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GDC 0853

GDC-0853; RG 7845

3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3- yl)piperazin-l-yl]-2-pyridyl]amino]-6-oxo-lH-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-l, 2,6,8- tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one

phase 1

Patients with Patients with Resistant B-Cell Lymphoma or Chronic Lymphocytic Leukemia..

@genentech‘s Btk inhibitor

https://clinicaltrials.gov/ct2/show/NCT01991184

Bruton tyrosine kinase inhibitor

• 01 Sep 2015 Phase-I clinical trials in Autoimmune disorders (In volunteers) in USA (PO, Capsule and Tablet) (NCT02699710)
• 16 Oct 2014 Discontinued – Phase-I for Non-Hodgkin’s lymphoma (Second-line therapy or greater) in USA (unspecified route)
• 16 Oct 2014 Discontinued – Phase-I for Chronic lymphocytic leukaemia (Second-line therapy or greater) in USA (unspecified route)

BTK inhibitor GDC-0853 An orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, GDC-0853 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival.

Patent

https://www.google.co.in/patents/WO2013067274A1?cl=en

part

Example 271a (S)-tert- utyl 4-(6-(5-Chloro-2-methoxypyridin-3- ylamino)pyridin-3 -yl)-3 -methylpiperazine- 1 -carboxylate 271 a

271 c

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1 ,4-dioxane (40 mL), {S)-tert- vXy\ 4-(6-amino pyridin-3- yl)-3-methylpiperazine-l -carboxylate lOlh (2.04 g, 7.0 mmol), 3-bromo-5-chloro-2- methoxypyridine (2.8 g, 12.6 mmol), Pd₂(dba)₃ (640 mg, 0.70 mmol), XantPhos (404.6 mg, 0.70 mmol), and cesium carbonate (4.56 g, 14.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100 °C for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1 :3 ethyl acetate/petroleum ether to afford 271a (1.7 g, 57%) as a yellow solid. MS-ESI: [M+H]⁺ 434.2

Example 271b tert-Butyl (55)-4-(6- {[5-(2- {4,4-Dimethyl-9-oxo-l ,10- diazatricyclo[6.4.0.0²‘⁶]dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-2- methoxypyridin-3-yl] amino}pyridin-3-yl)-3-methylpiperazine-l-carboxylate 271b

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 271a (650 mg, 1.50 mmol), {3-[(acetyloxy)methyl]-2- {4,4-dimethyl-9-oxo-l ,10-diazatricyclo[6.4.0.0²‘⁶]dodeca-2(6),7- dien-10-yl}pyridin-4- yl}boronic acid 199e (1.79 g, 4.5 mmol), Pd₂(dba)₃ (137.2 mg, 0.15 mmol), P(cy)₃(167.4 mg, 0.60 mmol), Cs₂C0₃ (978 mg, 3.0 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 1 10°C for 16 h. After this time the reaction was cooled to room temperature. Lithium hydroxide monohydrate (1.89 g, 45 mmol) and water (2.0 mL) were added. The resulting mixture was stirred at 45°C for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3 : 1 ethyl acetate/petroleum ether to afford 271b (290 mg, 27%) as a yellow solid. MS-ESI: [M+H]⁺ 709.3

Example 271c 10-[3-(Hydroxymethyl)-4-[5-( {5-[(2S)-2-methylpiperazin-l – yl]pyridin-2-yl} amino)-6-oxo- 1 ,6-dihydropyridin-3-yl]pyridin-2-yl]-4,4-dimethyl- 1,10- diazatricyclo[6.4.0.0²‘⁶] dodeca-2(6),7-dien-9-one 271c

A solution of 271b (286.6 mg, 0.40 mmol) in dioxane/HCl (30 mL) was stirred at 50 °C for 2 h. It was evaporated under reduced pressure to afford 271c (450 mg, crude) as a black solid. MS-ESI: [M+H]⁺ 595.3

Example 271 3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3- yl)piperazin-l-yl]-2-pyridyl]amino]-6-oxo-lH-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-l, 2,6,8- tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one 271

To a solution of 271c (450 mg, 0.75 mmol) in methanol (10 mL) was added oxetan-3- one (162 mg, 2.25 mmol), NaBH₃CN (141.8 mg, 2.25 mmol), and ZnCl₂ (306 mg, 2.25 mmol). The reaction was stirred at room temperature for 3 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with dichloromethane (3 X 10 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 271 (23.0 mg, 8.8%, over two steps) as a yellow solid. MS-ESI: [M+H]⁺651.3. 1H NMR (500 MHz, CDC1₃) δ 9.76 (s, 1H), 8.74 (d, J= 2.0 Hz, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 4.5 Hz, 1H), 7.35 (dd, J = 2.5 Hz, 8.5 Hz, 1H), 6.87 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 5.16-5.13 (m, 1H), 4.72-4.69 (m, 5H), 4.54-4.53 (m, 1H), 4.36-4.35 (m, 1H), 4.19-4.17 (m, 2H), 3.89-3.87 (m, 1H), 3.56-3.49 (m, 2H), 3.11-3.09 (m, 2H), 2.60-2.48 (m, overlap, 7H), 2.24-2.21 (m, 1H), 1.29 (s, 6H), 1.02 (d, J= 6.0 Hz, 3H)

pipeline

http://www.gene.com/medical-professionals/pipeline

Pictrelisib, GDC-0941, RG7321 and GNE0941

//////GDC 0853, genentech,  Btk inhibitor, phase 1, Patients with Resistant B-Cell Lymphoma,  Chronic Lymphocytic Leukemia, Bruton tyrosine kinase inhibitor,  GDC-0853,  RG 7845

N1(CCN(CC1C)C2COC2)c3cnc(cc3)NC=4C(N(\C=C(/C=4)c5c(c(ncc5)N6CCn7c(C6=O)cc8CC(Cc78)(C)C)CO)C)=O
ACD/Labs0326161638

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M END