45 (s, 6H); MS m/e 609.16 (M+H+);

13CNMR (DMSO-d6, 400MHz) 161.42 (d, J=249.49 Hz), 156.85 (d, J=250.25 Hz), 153.18, 148.39, 141.69 (d, J=3.05 Hz), 139.45 (dd, J=9.16, 1.53 Hz), 139.32 (dd, J=8.39, 1.53 Hz), 138.58, 134.68, 131.39, 129.96, 128.40,
127.12 (d, J=17.55 Hz), 125.72 (d, J=12.97 Hz), 123.15 (d, J=2.29 Hz), 122.49 (d, J=3.05 Hz), 119.04
(d, J=25.18 Hz), 116.30, 114.52 (d, J=22.13 Hz), 68.11, 51.97 (d, J=5.34 Hz ), 45.53, 44.78, 44.29,
31.01, 30.53.

19F-NMR (JEOL 500 MHz, CDCl3) -113.55, -116.73.

HPLC (XBridge 5μ C18 4.6x50mm, 4 mL/min, Solvent A: 10 % MeOH/water with 0.2 % H3PO4, Solvent B: 90 % MeOH/water with0.2 % H3PO4, gradient with 0-100 % B over 4 minutes): 2.56 minutes, Purity, 99.7%.

HRMS (m/z,Obs.): 609.12065 [M+H]+; (Calc.): 609.11877. Formula: C29H29Cl2F2N2O4S. Anal. Calcd. for
C29H28N2O4SCl2F2•0.10 C2H6O•0.10 C4H5O2: C, 57.05; H, 4.75; Cl, 11.42; F, 6.10; N, 4.50; S, 5.15.
Found: C, 57.14; H, 4.54; Cl, 11.57; F, 5.94; N, 4.36; S, 5.07. The residual solvents, ethyl acetate (1.39
weight %), ethanol (0.74 weight %), dichloromethane (0.05 weight %), and heptane (< 0.05 weight %)
were identified in the sample by GC/MS and the retention times were matched with the reference standards.

Image result for BMS-852927

Liver X receptors (LXRs) belong to a family of nuclear hormone receptors that are endogenously activated by cholesterol and its oxidized derivatives to mediate transcription of genes involved in maintaining glucose, cholesterol, and fatty acid metabolism. LXRa is found predominantly in the liver, with low levels found in kidney, intestine, spleen, and adrenal tissue. LXRp is ubiquitous in mammals and was found in nearly all tissues examined. Given the intricate link between lipid metabolism and cancer cell growth, the ubiquitous expression of LXRp in some types of cancer is unlikely to be coincidental, allowing cancer cells to synthesize lipids and lipoprotein particles to sustain their growth. At the same time, however, such stable basal expression levels make LXRp an ideal therapeutic target.

Examples of LXR agonists reported in the literature

PATENT

WO 2010138598

PATENT

WO 2012135082

PATENT

WO 2014028461

PATENT

WO 2016100619

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016100619&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

https://www.google.com/patents/US8618154?cl=enIt

Figure US08618154-20131231-C00002

Example 9 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

Example 9a Preparation of 2-(2,6-dichlorophenyl)-2-methylpropanenitrile

To a 1 M solution of potassium tert-butoxide (403 mL, 403 mmol) at −66° C. (acetone/dry ice) was slowly added 2-(2,6-dichlorophenyl)acetonitrile (25.0 g, 134 mmol) in anhydrous THF (150 mL). The mixture was stirred at −66° C. for 20 minutes. Then, iodomethane (33.6 mL, 538 mmol) was added drop-wise over 25 minutes at −66° C. At this stage, it was exothermic and a large amount of light yellow precipitate was observed. The suspension was stirred at −60° C. for 30 minutes. The reaction mixture was quenched with 200 mL ice water, and extracted with ether (3×150 mL). The organics were combined, washed with 150 mL brine, dried over Na₂SO₄, and concentrated on a rotary evaporator. The crude product (30 g, yellow oil) was purified by column chromatography (ISCO, 330 g silica, 20% EtOAc in hexanes) to afford 2-(2,6-dichlorophenyl)-2-methylpropanenitrile (28.2 g, 132 mmol, 98% yield) as a light yellowish oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.35 (d, 2H, J=8.03 Hz), 7.16 (t, 1H, J=8.0 Hz), 2.09 (s, 6H); ¹³C-NMR (CDCl₃, 126 MHz) δ134.6, 133.8, 131.4, 129.0, 124.1, 38.6, 29.2; MS m/e 214.10 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 3.16 minutes.

Example 9b Preparation of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide

2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N₂. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na₂SO₄, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). ¹H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.32 minutes.

Example 9c Preparation of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate

To a mixture of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (48.0 g, 119 mmol), K₂CO₃(41.0 g, 297 mmol) in toluene (180 mL) and THF (180 mL) at 55° C. was added slowly a solution of ethyl 3-bromo-2-oxopropanoate (23.3 mL, 166 mmol) in 24 mL of THF over 50 minutes. The reaction mixture was kept at 55° C. for 1.5 hours. A white slurry was observed. The reaction mixture was cooled to 5° C. HCl (0.5N, 450 mL) was added drop-wise (end point pH=9˜10). After addition, the suspension was cooled to 0° C. The solid was collected by filtration, washed with water (2×50 mL), and then dried in a vacuum oven at 60° C. overnight. Ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (59 g, 114 mmol, 96% yield) was obtained as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.11 (m, 3H), 6.96 (m, 2H), 6.72 (t, 1H, J=8.28 Hz), 4.35 (m, 2H), 4.25 (d, 1H, J=10.5 Hz), 3.80 (d, 1H, J=10.8 Hz), 1.98 (s, 3H), 1.93 (s, 3H), 1.38 (t, 3H, J=7.03 Hz); ¹³C-NMR (CDCl₃, 126 MHz) δ 173.0, 171.5, 159.8, 157.8, 137.3, 135.7, 132.1, 131.1, 128.1, 127.4, 125.6, 122.2, 120.1, 93.5, 62.5, 45.5, 30.2, 14.0; MS m/e 517.05 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.74 minutes.

Example 9d Preparation of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole,4-carboxylate

To a mixture of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (38 g, 73 mmol) in EdOH (200 mL) was added TFA (25.0 g, 220 mmol). The mixture was stbsequently heated tn 95° C. HPLC analysis after 2.5 hours showed <1% of alcohol intermediate remaining The mixture was diluted with 300 mL of CH₂Cl₂and cooled to approximately 5° C. with an ice bath. The mixture was neutralized with 1N NaOH (120 mL) and the organic layer was separated. The aqueous layer was dxtracted with CH₂Cl₂(2×100 mL). The combined organic layers were concentrated on a rotary evaporator to give crude material. Recrystallization in EtOH (5 mL/1 g) provided 32 g of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophdnyl)propan-2-yl)-1H-imidazole-4-carboxylate as `n off-white solhd (86% yield). ¹H-NMR (DMSO-d_{6, 400 MHz) δ 7.92 (s, 1H), 7.16 (d, 1H, J=8.0 Hz), 7.22 (m, 3H), 7.11 (m, 1H), 7.04 (t, 1H, J=12.0 Hz), 4.25 (q, 2H, J=8.0 Hz), 1.94 (s, 6H(, 1.27 (t, 3H, J=8.0 Hz); MS m/e 502.68 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 3.87 minutes.}

Example 9e Prepar`tion of 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol

To a mixture of methylmagnesium bromide (60.0 mL, 180 mmol, 3M in ether) in 120 ml, of THF cooled with an ice/salt bath (−15 to −17° C.) was added slowly a solution of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole-4-carboxylate (30 g, 60 mmol) in 65 mL of CH₂Cl₂and 87 mL of THF over 45 minutes. The internal temperature was carefully kept below 0° C. A further 2×20 mL of CH₂Cl₂was used to wash forward the residual material. The reaction mixture temperature was maintained below 0° C. for 1 hour with stirring. Then the reaction mixture was diluted with 100 mL of CH₂Cl₂, and saturated NH₄Cl was added slowly. The resulting mixture was extracted with CH₂Cl₂(2×80 mL). Organics were combined, washed with brine, dried with Na₂SO₄, and concentrated on a rotary evaporator to afford 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (28.5 g, 58.6 mmol, 98% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.13 (dd, 1H, J=9.03, 2.01 Hz), 7.09 (s, 1H), 7.07 (s, 1H), 6.93 (m, 2H), 6.75 (t, 1H, J=8.16 Hz), 6.55 (s, 1H), 3.18 (s, 1H), 2.00 (s, 6H), 1.58 (s, 6H); ¹³C-NMR (CDCl₃, 126 MHz) δ 158.1, 156.1, 154.5, 147.8, 139.3, 135.7, 131.3, 130.3, 127.8, 126.9, 122.7, 119.8, 115.1, 68.7, 44.8, 31.1, 29.9; MS m/e 485.05 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.78 minutes.

Example 9 Preparation of 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

To a 1 L 3-necked round bottom flask under nitrogen was added 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (12.0 g, 24.7 mmol), [2-fluoro-6-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (9.78 g, 29.6 mmol), K₂CO₃(10.2 g, 74 mmol), DME (120 mL) and water (12 mL). The mixture was heated to 60° C., and then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex (4.06 g, 4.94 mmol) was added under nitrogen. The reaction mixture was heated to 80° C. for 30 minutes. The resulting darkly colored mixture was cooled with an ice bath, and partitioned in 200 mL of CH₂Cl₂and 200 mL of water. The organic layers were combined and dried with Na₂SO₄. After concentration, the crude product was purified by flash chromatography (ISCO, 330 g silica, 0% to 100% EtOAc in hexanes) to afford 12.79 g of crude product (85% yield) as a light yellow solid.

Recrystallization was carried out by dissolving 9.5 g of crude product in acetone (80 mL) at 65° C. The resulting solution was cooled slowly to 25° C. over 5 hours, and then cooled to 0° C. for an additional 30 minutes. Crystals began to form at 45° C. The solid was collected by filtration and rinsed with cold acetone. After drying in an oven at 45° C. under vacuum for 14 hours, 4.9 g of pure product was obtained. To recover additional crystalline product, the mother liquid was concentrated to approximately 10 mL and passed through a silica pad. EtOAc (100 mL) was used to elute the compound. The filtrate was concentrated under vacuum to give a crude solid. The crude solid was recrystallized in acetone following the procedure above to afford an additional 2.5 g of product. The combined recovery for the two crops after recrystallization was a 78% yield. ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.94 (m, 2H), 7.63 (dd, 1H, J=11.29, 1.51 Hz), 7.34 (d, 1H, J=9.54 Hz), 7.14 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 5.58 (t, 2H, J=5.27 Hz), 4.96 (d, 2H, J=4.27 Hz), 4.70 (s, 1H), 3.46 (s, 3H), 1.96 (s, 6H), 1.45 (s, 6H); MS m/e 609.16 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.56 minutes.

