AbbVie'S Investigational Oncology Compound ABT-199/GDC-0199, Venetoclax

ABT 199, RG 7601, GDC 0199

Venetoclax

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

SYNTHESIS UPDATED BELOW ..............

 CAS 1257044-40-8 [RN]

2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

ABT 199

• Molecular Formula: C₄₅H₅₀ClN₇O₇S
• Average mass: 868.439209 Da
• Monoisotopic mass: 867.318115 Da
• 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

NORTH CHICAGO, Ill., May 31, 2014/NEWS.GNOM.ES/ — AbbVie (NYSE: ABBV) released interim results from a Phase Ib clinical trial of ABT-199/GDC-0199, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, in combination with rituximab (Abstract 7013). Results showed anoverall response rate (ORR) of 84 percent, in patients with relapsed/refractory chronic lymphocytic leukemia(CLL), the most common leukemia in the UnitedStates. These results were presented at the 50^thAnnual Meeting of the American Society of ClinicalOncology (ASCO), May 30 – June 3 in Chicago.

http://news.gnom.es/pr/abbvie-presents-new-results-from-studies-of-investigational-oncology-compound-abt-199gdc-0199-at-the-2014-american-society-of-clinical-oncology

ABT-199 is a so-called BH3-mimetic drug, which is designed to block the function of the protein Bcl 2. In 1988, it was discovered that Bcl-2 allowed leukaemia cells to become long-lived, a discovery made at the Walter and Eliza Hall Institute by Professors David Vaux, Suzanne Cory and Jerry Adams. Subsequent research led by them and other institute scientists, including Professors Andreas Strasser, David Huang, Peter Colman and Keith Watson, has explained much about how Bcl-2 and related molecules function to determine if a cell lives or dies. These discoveries have contributed to the development of a new class of drugs called BH3-mimetics that kill, and thereby rapidly remove, leukaemic cells by blocking Bcl-2. (source:http://www.wehi.edu.au).

Highlights of recent research using this agent

GDC-0199 (RG7601) is a novel small molecule Bcl-2 selective inhibitor designed to restore apoptosis, also known as programmed cell death, by blocking the function of a pro-survival Bcl-2 family protein. The Bcl-2 family proteins, which are expressed at high levels in many tumors, play a central role in regulating apoptosis and, consequently, are thought to impact tumor formation, tumor growth and resistance.

Venetoclax (previously: GDC-0199, ABT-199, RG7601 )^[1] is a small molecule oral drug being investigated to treat chronic lymphocytic leukemia (CLL).^[2][3]

In 2015, the FDA granted Breakthrough Therapy Designation to venetoclax for CLL in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation.^[3]

Mechanism of action

Venetoclax (a BH3-mimetic^[4]) acts as a Bcl-2 inhibitor, ie. it blocks the anti-apoptotic B-cell lymphoma-2 (BCL2) protein, leading toprogrammed cell death in CLL cells.^[2]

Clinical trials

A phase 1 trial established a dose of 400mg/day.^[2]

A trial of venetoclax in combination with rituximab had an encouraging complete response rate.^[5]

A phase 2 trial met its primary endpoint which was overall response rate.^[3] Interim results from a Phase 2b trial are encouraging, especially in patients with the 17p deletion.^[2]

A phase 3 trial (NCT02005471)^[1] has started.^[3]

NOW IN PHASE 3  UPDATED............

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (hereafter, “Compound 1”) is a potent and selective Bcl-2 inhibitor having, inter alia, antitumor activity as an apoptosis-inducing agent. Compound 1 has the formula:

Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1. The disclosures of U.S. 2010/0305122; 2012/0108590; 2012/0157470 and 2012/0277210 are hereby incorporated by reference in their entireties.

PATENT

US 2015183783

http://www.google.com/patents/US20150183783

PATENT

CN 104370905

http://www.google.com/patents/CN104370905A?cl=en





ABT-199 is developed AbbVie Bel-2 inhibitors, I trial (NCT01328626) enrolled 84 patients with relapsed type / refractory CLL / SLL patients and 44 cases of relapsing / refractory non-Hodgkin lymphoma patients. ABT-199 treatment response CLL / SLL rate of 79% (complete response rate of 22%), median duration of response time was 20.5 months; ABT-199 treatment of non-Hodgkin's lymphoma response rate of 48% (complete response rate was 7.5%). The efficacy of ABT-199 is capable of obinutuzumab, idelalisib, ibrutinib rival, is expected to become the first listed Bcl_2 inhibitors, ABT-199 is currently ongoing Phase III clinical study.
ABT-199 compound CAS number 1257044-40-8, the compound is structured as follows:

Patent W02012058392, W02012071336, W02010138588 et al. Discloses the preparation of ABT-199 in order to -IH- 5-bromo-pyrrolo [2, 3-b] pyridine as raw material to protect hydroxylation, after replacing the compound 5, and reaction of compound 6, hydrolysis to give compound 9, compound 10 and compound 9 obtained by condensation of ABT-199, a specific line as follows:

 use of 2-fluoro-4-nitrobenzoate (A) as a raw material, and substituted 5-hydroxy-7-aza-indole (B), reduction to produce compound ( D), the compound (D) with the compound by cyclization after (H) substitution, hydrolysis to yield compound (J), and then with the compound (K) to afford ABT-199.