Alternatively, Example 9 was prepared as follows:

To a 1 L 3-necked round bottom flask under nitrogen was added methyltetrahydrofuran (“MeTHF”, 6.9 kg), 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (1.994 kg, 4.1 moles) and (2-fluoro-6-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.38 kg, 4.19 moles). The mixture was agitated at 23° C. for 15 min until all the solids dissolved. At the conclusion of this period, (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.022 kg, 0.041 moles) and Pd(OAc)₂(0.01 kg, 0.045 moles) were added as a slurry via a subsurface line. Upon completion of addition, the mixture was rinsed with additional MeTHF (1.65 kg). The resulting mixture was evacuated to less than 80 Torr and backfilled with nitrogen. This process was repeated two more times. After completion of the degassing sequence, the reaction mixture was agitated for at least 15 min and a clear, golden color was observed. In a separate reaction vessel, a solution of potassium hydroxide (0.352 kg) in water (10.00 kg) was prepared and degassed by sparging the solution with nitrogen gas for at least 15 min prior to use. The KOH solution (10.35 kg) was transferred into the reactor by vacuum. The reaction temperature exhibited a known exotherm from 20° C. to 29° C. Upon completion of addition, the resulting biphasic mixture was degassed by a series of pressure swings. The mixture was warmed to between 45-50° C. where it was stirred for at least 2 h. After this time, the reaction mixture was analyzed by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 23° C. and the stirring was stopped. The mixture was allowed to separate for 30 min and the lower spent KOH stream was removed. The product rich organic was passed through a column of thiourea functionalized silica gel (0.782 kg) (Silicycle) at ˜0.1 kg per min to remove the palladium. The product rich organic phase was washed with a 5% NaHCO₃solution (5 vol) and the phases separated. The organic phase was washed with water (5 vol) and the organic and aqueous phases separated.

The product rich organic phase was polish filtered into a clean reaction vessel and then concentrated to ˜8 volumes (˜16 L) under vacuum (80 Torr, Tjacket=60° C.). Once at the prescribed volume, the reaction mixture was allowed to cool to 25° C. Once at the prescribed temperature the reaction mixture was seeded with 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (0.5%, 0.008 kg). The resulting slurry was stirred at 25° C. for about 18 h. At the conclusion of this period, the reaction mixture was concentrated to ˜8 L under vacuum (150 Torr, Tjacket=60° C.). Once at the prescribed volume, the reaction mixture was heated to 50° C. and isopropyl acetate (IPAc, 13.90 kg) was added to the reactor during a 90 min period. Upon completion of addition, the reaction mixture was cooled to 25° C. during a 3 h period. Once at the prescribed temperature the reaction mixture was stirred at room temperature for about 16 h. At the conclusion of this period, the reaction mixture was filtered, deliquored, and washed with additional IPAc (10.4 kg). The filter cake was dried via suction on the filter under a stream of dry nitrogen to yield a white solid. The white solid was transferred to a dryer and dried at 50° C. under full vacuum to afford 2.03 kg of product (81% yield, 99.40 AP, 98 wt %).

PAPER

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitroproperties, excellent pharmacokinetic parameters, and a favorable lipid profile.

Discovery of Highly Potent Liver X Receptor β Agonists

Ellen K. Kick ^*†§, Brett B. Busch^‡§, Richard Martin^‡, William C. Stevens^‡, Venkataiah Bollu^‡, Yinong Xie^‡, Brant C. Boren^‡, Michael C. Nyman^‡, Max H. Nanao^‡, Lam Nguyen^‡, Artur Plonowski^‡, Ira G. Schulman^‡, Grace Yan^‡,Huiping Zhang †, Xiaoping Hou †, Meriah N. Valente †, Rangaraj Narayanan #, Kamelia Behnia #, A. David Rodrigues #, Barry Brock #, James Smalley #, Glenn H. Cantor #, John Lupisella ∥, Paul Sleph ∥, Denise Grimm ∥,Jacek Ostrowski ∥, Ruth R. Wexler †, Todd Kirchgessner ∥, and Raju Mohan^‡

^†Department of Discovery Chemistry, ^∥Department of Cardiovascular Biology, ^#Pharmaceutical Candidate Optimization, Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States

^‡ Exelixis Inc., 210 East Grand Avenue, South San Francisco, California 94080, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00234

Publication Date (Web): October 23, 2016

*Tel: 609 466-5053. E-mail: ellen.kick@bms.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00234

WO2007002563A1	Jun 26, 2006	Jan 4, 2007	Exelixis, Inc.	Imidazole based lxr modulators
WO2008073825A1	Dec 7, 2007	Jun 19, 2008	Exelixis, Inc.	Lxr and fxr modulators

Citing Patent	Filing date	Publication date	Applicant	Title
US8901106	Mar 26, 2012	Dec 2, 2014	Bristol-Myers Squibb Company	Imidazole prodrug LXR modulators
US20140163081 *	Nov 21, 2013	Jun 12, 2014	Exelixis Patent Company Llc	Lxr modulators
US20150299136 *	May 4, 2015	Oct 22, 2015	Bristol-Myers Squibb Company	Lxr modulators

///////////Discovery, Highly Potent, Liver X Receptor β Agonists, ABCA1, ABCG1, Liver X receptor, LXRα, LXRβ, α-1-acid glycoprotein, BMS-852927, BMS 852927

CS(=O)(=O)c1cc(cc(F)c1CO)c2cc(F)c(cc2)n3cc(nc3C(C)(C)c4c(Cl)cccc4Cl)C(C)(C)O

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain from Lilly Research Laboratories

October 1, 2016 9:40 am / Leave a comment

2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6Hpyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one

l-[2-(2,3-dihydro- lH-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl]-2-[2-(lH- l ,2,3-triazol-4-yl)ethoxy]ethanone.

CAS 1619971-30-0

1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-[2-(1H-1,2,3-triazol-4-yl)ethoxy]ethanone;
Molecular Formula:	C₂₁H₂₃N₇O₂
Molecular Weight:	405.45302 g/mol

US2014200231

Scheme A

Scheme B

Scheme C

Scheme E

Autotaxin is an enzyme reported to be the source of lysophosphatidic acid (LPA) which up-regulates pain-related proteins through one if its cognate receptors, LPAi_. LPA is an intracellular lipid mediator which influences a multiplicity of biological and biochemical processes. Targeted inhibition of autotaxin-mediated LPA biosynthesis may provide a novel mechanism to prevent nerve injury-induced neuropathic pain.

Compounds that inhibit autotaxin are desired to offer a potential treatment option for patients in need of treatment for pain.

Pain associated with osteoarthritis (OA) is reported to be the primary symptom leading to lower extremity disability in OA patients. Over 20 million Americans have been diagnosed with OA, the most common of the arthropathies. The currently approved treatments for OA pain may be invasive, lose efficacy with long term use, and may not be appropriate for treating all patients. Additional treatment options for patients suffering from pain associated with OA are desired. Compounds that inhibit autotaxin represent another possible treatment option for patients with pain associated with OA.

U.S. Patent 7,524,852 (‘852) discloses substituted bicyclic pyrimidine derivatives as anti-inflammatory agents.

PCT/US2011/048477 discloses indole compounds as autotoxin inhibitors.

There is a need for novel compounds that provide autotaxin inhibition. The present invention provides novel compounds which are autotaxin inhibitors. The present invention provides certain novel compounds that inhibit the production of LPA.

Autotaxin inhibitor compounds are desired to provide treatments for autotaxin mediated conditions, such as pain and pain associated with OA.

PAPER

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC₅₀ of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC₅₀ = 2 nM), PK properties, and a robust PK/PD relationship.

Image result for Lilly Research Laboratories

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States

ACS Med. Chem. Lett., 2016, 7 (9), pp 857–861

DOI: 10.1021/acsmedchemlett.6b00207

*E-mail: jonessp@lilly.com. Tel: +1-317-277-5543.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00207

Spencer Jones

Senior Research Scientist at Eli Lilly and Company

2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6Hpyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (9)

………… Purified the resulting residue by silica gel chromatography (gradient elution: 0-9% methanol in ethyl acetate ) to give the title compound……..

1H NMR (400 MHz, CDCl3): 60:40 mixure of rotamers * indicates minor rotamer δ 8.18 (bs, 0.6H), *8.13 (bs, 0.4H), 7.49 (s, 1H), 7.21-7.09 (m, 4 H), 5.70-5.50 (m, 1H), 4.87-4.78 (m, 1H), 4.75 (s, 1.2H), *4.67 (s, 0.8H), 4.64 (s, 1.2H) *4.53 (s, 0.8H), *4.30 (s, 0.8H), 4.28 (s, 1.2H), 3.93 (t, J = 5.6 Hz, 2H), 3.43 (dd, J = 16.2, 7.1 Hz, 2H), 3.10 (t, J = 5.6 Hz, 2H), 2.89 (dd, J = 16.2, 4.9 Hz, 2H).

13C NMR (400 MHz, CDCl3): * indicates minor δ *169.3, 16 169.2, 167.0, *166.8, *162.4, 162.2, 152.8, *152.3, 141.1, 137.8, 130.9, 126.7, 124.9, 115.9, 69.8, 69.3, *69.0, 52.7, *52.5, 51.2, 49.0, *47.9, 40.1, 24.7.

LC/MS (ESI+ ): (m/z) 406 (C21H24N7O2 = (M+1)+ ).

PATENT

WO-2014110000-A1

Example 2

Synthesis of l-[2-(2,3-dihydro- lH-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl]-2-[2-(lH- l ,2,3-triazol-4-yl)ethoxy]ethanone.

Stir a mixture of 2-[2-(lH-triazol-5-yl)ethoxy]acetic acid 2,2,2-trifluoroacetic acid

(20.22 g; 70.90 mmol), N-(2,3-dihydro- lH-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-amine dihydrochloride hydrate (27.99 g; 81.54 mmol) and triethylamine (98.83 mL; 709.03 mmol) in dimethylformamide (404.40 mL) at 0°C. Add a solution of 1-propanephosphonic acid cyclic anhydride (50% solution in DMF; 51.89 mL; 81.54 mmol) over 30 minutes, and stir the mixture at room temperature for 18 hours.