Preparation of a compound of Example (F) of the
Example

First step: Synthesis of Compound (C)
  2-fluoro-4-nitrobenzoate in IL three-necked flask 50. 0g, dissolved with dimethylformamide N'N- 250ml, was added successively 5-hydroxy-7-aza-indole indole 33. 6g, potassium carbonate 34. 7g, the reaction was heated to 50 degrees under nitrogen gas protection for 2 hours, poured into 2L of ice water was added and extracted three times with ethyl acetate, the organic phase was dried with saturated sodium chloride spin dry to give Compound (C) crude 82. 0g, crude without purification in the next reaction direct investment.
Step two: Synthesis of Compound (D)
  The compound of the previous step (C) of the crude product was dissolved in methanol 400ml, was added 10% palladium on carbon 4. 0g, through the reaction of hydrogen at atmospheric pressure, after the end of the reaction by TLC spin solvent to give compound (D) The crude product 73. 2g, crude without purification in the next reaction direct investment.
The third step: Synthesis of compound (F)
  Take the previous step the compound (D) crude 20. 0g, t-butanol were added 150ml, compound (E) 10. g, potassium carbonate 9. 7g, completion of the addition the reaction was refluxed for 48 hours the reaction solution was cooled, added acetic acid ethyl ester was diluted, washed with water three times, the combined aqueous phases extracted once with ethyl acetate, the combined ethyl acetate phases twice, dried over anhydrous sodium sulfate and the solvent was spin, the crude product obtained was purified by silica gel column chromatography to give 13. 9g, three-step overall yield of 57.4%.
Preparation Example II Compound (H),

[0029] Take compound (G) (prepared according to W02012058392 method) 5. 0g, dissolved with 50ml of dichloromethane, was added triethylamine 5. 6ml, the reaction solution was cooled to 0-5 ° with stirring, was added dropwise methanesulfonyl chloride 2. 7g, the addition was complete the reaction was warmed to room temperature overnight, after the end of the reaction by TLC the reaction was quenched with water, the organic phase was dried over anhydrous sodium sulfate and the solvent was spin, purified by silica gel column chromatography to give compound (H) 6. 5g , a yield of 99%.
Three ABT-199 Preparation of  Example

First step: Synthesis of Compound (I)
  In IOOml three-necked flask were added the compound (F) 2. 5g, compound ⑶2. 3g, potassium carbonate I. 9g, Ν 'was added and reacted at 50 degrees N- dimethylformamide 15ml, nitrogen atmosphere, TLC detection After the reaction, the reaction solution was poured into ice-water, extracted with ethyl acetate twice added ethyl acetate phase was dried over anhydrous sodium sulfate spin, and purified by silica gel column chromatography to give compound (I) 3. 6g, yield 88 %.
Step two: Synthesis of Compound (J)
  In IOml single jar Compound (I) I. 0g, followed by adding water 5ml, ethanol 5ml, tetrahydrofuran 5ml, sodium hydroxide 136mg, the reaction was stirred at room temperature the reaction, ethyl acetate was added after dilution of the reaction by TLC, adjusted with IN hydrochloric acid PH4-5, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and spin dried to give compound (J) 907mg, 93% yield.
Step two: Synthesis of ABT-199
In a 25ml single neck flask was added the compound (J) 100mg, EDCI67mg, dichloromethane 10ml, the reaction was stirred for 30 minutes, was added the compound (K) (prepared in accordance with W02012058392) 55mg, finally added a catalytic amount of DMAP, the force After opening the reaction was stirred overnight, after the end of the reaction by TLC the solvent was spin, HPLC purified preparation obtained by pure ABT-199 ^ 9811, 65% yield.

PATENT

WO 2014165044

http://www.google.com/patents/WO2014165044A1?cl=en

PATENT

US 2014275540

http://www.google.com/patents/US20140275540

• 
• An exemplary reaction according to Scheme 2 is shown below.
  Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. Pat. No. 3,813,443 and Proceedings of the Chemical Society, London, 1907, 22, 302.
• 

  
  

  Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 and J. Am. Chem. Soc., 1950, 72, 1215-1218.
• 
  
  
• In another embodiment, the compound of formula (1) is prepared from compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in WO 2009/117626 and Organometallics, 2008, 27 (21), 5605-5611.
• 

   

  
  

  • Example 1 Synthesis of tert-butyl 4-bromo-2-fluorobenzoate (Compound (C))
    To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro1-iodobenzene, “Compound (A)” (5 g, 1.0 eq) and THF (25 ml). The solution was cooled to −5° C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 1 h. Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10% citric acid (10 ml), and then diluted with 25% NaCl (10 ml). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3×10 ml). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency=67%, potency adjusted yield=88%) was taken to the next step without further purification. ¹H NMR (DMSO-d₆): δ 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (t, J=8.2 Hz, 1H).
  • Example 2 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (Compound (D))
  • 
    
    To a 3 L three-neck Morton flask were charged 1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20° C. for 15 min. The resulting solution was cooled to about zero to 5° C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10° C., and rinsed with DMF (30 mL). The reaction mixture was stirred at 10° C. for 1 hour (an off-white slurry) and adjusted the internal temperature to ˜45° C. over 30 min. The reaction mixture was stirred at 45-50° C. for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion % by HPLC). The solution was cooled to ˜20° C. The solution was stirred at 20° C. overnight.
  • 
    
    Water (1200 mL) was added slowly to the reaction mixture at <30° C. over 1 hour (slightly exothermic). The product slurry was adjusted to ˜20° C., and mixed for NLT 2 hours. The crude product was collected by filtration, and washed with water (400 mL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50° C. overnight to give the crude product (236.7 g).
  • 
    
    Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted: 200.7 g) was charged back to a 3 L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over 1 hr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78° C.). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to ˜−10° C. at a rate of approximate 10° C./hour), and mixed for 2 hr. The product was collected by filtration, and rinsed with heptane (200 ml).
  • 
    
    The solid was dried under vacuum at ˜50° C. overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191° C. (uncorrected). ¹H NMR (DMSO-d₆): δ 1.40 (s, 9H), 6.41 (dd, J=3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3, 1.8 Hz, 1H), 7.51 (t, J=3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
  • Example 3 Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde (Compound (F))
  • 
    
    To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456 mol) and CH₂Cl₂ (80 mL). The solution was cooled down <−5° C., and POCl₃ (64.7 g, 0.422 mol) added slowly over 20 min @<20° C. (exothermic), rinsed with CH₂Cl₂ (6 mL). The slightly brown solution was adjusted to 20° C. over 30 min, and mixed at 20° C. for 1 hour. The solution was cooled back to <5° C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ˜0.292 mol) was added, and rinsed with in CH₂Cl₂ (10 mL) (slightly exothermic) at <20° C. The solution was heated to refluxing temperature, and mixed overnight (21 hours).
  • 
    
    To a 1000 mL three neck RB flask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12% brine, and 130 mL of CH₂Cl₂. The mixture was stirred and cooled down to <5° C. The above reaction mixture (clear and brown) was transferred, quenched into it slowly while maintaining the internal temperature <10° C. The reaction vessel was rinsed with CH₂Cl₂ (10 mL). The quenched reaction mixture was stirred at <10° C. for 15 min. and allowed to rise to 20° C. The mixture was stirred 20° C. for 15 min and allowed to settle for 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extracted with CH₂Cl₂ (50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K₃PO₄ aq. solution (40 g). The organic was dried over MgSO₄, filtered and rinsed with CH₂Cl₂ (30 ml). The filtrate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency=90.9 wt % by qNMR, ˜100%). ¹H NMR (CDCl₃): δ 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H), 2.31 (tt, J=6.4, 2.2 Hz, 2H), 2.36 (t, J=2.2 Hz, 2H), 10.19 (s, 1H).
  • Example 4 Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde (Compound (G))
  • 
    
    To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). The mixture was stirred at 20° C. for 5 min. 21.0 wt % K₂CO₃ aq. solution (76.0 g) was added. The mixture was stirred at room temperature (rt) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N₂ for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N₂. The reaction mixture was evacuated and purged with N₂ for three times (an orange colored mixture). The bottle was back filled with N₂ and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixture was stirred at 30° C. overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material <2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO₃-2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20° C. for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO₃ aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. ¹HNMR (CDCl₃): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
  • Example 5 Synthesis of tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate (Compound (H))
  • 
    