Concentrate the reaction mixture under reduced pressure to give a residue. Add water (200 mL) and extract the mixture with ethyl acetate (4 x 250 mL) and

dichloromethane (4 x 250 mL). Wash the combined organic layers with saturated aqueous sodium bicarbonate (2 x 100 mL) and brine (100 mL), then dry over anhydrous sodium sulfate. Filter the mixture and concentrate the solution under reduced pressure to give a red solid (25.70 g) that is slurried in ethyl acetate/methanol (9: 1 mixture; 200 mL) for 2 hours at room temperature. Filter the resulting solid and wash with cold ethyl acetate (50 mL) to give a solid (ca.18.2 g) that is re-slurried in ethyl acetate (200 mL) at reflux for 1 hour. On cooling to room temperature, stir the mixture for 1 hour and filter the resulting light pink solid.

Slurry the light pink solid in water/methanol (1 : 1 mixture; 200 mL) and heat the mixture at 50°C for 30 minutes. Add ammonium hydroxide solution (32% ; 50 mL) and continue to heat the mixture at 50°C for 30 minutes. Upon cooling to room temperature, add additional ammonium hydroxide solution (32% ; 50 mL) and continue stirring for 1 hour at room temperature. Filter the resulting light gray solid, dry and slurry again in ethyl acetate (200 mL) for 1 hour to afford a light gray solid that is filtered, washed with ethyl acetate (25 mL), and dried to give the title compound (12.42 g; 43%) as a gray solid. MS (m/z): 406 (M+l).

PATENT

US-20140200231-A1

https://www.google.com/patents/US20140200231

Scheme E

Preparation 7

Synthesis of 2-[2-(lH-triazol-5-yl)ethoxy]acetic acid.

Pressurize 1 atmosphere of hydrogen (g) to a flask containing [2-(l-benzyl-lH- l,2,3-triazol-5-yl)ethoxy]acetic acid (10.1 g; 1.00 equiv; 38.66 mmoles) and palladium (II) chloride (3 g; 16.92 mmoles; 3.00 g) in isopropyl alcohol (300 mL) and water (60 mL). Maintain the flask under a hydrogen atmosphere for 3 h, then filter through Celite™ and concentrate. Add toluene (2×50 mL) and concentrate to afford the title compound (7.96 g, 100%). ^]H NMR (d₆-DMSO): 2.86 (t, / = 7 Hz, 2 H), 3.65 (t, / = 7 Hz, 2 H), 3.98 (s, 2 H), 7,77 (s, 1 H), 13.4 – 13.6 (br s, 2 H).

Example 1

Synthesis of l-[2-(2,3-dihydro-lH-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl]-2-[2-(lH-l,2,3-triazol-4- l)ethoxy]ethanone.

Add N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (4.2 g, 15.8 mmol) to a mixture of 2-[2-(lH-triazol-5-yl)ethoxy]acetic acid (2.7 g, 15.8 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol), and dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5.44 g, 28.4 mmol) in dichloromethane (40 mL) at 25 °C. Add triethylamine (4.40 mL, 31.6 mmol) to the reaction mixture and stir for 16 h. Wash with water (2 x 50 mL) and concentrate the organic layer. Purify by silica gel column chromatography, eluting with ethyl acetate/methanol, to give the title compound (4.0 g, 60%) as a solid. MS (m/z): 420 (M + Η). Preparation 8

Synthesis of 2-chloro-l-[2-(2,3-dihydro-lH-inden-2-ylamino)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl]ethanone.

To N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (11.0 g, 41.3 mmol) and triethylamine (7.48 mL, 53.7 mmol) in dichloromethane (200 mL), add 2- chloroacetyl chloride (3.61 mL, 5.13 g, 45.4 mmol) dropwise over five minutes at 23 °C. Stir for 30 minutes and pour the reaction mixture into 1 : 1 50% saturated aqueous sodium bicarbonate: dichloromethane (75 mL). Separate the organic layer from the aqueous layer and further extract the aqueous layer with dichloromethane (2 x 25 mL). Combine the organic extracts and dry over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in chloroform (10 mL) and purify via silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (9.75 g, 69%). ^]H NMR (CDC1₃, * = minor amide rotamer) δ 2.77* (t, 2H), 2.84 (dd, 2H), 2.87 (t, 2H), 3.35 (dd, 2H), 3.76 (t, 2H), 3.85* (t, 2H), 4.12 (s, 2H), 4.52* (s, 2H), 4.57 (s, 2H), 4.72-4.82 (m, IH), 5.48-5.64 (m, IH), 7.12-7.21 (m, 4H), 8.03-8.10 (m, IH).

Preparation 9

Synthesis of 2-(but-3-yn-l-yloxy)-l-[2-(2,3-dihydro-lH-inden-2-ylamino)-7,8- dihydropyrido[4,3-d]p rimidin-6(5H)-yl]ethanone.

To sodium hydride (60 wt% in mineral oil, 1.58 g, 39.6 mmol) in tetrahydrofuran (50 mL) at 23 °C, add 3-butyn-l-ol (7.93 g, 8.59 mL, 113.2 mmol) dropwise, then stir at 23 °C for 20 minutes. Add this solution to 2-chloro-l-[2-(2,3-dihydro-lH-inden-2- ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (9.70 g, 28.3 mmol) in tetrahydrofuran (150 mL) at 23 °C and stir for one hour. Pour the reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether (x 2) and ethyl acetate (x 2). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting crude product by silica gel column chromatography (gradient elution: 20% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (8.16 g, 77%). MS (m/z): 377 (M + 1).

Example la

Alternative synthesis of l-[2-(2,3-dihydro- lH-inden-2-ylamino)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl]-2-[2-(lH- l,2,3-triazol-4- l)ethoxy]ethanone.

Sparge a solution of 2-(but-3-yn- l-yloxy)-l-[2-(2,3-dihydro-lH-inden-2- ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (8.15 g, 21.7 mmol) and L-ascorbic acid sodium salt (8.58 g, 43.3 mmol) in dimethylformamide (60 mL) and water (60 mL) with nitrogen for ten minutes, then evacuate and backfill with nitrogen three times. Add copper (II) sulfate pentahydrate (1.08 g, 4.33 mmol) and heat to 90 °C, then add azidotrimethylsilane (23.1 mL, 20.0 g, 173 mmol) dropwise and stir for one hour. Cool reaction mixture to 23 °C and pour into water (50 mL). Extract this mixture with ethyl acetate (4 x 50 mL). Combine the organic extracts and wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate.

Purify the resulting crude product by silica gel column chromatography (gradient elution: 0 to 10% methanol in ethyl acetate) to give the title compound (3.60 g, 40%). MS (m/z): 420 (M + 1). Preparation 10

Synthesis of tert-butyl-2-(2,3-dihydro-lH-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate.

Charge 450 rriL (2.58 mol) of N-ethyl-N-isopropylpropan-2-amine into a 15 °C solution of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (220 g, 860.37 mmol) and 2,3-dihydro-lH-inden-2-amine (137.7 g, 1.03 mol) in 1- methylpyrrolidin-2-one (3.6 L). Heat the resulting mixture to 80 °C for 16 h, then cool to 30 °C and transfer the resulting mixture into 5 L of water at 25 °C. Filter the resulting solid and rinse the filter cake with water (2 x 300 rriL). Reslurry the solid in ethyl acetate (350 iriL) for 45 min at 15 °C. Filter the slurry, rinsing with 15 °C ethyl acetate ( 2 x 250 rriL), and dry to give the title compound (226 g, 75%) as an off-white solid. ‘H NMR (d₆-DMSO) 1.45 (s, 9 H), 2.87 (dd, /= 7.2, 15.8 Hz, 2 H), 3.24 (dd, /= 7.2, 15.8 Hz, 2 H), 4.36 (d, 10.4 Hz, 2 H), 4.44 (d, /= 12.8 Hz, 2 H), 4.60 (m, 1 H), 7.14 (m, 2 H), 7.20 (m, 2 H), 7.55 (d, /= 6.8 Hz, 1 H), 8.27 (d, /= 7.2 Hz, 1 H).

Preparation 11

Synthesis of N-(2,3-dihydro-lH-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- amine dihydrochloride hydrate.

Charge 670 rriL of 5 M hydrochloric acid (3.35 mol) to a solution of tert-butyl 2-

(2,3-dihydro-lH-inden-2-ylamino)-5,7-dihydro-6H pyrrolo[3,4-d]pyrimidine-6- carboxylate (226 g, 641.25 mmol) in tetrahydrofuran (2.0 L) at 17 °C, maintaining the internal temperature below 26 °C during the addition. Heat the resulting solution to 50 °C for 16 h, cool to 25 °C and dilute with 500 rriL of water and 500 mL of tert- butylmethylether. Separate the resulting layers and extract with tert-butylmethylether (3 x 1 L). Concentrate the water phase down to a reaction volume of ca. 200 mL, and filter the resulting slurry. Rinse the cake with tert-butylmethylether (2 x 200 mL) and dry to give the title product (177 g, 80%) as a light brown solid. MS (m/z): 253.2 (M-2HC1- H₂0+1).

Preparation 12

Syntheis of tert-butyl 2-but-3-ynox acetate.

Stir a mixture of but-3-yn-l-ol (6.00 g; 85.60 mmol), tetrabutylammonium sulfate (2.07 g; 8.54 mmol) and sodium hydroxide (40% wt/wt; 150 mL) in dichloromethane (150 mL) at 0°C. Add tert-butyl bromoacetate (19.34 mL; 128.40 mmol) dropwise and stir the mixture for 2.5 hours at room temperature. Dilute the reaction mixture with dichloromethane (200 mL) and water (100 mL), separate the layers, and further extract the aqueous layer with dichloromethane (2 x 100 mL). Wash the combined organic layers with brine (100 mL), dry over anhydrous sodium sulfate, and concentrate to afford the crude title compound as a brown oil (11.93 g). Purify the oil by silica gel column chromatography, eluting with hexane: ethyl acetate (0% to 10% mixtures) to give the title compound (11.35 g; 72%) as a colorless oil. ^]H NMR (CDCI₃) δ 1.48 (s, 9H), 2.00 (m, 1H), 2.52 (m, 2H), 3.67 (m, 2H), 4.01 (bs, 2H).

Preparation 13

Synthesis of tert-butyl 2-[2-(lH-triazol-5- l)ethoxy]acetate.

Stir tert-Butyl 2-but-3-ynoxyacetate (11.34 g; 61.55 mmol) and copper(I)iodide (584 mg; 3.07 mmol) in a mixture of dimethylformamide (56.70 mL) and methanol (11.34 mL) at 0°C. Add azido(trimethyl)silane (12.33 mL; 86.47 mmol) dropwise and heat the mixture at 90°C for 18 hours.