    To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
  • 
    
    12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20° C. for NLT 30 min and allowed to settle for NLT 15 min. The lower aq. phase (˜560 mL) was separated (note: leave any emulsion in the upper organic phase). The organic phase was washed with 10% citric acid solution (500 g×2). 500 g of 5% NaHCO₃ aq. solution was charged slowly into the flask. The mixture was stirred at 20° C. for NLT 30 min., and allowed to settle for NLT 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20° C. for NLT 15 min., and allowed to settle for NLT 15 min. The upper organic phase was concentrated to ˜200 mL volume under vacuum. The solution was adjusted to −30° C., and filtered off the inorganic salt. Toluene (50 mL) was used as a rinse. The combined filtrate was concentrated to ˜100 mL volume. Acetonitrile (400 mL) was added, and the mixture heated to ˜80° C. to achieve a clear solution. The solution was cooled down slowly to 20° C. slowly at rate 10° C./hour, and mixed at 20° C. overnight (the product is crystallized out at ˜45-50° C., if needed, seed material may be added at 50° C.). The slurry was continued to cool down slowly to ˜−10° C. at rate of 10° C./hours. The slurry was mixed at ˜−10° C. for NLT 6 hours. The product was collected by filtration, and rinsed with pre-cooled acetonitrile (100 mL). The solid was dried under vacuum at 50° C. overnight (72.0 g, 85%). MS-ESI: 419 (M+1); mp: 109-110° C. (uncorrected); ¹H NMR (CDCl₃): δ 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).
  • Example 6 Synthesis of 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine dihydrochloride (Compound (I))
  • 
    
    To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the Boc reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3 g of concentrated hydrochloride aq. solution added to the slurry. The reaction mixture was adjusted to an internal temperature of ˜65° C. (a clear and colorless solution achieved). The reaction mixture was agitated at ˜65° C. for NLT 12 hours.
  • 
    
    The product slurry was cooled down to −5° C. slowly (10° C./hour). The product slurry was mixed at ˜−5° C. for NLT 2 hours, collected by filtration. The wet cake was washed with IPA (72 mL) and dried at 50° C. under vacuum overnight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm). MS-ESI: 319 (M+1); ¹HNMR (CDCl₃): δ 0.86 (s, 6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).
  • Example 7 Synthesis of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-benzenesulfonamide (Compound (N))
  • 
    
    To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80° C. and agitated for no less than 12 hours.
  • 
    
    The product solution was cooled down to 40° C. and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20° C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10° C. and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40° C. for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75° C. under vacuum to give 12.7 g of the desired product in 99.9% purity and in 91% weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH₂, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).
  • Example 8 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (Compound (K))
  • 
    
    General Considerations:
  • 
    
    this chemistry is considered air and moisture sensitive. While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.
  • 
    
    To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K₃PO₄ (285 ml) was added and the biphasic mixture was stirred for 30 min. The layers were separated and the organic layer was washed with 25% NaCl (145 ml). The organic layer concentrated to 120 g and used in the coupling reaction without further purification.
  • 
    
    NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution −30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd₂dba₃ (0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 μm inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml).
  • 
    
    The resulting mixture was heated to 55° C. with stirring for NLT 16 h, then cooled to 22° C. The mixture was diluted with 12% NaCl (300 g) followed by THF (300 ml). The layers were separated.
  • 
    
    The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO₃ (23 g), and water (262 ml). After 1 h the layers were separated.
  • 
    
    The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO₃ (23 g), and water (262 ml). After 1 h the layers were separated. The organic layer was washed with 12% NaCl (300 g), then filtered through a 0.45 μm inline filter. The filtered solution was concentrated in vacuo to ˜300 mL, and chased three times with heptane (600 mL each) to remove THF.
  • 
    
    The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 ml). The mixture was heated to 75° C., held for 15 min, and then cooled to 65° C. over NLT 15 min. Seed material was charged and the mixture was held at 65° C. for 4 hours. The suspension was cooled to 25° C. over NLT 8 h, then held at 25° C. for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50° C. under vacuum.
  • 
    
    Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155° C. ¹H NMR (DMSO-d₆): δ 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J=6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02-3.19 (m, 4H), 6.33 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.72 (dd, J=9.0, 2.4 Hz, 1H), 6.99-7.06 (m, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, J=6.7 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 11.53 (s, 1H).
  • Example 9 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Compound (L))
  • 
    
    Solution preparation: 10% KH₂PO₄ (aq): KH₂PO₄ (6 g) in water (56 g); 2:1 heptane/2-MeTHF:heptane (16 mL) in 2-MeTHF (8 mL).
  • 
    
    Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55° C. until reaction completion. The reaction mixture was cooled to 22° C., washed with the 10% KH₂PO₄ solution (31 g) twice. The organic layer was then washed with water (30 g).
  • 
    
    After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (˜19 mL) and heated to no less than 50° C. Heptane (23 ml) was slowly added. The resulting suspension was cooled to 10° C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane/2-MeTHF (24 ml). Drying of the solids at 80° C. under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 0.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J=3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
  • Example 10 Synthesis of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (Compound (I))
  • Solution preparation prior to reaction: 10% Acetic Acid:Acetic Acid (37 mL) in water (333 g); 5% NaHCO₃:NaHCO₃ (9 g) in water (176 g); 5% NaCl:NaCl (9 g) in water (176 g).
  • Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25° C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et₃N (8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion.
    
    COMPD L
    
    
    

    • COMPD N

    N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35° C. and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL). The organic, product layer was then washed with 5% NaHCO₃ solution (185 mL) and then washed with 5% NaCl solution (185 mL) at 35° C. The lower, organic layer was separated and then concentrated to 8 vol (˜256 mL) diluted with methanol (26 mL) and warmed to 38° C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10° C. and then filtered. The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (˜2 vol, 64 mL). After drying the wet cake at 90° C., 32 g (84%) of Compound (I) was isolated.
  • 
    
  • ¹H NMR (DMSO-d₆): δ 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J=3.4, 1.9 Hz, 1H), 6.66 (dd, J=9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J=9.3, 2.3 Hz, 1H), 8.02 (d, J=2.61 Hz, 1H), 8.54 (d, J=2.33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).

FINAL COMPD 1

PATENT

Patent	Submitted	Granted
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2014275082]	2014-02-10	2014-09-18
Processes For The Preparation Of An Apoptosis-Inducing Agent [US2014275540]	2014-03-12	2014-09-18
APOPTOSIS INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2010305122]	2010-12-02
Panel of micrornas that silence the MCL-1 gene and sensitize cancer cells to ABT-263 [US8742083]	2010-12-23	2014-06-03
Treatment Of Cancers Using PI3 Kinase Isoform Modulators [US2014377258]	2014-05-30	2014-12-25
METHODS OF TREATMENT USING SELECTIVE BCL-2 INHIBITORS [US2012129853]	2011-11-22	2012-05-24
INHIBITION OF MCL-1 AND/OR BFL-1/A1 [US2015051249]	2013-03-14	2015-02-19
COMBINATION THERAPY OF A TYPE II ANTI-CD20 ANTIBODY WITH A SELECTIVE BCL-2 INHIBITOR [US2014248262]	2013-09-06	2014-09-04

References

1. New Drugs Online Report for venetoclax
2.  Hard-to-Treat CLL Yields to Investigational Drug. ASH Dec 2015 refs: Roberts AW, et al "Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia" N Engl J Med 2015; DOI: 10.1056/NEJMoa1513257.
3.  Phase 2 Study of Venetoclax in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion Meets Primary Endpoint
4.  ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia. 2011
5.  For Refractory CLL, Venetoclax's Complete Response Rate Is Tops. 2015

External links

• ABT-199 inc formula and structure

References

 1: Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2
inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Jan 6. doi: 10.1038/nm.3048. [Epub ahead of print] PubMed PMID: 23291630.

Venetoclax

Systematic (IUPAC) name
4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Identifiers
CAS Number	1257044-40-8
PubChem	CID: 49846579
ChemSpider	29315017
Chemical data
Formula	C45H50ClN7O7S
Molecular mass	868.44 g/mol

/////////

CC1(CCC(=C(C1)c2ccc(cc2)Cl)CN3CCN(CC3)c4ccc(c(c4)Oc5cc6cc[nH]c6nc5)C(=O)NS(=O)(=O)c7ccc(c(c7)[N+](=O)[O-])NCC8CCOCC8)C

OR

CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C

AbbVie: Evaluating Selective JAK1 Inhibitor, for RA Treatment ABT 494

ABT 494

(-)-(3S,4R)  cis form

CAS 1310726-60-3 FREE FORM

MF	C17H19F3N6O
MW	380.36757 g/mol

Tartrate form 

C17 H19 F3 N6 O . C4 H6 O6 . 4 H2 O ………….CAS 1607431-21-9

1-​Pyrrolidinecarboxami​de, 3-​ethyl-​4-​(3H-​imidazo[1,​2-​a]​pyrrolo[2,​3-​e]​pyrazin-​8-​yl)​-​N-​(2,​2,​2-​trifluoroethyl)​-​, (3S,​4R)​-​, (2R,​3R)​-​2,​3-​dihydroxybutanedioat​e, hydrate (1:1:4)

FREE FORM

(3s,,4R)-3-ethyl-4-(3H-imidazo[l,2-fl]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- l-carboxamide.