In a second batch, stir tert-butyl 2-but-3-ynoxyacetate (4.38 g; 23.77 mmol) and copper(I)iodide (226 mg; 1.19 mmol) in a mixture of dimethylformamide (22 mL) and methanol (6 mL) at 0°C. Add azido(trimethyl)silane (4.8 mL; 33.66 mmol) dropwise and the mixture heated at 90°C for 18 hours.

Upon cooling to room temperature, combine the crude products from both batches and concentrate the mixture to afford a greenish residue. Purify the crude product by filtration through a plug of silica eluting with dichloromethane: ethyl acetate (75% to 100% mixtures) to afford the title compound (14.15 g, 73%) as a colorless oil. MS (m/z): 228.15 (M+l).

Preparation 14

Synthesis of 2-[2-(lH-triazol-5-yl)ethoxy]acetic acid 2,2,2-trifluoroacetic acid.

Stir a mixture of ieri-butyl 2-[2-(lH-triazol-5-yl)ethoxy]acetate (14.15 g; 62.26 mmol) and trifluoroacetic acid (70.75 mL, 935.69 mmol) in dichloromethane (70.75 mL) for 2 hours at room temperature. Concentrate the reaction mixture under reduced pressure to provide the title compound containing additional trifluoroacetic acid (20.22 g, >100%) as a brown solid. MS (m/z): 172.05 (M+l).

Example 2

Synthesis of l-[2-(2,3-dihydro- lH-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl]-2-[2-(lH- l ,2,3-triazol-4-yl)ethoxy]ethanone.

Stir a mixture of 2-[2-(lH-triazol-5-yl)ethoxy]acetic acid 2,2,2-trifluoroacetic acid

Concentrate the reaction mixture under reduced pressure to give a residue. Add water (200 mL) and extract the mixture with ethyl acetate (4 x 250 mL) and

Preparation 15

Synthesis of 2-chloro- l-[2-(2,3-dihydro- lH-inden-2-ylamino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl]ethanone.

Stir a suspension of N-(2,3-dihydro-lH-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-amine dihydrochloride hydrate (14.4 g, 41.9 mmol) and triethylamine (14.3 g, 19.7 mL, 141.4 mmol) in dichloromethane (200 mL) at 23 °C for 10 minutes, then cool to -30 °C. Add 2-chloroacetyl chloride (5.49 g, 3.86 mL, 48.6 mmol) over two minutes and warm to 23 °C over 10 minutes. Add methanol (5 mL) and remove the solvent in vacuo. Slurry the crude reaction mixture in methanol (30 mL), add 50 g silica gel and remove solvent in vacuo. Load the resulting residue onto a loading column and purify via silica gel column chromatography (gradient elution: 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate) to give the title compound (11.5 g, 84%). MS (m/z): 329(M+1).

Preparation 16

Synthesis of 2-(but-3-yn-l-yloxy)-l-[2-(2,3-dihydro-lH-inden-2-ylamino)-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidin-6-yl]ethanone.

To sodium hydride (60 wt% in mineral oil, 2.06 g, 51.4 mmol) in tetrahydrofuran (86 mL) at 0 °C, add 3-butyn-l-ol (4.64 g, 5.03 mL, 64.3 mmol), then stir at 23 °C for 15 minutes. Add this solution to 2-chloro-l-[2-(2,3-dihydro-lH-inden-2-ylamino)-5,7- dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]ethanone (8.45 g, 25.7 mmol) in

tetrahydrofuran (86 mL) at 0 °C and stir for five minutes. Pour reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether and ethyl acetate (2 x 50 mL each). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Combine the crude product with the crude product from a second reaction (run reaction under identical conditions and stoichiometry employing 2-chloro- 1- [2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethanone (3.0 g, 9.1 mmol)) and purify by silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (2.90 g, 23%). MS

(m/z): 363(M+1). Example 2a

Alternative synthesis of l-[2-(2,3-dihydro-lH-inden-2-ylamino)-5,7-dihydro- pyrrolo[3,4-d]pyrimidin-6-yl]-2-[2-(lH-l,2,3-triazol-4-yl)ethoxy]ethanone.

Add dimethylformamide (27 mL) and water (27 mL) to a flask containing 2-(but- 3-yn-l-yloxy)-l-[2-(2,3-dihydro-lH-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl]ethanone (2.90 g, 8.00 mmol). Add copper (II) sulfate pentahydrate (400 mg, 1.60 mmol) and L-ascorbic acid sodium salt (3.17 g, 16.0 mmol). Evacuate flask and backfill with nitrogen (x 2), then add azidotrimethylsilane (7.37 g, 8.53 mL, 64.0 mmol) and heat the reaction to 90 °C for 70 minutes. Cool the reaction mixture to 23 °C and remove all solvent in vacuo. Suspend the residue in methanol/dichloromethane and then add silica gel and remove solvent in vacuo. Load this material onto a loading column and purify via silica gel column chromatography (gradient elution: 0-9% methanol in ethyl acetate) to give the title compound (980 mg, 30%). MS (m/z):

406(M+1).

/////////Autotaxin, LPA, osteoarthritis, tool molecule, lily, Spencer Jones, PRECLINICAL

N1(Cc2cnc(nc2C1)NC3Cc4ccccc4C3)C(=O)COCCc5cnnn5

Synthesis of 4-Heteroaryl–Quinazoline Derivatives as Potential Anti-breast Cancer Agents

September 28, 2016 3:44 am / Leave a comment

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Figure 1.

Figure 2.

Ethyl 2-[(6,7-dimethoxyquinazolin-4-yl)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (15b)

Yield: 76%; mp: 254–256°C; IR (cm⁻¹): 3200 (NH), 2974, 2854 (CH-aliphatic), 1656 (C=O); ¹H NMR (DMSO-d₆) δ ppm 1.03 (t, 3H, CH₃CH₂, J = 7.2 Hz), 1.21 (t, 2H, CH₂, J = 6.9 Hz), 2.88 (t, 2H, CH₂, J = 6.9 Hz), 3.40 (q, 2H, CH₂, J = 6.9 Hz), 3.88 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃), 3.96 (m, 4H, 2 CH₂), 4.24 (q, 2H, CH₃CH₂, J = 7.2 Hz), 7.40 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 8.99 (s, 1H, Ar-H), 12.00 (s, 1H, NH, D₂O exchangeable); Anal. Calcd for C₂₂H₂₅N₃O₄S: C, 61.81; H, 5.89; N, 9.83. Found: C, 61.93; H, 5.96; N, 9.98.

General procedure for the synthesis of compounds 15a,15b

A mixture of 4-chloro-6,7-dimethoxyquinazoline (1) (0.22 g, 1 mmol) and ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (14a) or ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (14b) (1 mmol) in isopropanol (15 mL) was heated under reflux for 10 h. The reaction was cooled, and the solid formed was filtered, dried, and crystallized from isopropanol.

Synthesis of 4-Heteroaryl–Quinazoline Derivatives as Potential Anti-breast Cancer Agents

A. E. Kassab, E. M. Gedawy, H. B. El-Nassan+

+Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt

E-mail: hala_bakr@hotmail.com

DOI10.1002/jhet.2634,

http://onlinelibrary.wiley.com/doi/10.1002/jhet.2634/full?elq_mid=11879&elq_cid=4828550

Asmaa Elsayed Abd Ellatief Kassab( A. E. Kassab)

4-Heteroaryl or heteroalkyl–quinazoline derivatives were prepared as dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The new compounds were tested for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results indicated that almost all the compounds showed moderate dual inhibition of both enzymes. Compound 3 (methyl piperidine-4-carboxylate derivative) showed the highest inhibitory activity against both enzymes with IC₅₀ 97.6 and 64.0 µM against EGFR and VEGFR-2 kinases, respectively. Most of the test compounds showed potent to moderate antitumor activity on MCF7 cell line. Five compounds (3, 9c, 11, 13, and 15b) showed potent cytotoxic activity with IC₅₀values between 10 and 17 µM.

Scheme 4.

Scheme 3.

Scheme 2.

Scheme 1.

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//////////4-Heteroaryl–Quinazoline Derivatives, Anti-breast Cancer Agents

JNJ 54166060

September 18, 2016 11:42 am / Leave a comment

JNJ 54166060

JNJ-54166060; JNJ 54166060; JNJ54166060.

(R)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone

[2-chloro-3-(trifluoromethyl)phenyl]-[(4R)-1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]methanone

Methanone, [2-chloro-3-(trifluoromethyl)phenyl][(4R)-1-(5-fluoro-2-pyridinyl)-1,4,6,7-tetrahydro-4-methyl-5H-imidazo[4,5-c]pyridin-5-yl]-

CAS 1627900-41-7 OF R ISOMER DESIRED

CAS 1627900-42-8 OF S ISOMER
Chemical Formula: C20H15ClF4N4O
Exact Mass: 438.0871

JNJ-54166060 is a potent P2X7 antagonist. Bioactivity data of JNJ-54166060: rP2X7 IC50=4 nM; rP2X7 IC50=115nM; HLM/RLM = 0.35/0.64, ED50 = 2.3 mg/kg in rats. JNJ-54166060 shows high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, JNJ-54166060 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.

The P2X7 receptor is a ligand-gated ion channel and is present on a variety of cell types, largely those known to be involved in the inflammatory and/ or immune process, specifically, macrophages and monocytes in the periphery and predominantly in glial cells (microglia and astrocytes) of the CNS. (Duan and Neary, Glia 2006, 54, 738-746; Skaper et al., FASEB J 2009, 24, 337-345;

Surprenant and North, Annu. Rev. Physiol. 2009, 71, 333-359). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of proinflammatory cytokines IL-1 β and IL-18 (Muller, et. Al. Am. J. Respir. Cell Mol. Biol. 201 1 , 44, 456-464), giant cell formation

(macrophages/ microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes) (Ferrari et al., J. Immunol. 2006, 176, 3877-3883; Surprenant and North, Annu. Rev. Physiol. 2009, 71, 333-359). P2X7 receptors are also located on antigen-presenting cells (keratinocytes, salivary acinar cells (parotid cells)), hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.

The importance of P2X7 in the nervous system arises primarily from experiments using P2X7 knock out mice. These mice demonstrate the role of P2X7 in the development and maintenance of pain as these mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation induced neuropathic pain (Chessell et al., Pain 2005, 114, 386-396). In addition P2X7 knock out mice also exhibit an anti-depressant phenotype based on reduced immobility in forced swim and tail suspension tests (Basso et al., Behav. Brain Res. 2009, 798, 83-90.). Moreover, the P2X7 pathway is linked to the release of the pro-inflammatory cytokine, IL-1 β, which has been linked to precipitation of mood disorders in humans (Dantzer, Immunol. Allergy Clin. North Am. 2009, 29, 247-264; Capuron and Miller, Pharmacol. Ther. 201 1 , 730, 226-238). In addition, in murine models of Alzheimer’s disease, P2X7 was upregulated around amyloid plaques indicating a role of this target in such pathology as well (Parvathenani et al., J. Biol. Chem. 2003, 278, 13309-13317).