(35,,4R)-3-ethyl-4-(3H- imidazo[l,2-fl]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- l-carboxamide,

(cis,)-3-ethyl-4-(3H-imidazo[l,2-fl]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide

1-​Pyrrolidinecarboxami​de, 3-​ethyl-​4-​(3H-​imidazo[1,​2-​a]​pyrrolo[2,​3-​e]​pyrazin-​8-​yl)​-​N-​(2,​2,​2-​trifluoroethyl)​-​, (3S,​4R)​-

rel-(-)-(3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

A Jak1 inhibitor potentially for the treatment of rheumatoid arthritis.

pharmaceutically acceptable salts thereof, stereoisomers thereof, and isomers thereof, is provided in U.S. Patent No. 8,426,411,

Abbott Laboratories ABBOTT ……INNOVATOR

AbbVie, a global biopharmaceutical company, today announced the start of a large Phase 3 clinical trial program to study the use of ABT-494, an investigational, once-daily, oral selective JAK1 inhibitor for the treatment of rheumatoid arthritis (RA). This program will include adult patients with inadequate responses (IR) to conventional or biologic disease-modifying antirheumatic drugs (DMARDs), as well as methotrexate-naive patients.

 

PATENT

WO2015061665

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=A5D5EBF2F64E79CDD5F7D34634E8A82A.wapp1nB?docId=WO2015061665&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The synthesis of the compounds of the invention, including (35,,4R)-3-ethyl-4-(3H-imidazo[l,2-fl]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- l-carboxamide, pharmaceutically acceptable salts thereof, stereoisomers thereof, and isomers thereof, is provided in U.S. Patent No. 8,426,411, the entire content of which is incorporated herein by reference.

For example, (3lS,,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide can be synthesized according to the following scheme:

N-Alkylation using alkyl halide, a-haloketone or oc-haloamide

A round bottom flask is charged with a base such as NaH (60% dispersion in mineral oil), K2CO3, or CS2CO3 (preferably NaH (60% dispersion in mineral oil), 0.9-1.5 equiv., preferably 0.95 equiv.) and an organic solvent (such as N, N-dimethylformamide (DMF), dichloromethane (DCM), 1,4-dioxane, or N-methyl-2-pyrrolidone (NMP), preferably DMF). The mixture is cooled to about -10 °C to ambient temperature (preferably about 0°C) and a solution of an appropriately substituted amine (preferably 1 equiv.) in an organic solvent (such as DMF) is added. Alternatively, the base may be added portionwise to a solution of the amine and an organic solvent at about 0°C to ambient temperature. The reaction mixture is stirred for about 5-90 min (preferably about 15-30 min) at about -10°C to ambient temperature (preferably about 0°C) followed by the addition of an alkyl halide, a-haloketone, or cc-haloamide (1-2 equiv., preferably 1.2 equiv.). Alternatively, a solution of an amine and a base in an organic solvent may be added to a solution of an alkyl halide, α-haloketone, or a-haloamide in an organic solvent at about 0°C. The reaction mixture is stirred at about -10°C to ambient temperature (preferably ambient temperature) for about 0.5-24 h (preferably about 1 h). Optionally, the organic solvent may be removed under reduced pressure.

Optionally, the reaction mixture or residue may be diluted with water, aqueous NH4CI, or aqueous NaHC03. If a precipitate forms the solid may be optionally collected via vacuum filtration to give the target compound. Alternatively, an organic solvent (such as ethyl acetate (EtOAc) or DCM) is added to the aqueous mixture and the layers are separated. The aqueous layer may optionally be extracted further with an organic solvent (such as EtOAc and/or DCM). The combined organic layers are optionally washed with additional aqueous solutions such as brine, dried over anhydrous Na2S04 or MgS04, filtered, and concentrated to dryness under reduced pressure.

The procedure above is illustrated below in the preparation of ie/t-butyl 2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate from ie/t-butyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate.

To a solution of iert-butyl 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylcarbamate (1.00 g, 2.57 mmol, Example #3 Step E) and DMF (13 mL) under nitrogen at about 0 °C was added NaH (60% dispersion in mineral oil, 0.113 g, 2.83 mmol) in one portion. After about 30 min, 2-bromoacetamide (0.391 g, 2.83 mmol) was added in one portion. After about 30 min, the ice bath was removed and the solution was stirred at ambient temperature for about 2 h. Saturated aqueous NH4Cl/water (1: 1, 100 mL) was added. After stirring for about 10 min, the mixture was filtered using water to wash the filter cake. The aqueous phase was extracted with EtOAc (50 mL). The filter cake was dissolved in EtOAc and added to the organic layer. The organic layer was dried over Na2S04, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to give tert-butyl 2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yljcarbamate (0.980 g, 82%): LC/MS (Table 1, Method n) Rt = 0.70 min; MS m/z 446 (M+H)+.

Similar reaction condition can also be used to synthesize benzyl 3-ethyl-4-(2-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)pyrrolidine-l-carboxylate from iert-butyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate and benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine- 1 -carboxylate.

Cyclization of a ketone using a dithiaphosphetane reagent (e.g., synthesizing (3S,4R)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-l-carboxylate from benzyl 3-ethyl-4-(2-((5-tosyl-5H-pyrrolo[2,3-Z>]pyrazin-2-yl)amino)acetyl)pyrrolidine-l-carboxylate)

To a solution of a ketone (preferably 1 equiv.) in an organic solvent such as tetrahydrofuran (THF) or 1,4-dioxane (preferably 1,4-dioxane) is added a thiolating reagent such as Lawesson’s reagent or Belleau’s reagent (2,4-bis(4-phenoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) (0.5-2.0 equiv., preferably Lawesson’s reagent, 0.5-0.6 equiv.). The reaction is heated at about 30°C to 120°C (preferably about 60-70°C) for about 0.5-10 h (preferably about 1-2 h). Optionally, additional thiolating reagent (0.5-2.0 equiv., preferably 0.5-0.6 equiv.) can be added to the reaction mixture and heating can be continued for about 0.5-10 h (preferably about 1-2 h). The reaction mixture is concentrated under reduced pressure.

Preparation of 8-((ds)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine from (3S,4R)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-l-carboxylate

To a solution of (cis)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-l-carboxylate (0.838 g, 1.541 mmol) is added a solution of HBr (2.50 mL, 15.19 mmol, 33% in acetic acid). The reaction mixture is stirred at ambient temperature for about 1 h. The reaction is diluted with diethyl ether or Et20 (50 mL) and water (20 mL). The layers are stirred for about 3 min and the organic layer is decanted then the procedure is repeated 5 times. The aqueous layer is cooled to about 0°C and is basified with saturated aqueous NaHC03solution (10 mL) to about pH 7. The aqueous layer is extracted with EtOAc (3 x 50 mL), combined, and dried over anhydrous Na2S04, filtered and concentrated to give a brown solid. The solid is dissolved in DCM (50 mL) and washed with water (3 x 20 mL), dried over anhydrous Na2S04, filtered and concentrated to afford 8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine (0.453, 61%) as a brown residue: LC/MS (Table 1, Method a) Rt = 1.73 min; MS m/r. 410 (M+H)+.

Hydrolysis of a sulfonamide (e.g., 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine to 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine)

To a flask containing a sulfonamide, for example, a sulfonyl-protected pyrrole, (preferably 1 equiv.) in an organic solvent (such as 1,4-dioxane, methanol (MeOH), or THF/MeOH, preferably 1,4-dioxane) is added an aqueous base (such as aqueous Na2C03 or aqueous NaOH, 1-30 equiv., preferably 2-3 equiv. for aqueous NaOH, preferably 15-20 equiv. for aqueous Na2C03). The mixture is stirred at about 25-100 °C (preferably about 60 °C) for about 1-72 h (preferably about 1-16 h). In cases where the reaction does not proceed to completion as monitored by TLC, LC/MS, or HPLC, additional aqueous base (such as aqueous Na2C03, 10-20 equiv., preferably 10 equiv. or aqueous NaOH, 1-5 equiv., preferably 1-2 equiv.) and/or a cosolvent (such as ethanol (EtOH)) is added. The reaction is continued at about 25-100°C (preferably about 60°C) for about 0.25-3 h (preferably about 1-2 h). In any case where an additional base labile group is present (for example, an ester a

trifluoromethyl, or a cyano group), this group may also be hydrolyzed. The reaction is worked up using one of the following methods. Method 1. The organic solvent is optionally removed under reduced pressure and the aqueous solution is neutralized with the addition of a suitable aqueous acid (such as aqueous HC1). A suitable organic solvent (such as EtOAc or DCM) and water are added, the layers are separated, and the organic solution is dried over anhydrous Na2S04 or MgS04, filtered, and concentrated to dryness under reduced pressure to give the target compound. Method 2. The organic solvent is optionally removed under reduced pressure, a suitable organic solvent (such as EtOAc or DCM) and water are added, the layers are separated, and the organic solution is dried over anhydrous Na2S04 or MgS04, filtered, and concentrated to dryness under reduced pressure to give the target compound. Method 3. The reaction mixture is concentrated under reduced pressure and directly purified by one of the subsequent methods.