In view of the clinical importance of P2X7, the identification of compounds that modulate P2X7 receptor function represents an attractive avenue into the development of new therapeutic agents. Such compounds are provided herein.

PATENT

US 20140275015

Example 11

(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

Step A. (2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

To a solution of Intermediate 1 (0.70 g, 3.27 mmol) in THF (20 mL) was added Intermediate 12 (0.87 g, 3.60 mmol) dropwise. The reaction was allowed to stir for 1 h then cooled to −78° C. To the cooled solution was added 3M MeMgBr in Et₂O (1.31 mL, 3.92 mmoL) and the reaction was let come to room temperature. The mixture was then quenched with 1N NaOH (50 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated. Chromatography of the resulting residue (SiO₂; MeOH (NH₃):DCM) gave the title compound (770 mg, 54%). ¹H NMR (400 MHz, CDCl₃) δ 8.43-8.34 (m, 1H), 7.92-7.73 (m, 2H), 7.70-7.33 (m, 4H), 6.08 (dtd, J=19.7, 11.7, 8.0 Hz, 3H), 1.54 (t, J=7.0 Hz, 3H). MS (ESI): mass calculated for C₂₀H₁₃ClF₄N₄O, 436.07. m/z found 437.1 [M+H]⁺.

Step B. (2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

To a solution of (2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (0.80 g, 1.83 mmol) in degassed EtOH (25 mL) was added 10% palladium on carbon (0.20 mg, 0.19 mmol). The reaction was placed under an atmosphere of hydrogen and let stir for 48 h. The reaction was diluted with DCM and filtered through a pad of Celite®. The solvent was concentrated and chromatography of the resulting residue (SiO₂; MeOH(NH₃):DCM) gave the title compound (500 mg, 62%). ¹H NMR (500 MHz, CDCl₃) δ 8.45-8.30 (m, 1H), 7.94 (dd, J=18.2, 10.7 Hz, 1H), 7.76 (d, J=5.7 Hz, 1H), 7.67-7.43 (m, 3H), 7.43-7.30 (m, 1H), 5.81 (dd, J=13.3, 6.7 Hz, 1H), 5.07 (d, J=5.6 Hz, 1H), 4.52 (d, J=6.7 Hz, 1H), 3.61-3.31 (m, 1H), 3.08-2.69 (m, 1H), 1.63-145 (m, 3H). MS (ESI): mass calculated for C₂₀H₁₅ClF₄N₄O, 438.08. m/z found 439.1 [M+H]⁺.

Example 40

(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as a single enantiomer by Chiral SFC purification of Example 11 performed using CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 70% CO₂, 30% EtOH. The enantiomeric purity was confirmed by analytical SFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 30% EtOH over 7 minutes. (100% single enantiomer, 2.29 min retention time). MS (ESI): mass calculated for C₂₀H₁₅ClF₄N₄O, 438.1. m/z found, 439.3 [M+H]⁺.

Intermediate 1: 1-(5-Fluoropyridin-2-yl)-1H-imidazo[4,5-c]pyridine

A solution of 5-azabenzimidazole (1.00 g, 8.40 mmol), 2-bromo-5-fluoropyridine (1.48 g, 8.40 mmol), copper (I) oxide (0.13 g, 0.84 mmol), 8-hydroxyquinoline (0.24 g, 1.68 mmol), and Cs₂CO₃(5.47 g, 16.8 mmol) in DMSO (4 mL) was irradiated in a microwave apparatus for 1 hour at 140° C. The reaction was diluted with H₂O (100 mL) and extracted with EtOAc (75 mL×3). The organic layers were combined, dried (Na₂SO₄), and concentrated. Chromatography of the resulting residue (SiO₂; MeOH(NH₃):DCM) gave the title compound (0.45 g, 25%). MS (ESI): mass calculated for C₁₁H₇FN₄, 214.07. m/z found 215.1 [M+H]⁺.

Intermediate 12: 2-Chloro-3-(trifluoromethyl)benzoyl chloride

To a suspension of 2-chloro-3-(trifluoromethyl)benzoic acid (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum.

PAPER

Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor

Devin M. Swanson ^*^†, Brad M. Savall^†, Kevin J. Coe^†, Freddy Schoetens^†, Tatiana Koudriakova^†, Judith Skaptason^†, Jessica Wall^†, Jason Rech^†, Xiahou Deng^†, Meri De Angelis^‡, Anita Everson^†, Brian Lord^†, Qi Wang^†,Hong Ao^†, Brian Scott^†, Kia Sepassi^†, Timothy W. Lovenberg^†, Nicholas I. Carruthers^†, Anindya Bhattacharya^†, and Michael A. Letavic^†

^†Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121 United States

^‡Janssen Research & Development, Discovery Sciences, A Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00989, http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00989

*Tel: 1-858-320-3306. E-mail: dswanso1@its.jnj.com.

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED₅₀ = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.

(R)-(2-Chloro-3 (trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (1)The title compound was obtained as a single enantiomer by Chiral SFC purification performed using CHIRALCEL OD-H (5 μm, 250 × 20 mm) and a mobile phase of 72% CO₂, 28% 1:1 EtOH/iPrOH. The enantiomeric purity was confirmed by analytical SFC using Whelk-al (S,S) (250 × 4.6 mm) and a mobile phase of 60% CO₂, 40% MeOH over 7 min (100% single enantiomer, 4.03 min retention time) (0.16 g, 41%).

¹H NMR (500 MHz, CDCl₃) δ 8.43–8.32 (m, 1H), 7.94 (dd,J = 18.3, 11.2 Hz, 1H), 7.80–7.70 (m, 1H), 7.65–7.29 (m, 4H), 5.91–5.74 (m, 1H), 5.14–4.46 (m, 1H), 3.60–3.30 (m, 1H), 3.30–3.04 (m, 1H), 3.06–2.68 (m, 1H), 1.76–1.35 (m, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 165.95–165.79 (s), 139.33–139.10 (d, J = 8.8 Hz), 137.50–137.15 (m), 135.54–135.31 (m), 131.24–131.08 (s), 130.68–130.52 (s), 130.42–130.26 (s), 128.08–127.83 (t, J = 5.7 Hz), 127.50–127.13 (m), 126.23–125.85 (dd, J = 20.4, 7.6 Hz), 123.69–123.54 (s), 122.56–122.40 (s), 116.00–115.72 (m), 52.32–52.16 (s), 47.41–47.25 (s), 41.25–41.09 (s), 35.57–35.41 (s), 24.49–24.19 (m), 19.96–18.59 (m).

HRMS calc. for C₂₀H₁₃ClF₄N₄O [M + H]⁺ 439.0943, found 439.0957.

Specific rotation: [α]²⁰_D – 52.6 (c 0.5, CHCl₃).

PATENT

https://www.google.com/patents/WO2014152604A1?cl=en

Example 40. (R* -(2-chloro-3-(trifluoromethyl phenyl (l-(5-fluoropyridin-2-yl -4-methyl- -dihydro-lH-imidazor4,5-c1pyridin-5(^‘4H -yl methanone.

The title compound, absolute configuration unknown, was obtained as a single enantiomer by Chiral SFC purification of Example 11 performed using CHIRALCEL OD-H (5μιη, 250x20mm) and a mobile phase of 70% CO2, 30% EtOH. The enantiomeric purity was confirmed by analytical SFC using a CHIRALCEL OD-H (250×4.6mm) and a mobile phase of 70% CO2, 30% EtOH over 7 minutes. (100% single enantiomer, 2.29 min retention time). MS (ESI): mass calculated for C2oH₁₅ClF₄N₄0, 438.1; m/z found, 439.3 [M+H]⁺.

Example 11. (2-Chloro-3-(trifluoromethyl)phenyl)(l-(5-fluoropyridin-2-yl)-4-methyl-6,7- dihvdro-lH-imidazor4,5-c1pyridin-5(4H)-yl)methanone.

Step A. (2-Chloro-3 -(trifluoromethyl)phenylX 1 -(5 -fluoropyridin-2-yl)-4-methyl- 1 H- imidazor4.5-c1pyridin-5(^‘4H)-yl)methanone.

To a solution of Intermediate 1 (0.70 g, 3.27 mmol) in THF (20 mL) was added

Intermediate 12 (0.87 g, 3.60 mmol) dropwise. The reaction was allowed to stir for 1 h then cooled to – 78 °C. To the cooled solution was added 3M MeMgBr in Et₂0 (1.31 mL, 3.92 mmoL) and the reaction was let come to room temperature. The mixture was then quenched with IN NaOH (50 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried (Na₂S0₄), and concentrated. Chromatography of the resulting residue (Si0₂; MeOH (NH₃):DCM) gave the title compound (770 mg, 54%). ^XH NMR (400 MHz, CDC1₃) δ 8.43 – 8.34 (m, 1H), 7.92 – 7.73 (m, 2H), 7.70 – 7.33 (m, 4H), 6.08 (dtd, J = 19.7, 11.7, 8.0 Hz, 3H), 1.54 (t, J = 7.0 Hz, 3H). MS (ESI): mass calculated for C2oH₁₃ClF_{4 4}0, 436.07; m/z found 437.1 [M+H]⁺.

Step B. (2-Chloro-3-(trifluoromethyl)phenyl)(l-(5-fluoropyridin-2-yl)-4-methyl-6J- dihydro-lH-imidazo[4.5-clpyridin-5(4H)-yl)methanone.

To a solution of (2-chloro-3-(trifluoromethyl)phenyl)(l-(5-fluoropyridin-2-yl)-4-methyl- lH-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (0.80 g, 1.83 mmol) in degassed EtOH (25 mL) was added 10% palladium on carbon (0.20 g, 0.19 mmol). The reaction was placed under an atmosphere of hydrogen and let stir for 48 h. The reaction was diluted with DCM and filtered through a pad of Celite ©. The solvent was concentrated and chromatography of the resulting residue (Si0₂; MeOH (NH₃):DCM) gave the title compound (500 mg, 62%). ¾ NMR (500 MHz, CDC1₃) δ 8.45 – 8.30 (m, 1H), 7.94 (dd, J = 18.2, 10.7 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 7.67 – 7.43 (m, 3H), 7.43 – 7.30 (m, 1H), 5.81 (dd, J = 13.3, 6.7 Hz, 1H), 5.07 (d, J = 5.6 Hz, 1H), 4.52 (d, J = 6.7 Hz, 1H), 3.61 – 3.31 (m, 1H), 3.08 – 2.69 (m, 1H), 1.63 – 145 (m, 3H). MS (ESI): mass calculated for C₂₀H₁₅ClF₄N₄O, 438.08; m/z found 439.1 [M+H]⁺.

Intermediate 12: 2-Chloro-3-(trifluoromethyl)benzoyl chloride.

Intermediate 1 : l-(^‘5-Fluoropvridin-2-vl)-lH-imidazor4,5-clpvridine.

A solution of 5-azabenzimidazole (1.00 g, 8.40 mmol), 2-bromo-5-fluoropyridine (1.48 g, 8.40 mmol), copper (I) oxide (0.13 g, 0.84 mmol), 8-hydroxyquinoline (0.24 g, 1.68 mmol), and CS2CO₃ (5.47 g, 16.8 mmol) in DMSO (4 mL) was irradiated in a microwave apparatus for 1 hour at 140 °C. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (75 mL x 3). The organic layers were combined, dried (Na₂S0₄), and concentrated. Chromatography of the resulting residue (S1O2; MeOH (NH₃):DCM) gave the title compound (0.45 g, 25%). MS (ESI): mass calculated for C11H7FN4, 214.07; m/z found 215.1 [M+H]⁺.

Patent ID	Date	Patent Title
US2016039809	2016-02-11	P2X7 MODULATORS
US2015322062	2015-11-12	P2X7 MODULATORS
US2014275015	2014-09-18	P2X7 MODULATORS

///////JNJ 54166060, JNJ-54166060, JNJ54166060, 1627900-42-8, P2X7 antagonists, 1627900-41-7

ClC1=C(C(N2CCC(N(C3=CC=C(F)C=N3)C=N4)=C4[C@H]2C)=O)C=CC=C1C(F)(F)F

(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol for the treatment of viral infections

September 18, 2016 10:32 am / Leave a comment

(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol

JNJ ?

cas 1402802-45-2

WO 2012136834, WO 2014053595

for the treatment of viral infections

Molecular Formula:	C₁₂H₂₂N₄O₂
Molecular Weight:	254.32868 g/mol

Inventors	Gowan David Mc, Pierre Jean-Marie Bernard Raboisson, Werner Embrechts, Tim Hugo Maria Jonckers, Stefaan Julien Last, Serge Maria Aloysius Pieters, Jaromir Vlach,
Applicant	Janssen R&D Ireland

(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol

Mark Hicken, Managing Director UK & Ireland, Janssen Ltd; Maggie Throup MP, Health Select Committee; Richard Mason, Head of Innovation, Johnson and Johnson; Dr Mark Lloyd Davies, Senior Director Government Affairs and Policy UK and Ireland, Johnson & Johnson

To the use of pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved. Toll-Like Receptors are primary transmembrane proteins characterized by an extracellular leucine rich domain and a cytoplasmic extension that contains a conserved region. The innate immune system can recognize pathogen-associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell behaviour.

It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (named TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which are represented in humans. Other mammals may express TLRs which are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.

For detailed reviews on toll-like receptors see the following journal articles. Hoffmann, J. A., Nature, 426, p 33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21, p 335-376, 2003; Ulevitch, R. J., Nature Reviews: Immunology, 4, p 512-520, 2004.

Compounds indicating activity on Toll-Like receptors have been previously described such as purine derivatives in WO 2006/117670, adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines in WO 2009/067081. However, there exists a strong need for novel Toll-Like receptor modulators having preferred selectivity, higher potency, higher metabolic stability, and an improved safety profile compared to the compounds of the prior art.

In the treatment of certain viral infections, regular injections of interferon (IFNα) can be administered, as is the case for hepatitis C virus (HCV), (Fried et. al. Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small molecule IFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, novel IFN inducers are potentially effective new class of drugs for treating virus infections. For an example in the literature of a small molecule IFN inducer having antiviral effect see De Clercq, E.; Descamps, J.; De Somer, P. Science 1978, 200, 563-565.

IFNα is also given in combination with other drugs in the treatment of certain types of cancer (Eur. J. Cancer 46, 2849-57, and Cancer Res. 1992, 52, 1056). TLR 7/8 agonists are also of interest as vaccine adjuvants because of their ability to induce pronounced Th1 response (Hum. Vaccines 2010, 6, 1-14; Hum. Vaccines 2009, 5, 381-394).

SYNTHESIS

50d

patent

WO 2014053595

https://www.google.com/patents/WO2014053595A1?cl=en

Experimental Section.

Into a 50 ml_ vial equipped with a magnetic stir bar was placed 2,4-dichloro-5- methoxypyrimidine (2.0 g, 1 1.7 mmol), and acetonitrile (20 ml_), diisopropylethylamine (3.02 g, 23.4 mmol) and (S)-3-aminoheptanol (4.59 g, 35.1 mmol). The reaction mixture was allowed to stir 15 hours at room temperature. The solvents were removed under reduced pressure. The crude was purified via silica gel column chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled and the solvents were removed under reduced pressure to afford a white solid, B.

B C

To a thick wall glass vial equipped with a magnetic stir bar was added B (1 g, 3.66 mmol), NH₃ (10 ml_, aq.), ammonium bicarbonate (3.34 g, 42.3 mmol) and copper(l) oxide (121 mg, 0.85 mmol). The vial was sealed and placed into an oil bath and heated to 150°C for 15 hours. The reaction mixture was extracted with dichloro- methane (3 x 25 ml_), the organic layers were pooled and dried over magnesium sulfate. The solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. Crude C was purified via HPLC.

c 1

C (463 mg, 1.82 mmol) was dissolved in THF (13 ml_) and cooled to -78°C. NaH (145 mg, 3.64 mmol, a 60% dispersion in mineral oil) was added in one portion and stirred at -78°C for 30 minutes. Isobutyryl chloride (389 μΙ_, 3.64 mmol) was added dropwise at -78°C and stirred for 10 minutes. The cooling bath was removed and the mixture was allowed to reach room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water and concentrated in vacuo. The residue was purified by HPLC (RP Vydac Denali C18 10 μηι, 200 g, 5 cm, mobile phase 0.25% NH4HCO₃ solution in water, acetonitrile), the desired fractions were collected, and the solvents were removed under reduced pressure to afford the pure product.

LC-MS m/z = 395 (M+H), Retention time 1.1 minutes, LC method A.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83 (t, J=6.90 Hz, 3 H) 0.98 – 1.07 (m, 12 H) 1.16 – 1.35 (m, 4 H) 1.44 – 1.62 (m, 2 H) 1.84 (q, J=6.78 Hz, 2 H) 2.45 (spt, J=7.00 Hz, 1 H) 2.96 (br. s., 1 H) 3.80 (s, 3 H) 3.92 – 4.07 (m, 2 H) 4.18 – 4.31 (m, 1 H) 6.69 (d, J=9.03 Hz, 1 H) 7.60 (s, 1 H) 9.49 (s, 1 H).

Synthetic scheme for the preparation of A

Preparati

valeraldehyde A2

To a solution of valeraldehyde (43 g, 500 mmol) in THF (1 L) was added A1 (200 g, 532 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated and the residue was diluted in petroleum ether and filtered. The solvents of the filtrate were removed under reduced pressure and the residue was purified by silica chromatography using a petroleum ether to 3% ethyl acetate in petroleum ether gradient to give A2 (90 g) as a colorless oil.

¹H NMR (400 MHz, CDCI₃): δ ppm 6.81 -6.77 (m, 1 H), 5.68-5.64 (td, J=1.2Hz, 15.6 Hz, 1 H), 2.11-2.09 (m, 2H), 1.41 (s, 9H), 1.38-1.26 (m, 4H), 0.85-0.81 (t, J=7.2Hz, 3H).

/7-butyl lithium (290 mL, 725 mmol) was added to a stirred solution of A3 (165 g, 781 mmol) in THF (800 mL) at -78°C. The reaction mixture was stirred for 30 minutes then A2 (90 g, 488.4 mmol) in THF (400 mL) was added and the reaction was stirred for 2 hours at -78°C. The mixture was quenched with sat., aq. NH₄CI solution and warmed to room temperature. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by column chromatography eluting with 5% ethyl acetate in petroleum ether to afford a colorless oil, A4 (132 g).

¹H NMR (400 MHz, CDCI₃): δ ppm 7.36-7.16 (m, 10H), 3.75-3.70 (m, 2H), 3.43-3.39 (d, J=15.2Hz, 1 H), 3.33-3.15 (m, 1 H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (s, 9H), 1.26-1.17 (m, 7H), 0.83-0.79 (t, J=7.2Hz, 3H).

Preparatio

A4 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0°C in small portions. The resulting mixture was stirred at the same temperature for 2 hours and then allowed to warm to room temperature. The mixture was quenched with a sat. aq. NH₄CI solution. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The combined organic layers were dried over sodium sulfate, the solids were removed via filtration and concentrated to afford crude A5 (100 g), which was used in the next step without further purification.

¹H NMR (400 MHz, CDCI₃): δ ppm 7.33-7.14 (m, 10H), 3.91 -3.86 (m, 1 H), 3.80-3.77 (d, J=13.6Hz, 1 H), 3.63-3.60 (d, J=13.6Hz, 1 H), 3.43-3.42 (m, 1 H), 3.15-3.10 (m, 1 H), 2.70-2.63 (m, 2H), 1.65-1.28 (m, 10H), 0.89-0.81 (m, 3H).

Preparation of A

A5 A

A solution of A5 (38 g, 116.75 mmol) and 10% Pd/C in methanol (200 ml_) was hydrogenated under 50 PSI hydrogen at 50°C for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give A.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16-3.15 (m, 1 H), 1.71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.33-1.26 (m, 4H), 0.90-0.87 (t, J=6.8Hz, 3H).

Analytical Method.

Compounds 1-8 in the table below were characterized by LC-MS according to the following LC-MS method.

Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μηι, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (10 mM ammonium acetate in H₂0/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.7 minutes. An injection volume of 0.75 μΙ_ was used. Cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.

Paper

Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure–activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.

Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus

David McGowan ^*^†, Florence Herschke ^*^†, Frederik Pauwels^†, Bart Stoops^†, Stefaan Last^†, Serge Pieters^†, Annick Scholliers^†, Tine Thoné^†, Bertrand Van Schoubroeck^†, Dorien De Pooter^†, Wendy Mostmans^†, Mourad Daoubi Khamlichi^‡, Werner Embrechts^†, Deborah Dhuyvetter^†, Ilham Smyej^†, Eric Arnoult^†, Samuël Demin^†, Herman Borghys^†, Gregory Fanning^†, Jaromir Vlach^†, and Pierre Raboisson^†

^†Janssen Infectious Diseases Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium

^‡Villapharma Research S.L., Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo, Km. 2.5, Av. Azul 30320 Fuente Álamo de Murcia, Murcia, Spain

J. Med. Chem., 2016, 59 (17), pp 7936–7949

DOI: 10.1021/acs.jmedchem.6b00747, http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.6b00747

*For D.M.: phone, +32 6414 1019; E-mail, dmcgowan@its.jnj.com., *For F.H.: phone, +32 6414 1644; E-mail, fherschk@its.jnj.com.

(S)-3-((2-Amino-5-methoxypyrimidin-4-yl)amino)heptan-1-ol (50d)

¹H NMR (360 MHz, DMSO-d₆) δ 7.34 (s, 1H), 6.16 (d, J = 9.15 Hz, 1H), 5.48 (s, 2H), 4.42 (t, J = 5.12 Hz, 1H), 4.04–4.20 (m, 1H), 3.66 (s, 3H), 3.36–3.44 (m, 2H), 1.37–1.73 (m, 4H), 1.11–1.35 (m, 4H), 0.84 (t, J = 6.95 Hz, 3H).

¹³C NMR (101 MHz, DMSO-d₆) δ 158.0, 154.6, 135.5, 133.2, 58.0, 56.7, 46.1, 37.5, 34.0, 27.9, 22.1, 14.0.

ESI-HRMS (TOF) m/z: 255.1816 [M + H]⁺ (calcd for C₁₂H₂₂N₄O₂: 254.1743).

[α]_D²⁰ + 25.2 (c 0.81, DMF).

PATENT

http://www.google.com.na/patents/US20140045849

David McGowan, Pierr Jeane-Marie Bernar Raboisson, Werner Embrechts, Tim Hugo Maria Jonckers, Stefaan Julien Last, Serge Maria Aloysius Pieters, Jaromir Vlach,

Preparation of Compounds.

Compounds of formula (I), where R₁is hydrogen atom are prepared according to scheme 1

Compounds of formula (I), when R₁is alkyl, cycloalkyl, trifluoromethyl, or alkoxy and where R₂is aromatic or aliphatic, can be prepared according scheme 4. This reaction scheme begins with a crossed-Claisen reaction where an acyl chloride reacts with ester intermediate A (shown in scheme 1) to form intermediates (G) as in scheme 3. From intermediate G, the reaction scheme follows the same pathway to the products as in scheme 3. This is a general scheme using methods known to a skilled person, see for instance The Journal of American Chemical Society volume 127, page 2854 (2005).

Synthetic Scheme for the Preparation of AA-9

A solution of AA-6 (38 g, 116.75 mmol) and 10% Pd/C in methanol (200 mL) was hydrogenated under 50 PSI hydrogen at 50° C. for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give crude product AA-7 (17 g).

The crude product was dissolved in dichloromethane (200 mL), triethylamine (26.17 g, 259.1 mmol) and di-tert-butyl dicarbonate (84.7 g, 194.4 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in petroleum ether to give AA-8 (13 g) as colorless oil.

¹H NMR (400 MHz, CDCl₃): δ ppm 4.08-4.03 (br, 1H), 3.68 (m, 1H), 3.58-3.55 (m, 2H), 3.20-2.90 (br, 1H), 1.80-1.73 (m, 1H), 1.42-1.17 (m, 15H), 0.85-0.82 (t, J=6.8 Hz, 3H).

AA-8 (42 g, 0.182 mol) was dissolved in dioxane (200 mL) and dioxane/HCl (4M, 200 mL) was added at 0° C. The resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated to afford the crude product. A dichloromethane/petroleum ether mixture (50 mL, 1:1, v/v) was added to the crude product, and the supernatant was decanted. This procedure was repeated two times to obtain an oil, AA-9 (26.6 g).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16-3.15 (m, 1H), 1.71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.33-1.26 (m, 4H), 0.90-0.87 (t, J=6.8 Hz, 3H)

Procedure for Preparation of Intermediate C-1.Reaction Scheme:

A suspension of intermediate B-1 (160 g, 0.74 mol) in POCl₃(900 mL) was heated to 100° C. under N₂with stirring for 5 hours. The reaction mixture was cooled to room temperature. The excess POCl₃was removed under reduced pressure, the oil residue was poured into cold, sat. aq. NaHCO₃(2 L) that was stirred for 30 minutes. The mixture was extracted with ethyl acetate (3×1.5 L). The combined organic layers were separated and washed with brine (1 L), dried over sodium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated to afford intermediate C-1 (70 g) as a yellow solid. The product was used in the next step without further purification.

Patent ID	Date	Patent Title
US2015274676	2015-10-01	ACYLAMINOPYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS AND FURTHER DISEASES
US2014045849	2014-02-13	PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS

WO2006053109A1 *	Nov 10, 2005	May 18, 2006	Synta Pharmaceuticals Corp.	Heteroaryl compounds
WO2012136834A1 *	Apr 10, 2012	Oct 11, 2012	Janssen R&D Ireland	Pyrimidine derivatives for the treatment of viral infections
US5434157 *	Jan 21, 1993	Jul 18, 1995	The Upjohn Company	6-aryl pyrimidine compounds and method for treating viral infections and inducing interferon production

Reference
1	*	ANGELICA M BELLO ET AL: “De Novo Design of Nonpeptidic Compounds Targeting the Interactions between Interferon-a and its Cognate Cell Surface Receptor“, JOURNAL OF MEDICINAL CHEMISTRY,, vol. 51, no. 9, 1 January 2008 (2008-01-01), pages 2734 – 2723, XP008157384, DOI: 10.1021/JM701182Y
2		DE CLERCQ, E.; DESCAMPS, J.; DE SOMER, P., SCIENCE, vol. 200, 1978, pages 563 – 565
3		FRIED: “Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection“, N ENGL J MED, vol. 347, 2002, pages 975 – 82

/////////////// treatment of viral infections, Pyrimidine Toll-like Receptor 7, Toll-like Receptor 8 Dual Agonists, Treat Hepatitis B Virus, PRECLINICAL, 1402802-45-2, JNJ ?

n1c(nc(c(c1)OC)N[C@@H](CCCC)CCO)N

IPI-549

September 14, 2016 2:55 pm / Leave a comment

IPI-549

CAS 1693758-51-8
MF : C30H24N8O2
Molecular Weight: 528.576

(S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Company	Infinity Pharmaceuticals Inc.
Description	Small molecule inhibitor of phosphoinositide 3-kinase (PI3K) gamma
Molecular Target	Phosphoinositide 3-kinase (PI3K) gamma
Mechanism of Action	Phosphoinositide 3-kinase (PI3K) gamma inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I
Standard Indication	Solid tumors
Indication Details	Treat solid tumors

Originator Intellikine
Developer Infinity Pharmaceuticals
ClassAntineoplastics; Small molecules
Mechanism of ActionPhosphatidylinositol 3 kinase delta inhibitors; Phosphatidylinositol 3 kinase gamma inhibitors

Phase I Solid tumours

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Most Recent Events

18 Apr 2016 Pharmacodynamics data from a preclinical study in Solid tumours presented at the 107^th Annual Meeting of the American Association for Cancer Research (AACR-2016)
01 Dec 2015 Phase-I clinical trials in Solid tumours (Monotherapy, Combination therapy, Late-stage disease, Second-line therapy or greater) in USA (PO)

IPI-549 is a potent and selective phosphoinositide-3-kinase (PI3Kγ) Inhibitor as an Immuno-Oncology Clinical Candidate (Kd = 0.29 nM). Bioactivity data of IPI-549: biochemcial IC50 (nM) for PI3K isoform: 3200 (α); 3500 (β); 16 (γ); and >8400 (δ) respectively. Cellar IC50 (nM) of IPI549 for PI3K isoform: 250 (α); 240 (β); 1.6 (γ); and 180 (δ) respectively. IPI-549 shows >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Image result for IPI-549

Patent

WO 2015051244

https://www.google.co.in/patents/WO2015051244A1?cl=en

Scheme 1

Scheme 2

Example 1

[00657] Compound 4 was prepared in 3 steps from compound A according to the following procedures:

Compound A was prepared according to Method A. It was coupled to 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid according to the following procedure: Compound A (27.4 mmol, 1.0 equiv), HOBt hydrate (1.2 equiv), 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.05 equiv) and

EDC (1.25 equiv) were added to a 200 mL round bottomed flask with a stir bar. N,N-Dimethylformamide (50 mL) was added and the suspension was stirred at RT for 2 min. Hunig’s base (4.0 equiv) was added and after which the suspension became homogeneous and was stirred for 22h resulting in the formation of a solid cake in the reaction flask. The solid mixture was added to water (600 mL) and stirred for 3h. The resulting cream colored solid was filtered and washed with water (2 x 100 mL) and dried. The solid was then dissolved in methylene chloride (40 mL) after which trifluoroacetic acid (10 equiv, 20 mL) was added and the reaction was stirred for 30 min at RT after which there is no more starting material by LC/MS analysis. The solution was then concentrated and coevaporated with a mixture of methylene choride/ethanol (1 : 1 v/v) and then dried under high vacuum overnight. The resulting solid was triturated with 60 mL of ethanol for lh and then collected via vacuum filtration. The beige solid was then neutralized with sodium carbonate solution (100 mL) and then transferred to a separatory funnel with methylene chloride (350 mL). The water layer was extracted with an additional 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to provide a pale yellow solid that was purified using flash silica gel chromatography (Combiflash, 24g column, gradient of 0-5% methanol/methylene chloride) to provide amide B. ESI-MS m/z: 459.4 [M+H]+.

[00658] Amide B was placed in a sealed tube (0.67 mmol, 1.0 equiv) followed by dichlorobis(acetonitrile)palladium (15 mol%), X-Phos (45 mol%), and cesium carbonate (3.0 equiv) Propionitrile (5 mL) was added and the mixture was bubbled with Ar for 1 min. 4-Ethynyl-l -methyl- lH-pyrazole (1.24 equiv) was added and the resulting orange mixture was sealed and stirred in an oil bath at 85 oC for 1.5h. The resulting brownish-black mixture was allowed to cool at which point there was no more SM by LC/MS analysis. The mixture was then filtered through a short plug of cotton using acetonitrile and methylene chloride. The combined filtrates were concentrated onto silica gel and purified using flash silica gel chromatography (Combiflash, 4g column, gradient of 0-5% methylene chloride/methanol). The resulting material was further purified by reverse phase HPLC (15-90%o acetonitrile with 0.1%o formic acid/water with 0.1%o formic water) to provide desired compound 4. ESI-MS m/z: 529.5 [M+H]+.

PAPER

WO 2015143012

https://www.google.com/patents/WO2015143012A1?cl=en

PAPER

IPI-549 NMR 1H

IPI-549 13C NMR

IPI-549 ASSAY

Compound 1 is coupled to 4-ethynyl-1-methyl-1H-pyrazole using the general procedure outlined above to provide compound 26 IPI-549, in 70% yield with >98% enantiomeric purity.

IPI-549

1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 6.8, 1.7 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H), 8.00 (s, 1H), 7.69 – 7.54 (m, 5H), 7.53 – 7.43 (m, 3H), 7.41 – 7.35 (m, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.74 (s, 1H), 6.42 (s, 2H), 4.56 (quin, J = 6.8 Hz, 1H).), 3.82 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H).

13C NMR (101 MHz, DMSO-d6) δ 162.73, 161.19, 160.93, 150.06, 147.51, 146.74, 141.05, 138.09, 137.81, 135.42, 133.66, 132.56, 131.90, 129.51, 129.24, 129.20, 129.17, 128.50, 126.16, 123.41, 123.31, 107.88, 102.44, 101.15, 90.40, 87.06, 85.94, 44.88, 38.62, 20.69.

ESI-HRMS: calcd for 529.2095 C30H25N8O2 (M+H)+ , found 529.2148.

[]D 22: +447.8o (c 1.007, DMSO)

COMPD1

compound 1 in 95% yield.

1H NMR (400 MHz, CDCl3) 8.41 (dd, J = 6.8, 1.7 Hz, 1H), 8.37 (dd, J = 4.4, 1.7 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.50-7.34 (m, 5H), 7.34-7.27 (m, 2H), 6.76 (dd, J = 7.1, 4.9 Hz, 1H), 6.57 (s, 1H), 5.54 (broad s, 2H), 4.79 (quin, J = 6.9 Hz, 1H), 1.36 (d, J = 6.5 Hz, 3H);

ESI-HRMS: calcd for C24H20ClN6O2 459.1331 (M+H)+ , found 459.1386. HPLC Purity: 96% AUC.

Abstract Image

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

Infinity Pharmaceuticals, Inc., 784 Memorial Drive, Cambridge, Massachusetts 02139, United States

ACS Med. Chem. Lett., 2016, 7 (9), pp 862–867

DOI: 10.1021/acsmedchemlett.6b00238

*E-mail: catherine.evans@infi.com., *E-mail: alfredo.castro@infi.com.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00238

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CLIP

Infinity Expands Pipeline with Addition of IPI-549, an Immuno-Oncology Development Candidate for the Treatment of Solid Tumors

– IPI-549, a Selective PI3K-Gamma Inhibitor, Targets the Immune-Suppressive Tumor Microenvironment –

– Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference –

September 18, 2015 07:41 AM Eastern Daylight Time

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) today announced the expansion of its pipeline with the addition of IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. Preclinical data demonstrating the potential of IPI-549 to disrupt the immune-suppressive tumor microenvironment and enable a heightened anti-tumor immune response are being presented today at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival Meeting in New York City. IPI-549 was discovered at Infinity and is expected to enter Phase 1 clinical development in early 2016.

“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients”

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“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients,” stated Vito Palombella, Ph.D., Infinity’s chief scientific officer. “Infinity’s ability to internally develop a selective PI3K-gamma inhibitor provides us with a unique opportunity to explore the impact that PI3K-gamma inhibition has on disrupting the tumor microenvironment. We look forward to initiating the first clinical study of IPI-549 in patients with solid tumors.”

“I have had the pleasure of collaborating with Infinity’s discovery team and am excited to have worked with IPI-549 in my laboratory,” Jedd Wolchok, M.D., Ph.D., chief of Melanoma and Immunotherapeutics Service, Lloyd J. Old/Ludwig Chair in Clinical Investigation Department of Medicine and Ludwig Center, at Memorial Sloan Kettering Cancer Center and the principal investigator for the planned Phase 1 clinical study of IPI-549. “IPI-549 is a novel, small molecule immuno-oncology agent, and I am looking forward to leading the Phase 1 study for this program.”

IPI-549 inhibits immune suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference

Today at the AACR meeting in New York City Infinity researchers are presenting preclinical data for IPI-549 in a poster entitled, “The potent and selective phosphoinositide-3-kinase-gamma inhibitor, IPI-549, inhibits tumor growth in murine syngeneic solid tumor models through alterations in the immune suppressive microenvironment.”

In vitro data showed that IPI-549 blocks both the migration of murine myeloid cells and the differentiation of myeloid cells to the M2 phenotype, which is a type of myeloid cell known to promote cancer growth and suppress anti-tumor immune responses. In vivo data in murine solid tumor models demonstrated that IPI-549 treatment also decreased tumor-associated myeloid cells found in the immune suppressive microenvironment. Additionally, IPI-549 treatment increased the number of intratumoral CD8⁺T-cells, which are known to play a role in inhibiting tumor growth.

IPI-549 has demonstrated dose-dependent, single-agent, anti-tumor activity in multiple solid tumor models, including murine models of lung, colon and breast cancer. Additionally, mice treated with IPI-549 in combination with checkpoint inhibitors showed greater tumor growth inhibition than either treatment as a monotherapy. Preclinical in vivo data also demonstrated that T-cells are required for the anti-tumor activity of IPI-549, which is a hallmark of immunotherapy.

Further details about the IPI-549 development program will be provided at Infinity’s R&D Day on Tuesday, October 6, 2015. R&D Day will be held in New York City from 7:30 a.m. to 12:00 p.m. ET. The event will be webcast beginning at 8:00 a.m. ET and can be accessed in the Investors/Media section of Infinity’s website, www.infi.com. A replay of the event will also be available.

Infinity is also developing duvelisib, an investigational, oral, dual inhibitor of PI3K-delta and PI3K-gamma. The PI3K pathway is also known to play a critical role in regulating the growth and survival of certain types of blood cancers. The investigational agent is being evaluated in registration-focused studies, including DYNAMO^TM, a Phase 2 study in patients with refractory indolent non-Hodgkin lymphoma, DYNAMO+R, a Phase 3 study in patients with previously treated follicular lymphoma, and DUO^TM, a Phase 3 study in patients with relapsed/refractory chronic lymphocytic leukemia. Duvelisib is an investigational compound and its safety and efficacy have not been evaluated by the U.S. Food and Drug Administration or any other health authority.

About Infinity Pharmaceuticals, Inc.

Infinity is an innovative biopharmaceutical company dedicated to discovering, developing and delivering best-in-class medicines to people with difficult-to-treat diseases. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging disease pathways. For more information on Infinity, please refer to the company’s website at www.infi.com.

Clip

IPI-549-01-A phase 1/1b first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.

Subcategory:

Other

Category:

Developmental Therapeutics—Immunotherapy

Meeting:

2016 ASCO Annual Meeting

Session Type and Session Title:

Poster Session, Developmental Therapeutics—Immunotherapy

Abstract Number: TPS3111

Poster Board Number:

Board #425a

Citation:

J Clin Oncol 34, 2016 (suppl; abstr TPS3111)

Author(s):

Anthony W. Tolcher, David S. Hong, Ryan J. Sullivan, James Walter Mier, Geoffrey Shapiro, Joseph Pearlberg, Les H. Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard Marvin Stern, Jedd D. Wolchok; START San Antonio, San Antonio, TX; Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, TX; Massachusetts General Hospital, Boston, MA; Department of Medicine, Dana-Farber/Harvard Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Infinity Pharmaceuticals, Inc., Cambridge, MA; Infinity Pharmaceuticals Inc., Cambridge, MA; Infinity Pharmaceuticals, Cambridge, MA; Memorial Sloan Kettering Cancer Center, New York, NY

Abstract Disclosures

Abstract:

Background: IPI-549 is a potential first-in-class potent and selective PI3K-γ inhibitor being developed as a novel orally administered immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with pembrolizumab (NCT02637531) in solid tumors. Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and pembrolizumab will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with pembrolizumab will occur following the dose escalation phase. All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment. This trial is currently enrolling patients in the US. Clinical trial information: NCT02637531

REFERENCES

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate
Catherine A. Evans, Tao Liu, André Lescarbeau, Somarajan J. Nair, Louis Grenier, Johan A. Pradeilles, Quentin Glenadel, Thomas Tibbitts, Ann M. Rowley, Jonathan P. DiNitto, Erin E. Brophy, Erin L. O’Hearn, Janid A. Ali, David G. Winkler, Stanley I. Goldstein, Patrick O’Hearn, Christian M. Martin, Jennifer G. Hoyt, John R. Soglia, Culver Cheung, Melissa M. Pink, Jennifer L. Proctor, Vito J. Palombella, Martin R. Tremblay, and Alfredo C. Castro
Publication Date (Web): July 22, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00238

Patent ID	Date	Patent Title
US2015290207	2015-10-15	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015225410	2015-08-13	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015111874	2015-04-23	HETEROCYCLIC COMPOUNDS AND USES THEREOF

///////immuno-oncology, IPI-549, isoform selectivity, neutrophil migration, phosphoinositide-3-kinase, PI3K-gamma inhibitor, IPI 549, IPI549. PRECLINICAL

O=C1N(C2=CC=CC=C2)C([C@@H](NC(C3=C(N=CC=C4)N4N=C3N)=O)C)=CC5=CC=CC(C#CC6=CN(C)N=C6)=C51

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Formula	CN101222922A	CN101222922B	Granted	2006/3/29	2026/3/29
2	Formula	CN102584712A		Examination	2006/3/29
3	Uses	CN102755318A	CN102755318B	Granted	2007/3/29	2027/3/29
4	Composition	CN102421291A		Examination	2010/2/24
5	Preparation	CN103108549A		Examination	2011/2/24
6	Uses	CN103997894A		Examination	2012/7/27

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Regioselective Epoxide Ring Opening for the Stereospecific Scale-Up Synthesis of BMS-960, A Potent and Selective Isoxazole-Containing S1P1Receptor Agonist

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1)

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DOI10.1002/jhet.2634,

Scheme 4.

Scheme 3.

Scheme 2.

Scheme 1.

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Example 11

(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

Step A. (2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

Step B. (2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

Example 40

(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

Intermediate 1: 1-(5-Fluoropyridin-2-yl)-1H-imidazo[4,5-c]pyridine

Intermediate 12: 2-Chloro-3-(trifluoromethyl)benzoyl chloride

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Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

IPI-549-01-A phase 1/1b first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.

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Regioselective Epoxide Ring Opening for the Stereospecific Scale-Up Synthesis of BMS-960, A Potent and Selective Isoxazole-Containing S1P₁Receptor Agonist

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P₁)