Formation of a urea using CDI or thiocarbonyldiimidazole, respectively (e.g., from 8-((3R,45)-4-ethylpyrrolidin-3-yl)-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine to (35,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide)

To a solution or slurry of an amine or amine salt (1-3 equiv., preferably 1-2 equiv.) in an organic solvent such as DCM, THF, or DMF (preferably DMF) at about 20 – 80 °C (preferably about 65 °C) is optionally added an organic base, such as triethylamine (TEA), N,N-diisopropylethylamine (DIEA), pyridine (preferably TEA) (1-10 equiv., preferably 1-5 equiv.) followed by CDI or 1,1 ‘-thiocarbonyldiimidazole (0.5-2 equiv., preferably 1 equiv.). After about 0.5-24 h (preferably about 1-3 h), a second amine or amine salt (1-10 equiv., preferably 1-3 equiv.) is added neat or as a solution or slurry in an organic solvent such as DCM, THF, or DMF (preferably DMF). The reaction is held at about 20 – 80 °C (preferably about 65 °C ) for about 2 – 24 h (preferably about 3 h). If the reaction mixture is heated, it is cooled to ambient temperature. The reaction mixture is partitioned between an organic solvent (such as EtOAc, DCM or 1,4-dioxane) and an aqueous base (such as saturated aqueous NaHC03 or saturated aqueous Na2C03, preferably saturated aqueous NaHC03). Optionally, the reaction mixture is concentrated under reduced pressure and the residue is partitioned as above. In either case, the aqueous layer is then optionally extracted with additional organic solvent such as EtOAc or DCM. The combined organic layers may optionally be washed with brine and concentrated in vacuo or dried over anhydrous Na2S04 or MgS04 and then decanted or filtered prior to concentrating under reduced pressure to give the target compound. Optionally, the reaction mixture is concentrated under reduced pressure and the residue is directly purified.

Chiral preparative HPLC purification

Chiral purification is performed using Varian 218 LC pumps, a Varian CVM 500 with

switching valves and heaters for automatic solvent, column and temperature control and a Varian 701 Fraction collector. Detection methods include a Varian 210 variable wavelength detector, an in-line polarimeter (PDR-chiral advanced laser polarimeter, model ALP2002) used to measure qualitative optical rotation (+/-) and an evaporative light scattering detector (ELSD) (a PS-ELS 2100 (Polymer Laboratories)) using a 100: 1 split flow. ELSD settings are as follows: evaporator: 46 °C, nebulizer: 24 °C and gas flow: 1.1 SLM. The absolute stereochemistry of the purified compounds was assigned arbitrarily and is drawn as such. Compounds of the invention where the absolute stereochemistry has been determined by the use of a commercially available enantiomerically pure starting material, or a stereochemically defined intermediate, or X-ray diffraction are denoted by an asterisk after the example number.

(ci5,)-3-ethyl-4-(3H-imidazo[l,2-fl]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide isolated using the above method has an Rt min of 1.52, and m/z ESI+ (M+H)+ of 381.

The starting materials and intermediates of the above synthesis scheme may be obtained using the following schemes:

Preparation of starting material of l-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid

Step A: ethyl pent-2-ynoate to (Z)-ethyl pent-2-enoate

To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF (100 mL) and pyridine (10.00 mL) is added ethyl pent-2-ynoate (5.22 mL, 39.6 mmol). The reaction mixture is sparged with hydrogen for about 10 min and an atmosphere of hydrogen is maintained via balloon. After about 15 h the reaction mixture is filtered through a pad of Celite®, diluted with Et20 (30 mL) and washed with saturated aqueous CuS04 (40 mL), followed by water (40 mL). The organic layer is separated, dried over anhydrous MgS04, filtered, and concentrated in vacuo to provide crude (Z)-ethyl pent-2-enoate (5 g, 98%). 1H NMR (DMSO-d6) δ 1.05 (t, 3H), 1.28 (t, 3H), 2.65 (m, 2H), 4.18 (q, 2 H), 5.72 (m, 1H), 6.21 (m, 1H).

Step B: (ds)-ethyl l-benzyl-4-ethylpyrrolidine-3-carboxylate (from (Z)-ethyl pent-2-enoate and N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine)

To a solution of N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0 mmol) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol) in DCM (50 mL) is added trifluoroacetic acid (TFA) (0.030 mL, 0.390 mmol) at RT. After about 2 days, the reaction mixture is concentrated in vacuo to provide crude (cis)-ethyl 1 -benzyl-4-ethylpyrrolidine-3- carboxylate (9.8 g, 96%) as an oil. LC/MS (Table 1, Method a) Rt = 1.62 min; MS m/z: 262 (M+H)+.

Step C: ethyl l-benzyl-4-ethylpyrrolidine-3-carboxylate to (ds)-ethyl 4-ethylpyrrolidine-3-carboxylate

A Parr shaker is charged with PdOH2 on carbon (2.243 g, 3.19 mmol) and (cis)-et yl l-benzyl-4-ethylpyrrolidine-3-carboxylate (16.7 g, 63.9 mmol) followed by EtOH (100 mL). The reaction mixture is degassed and purged with hydrogen gas and shaken on the parr shaker at 60 psi for about 4 days at ambient temperature. The reaction mixture is degassed and purged with nitrogen. The suspension is filtered through a pad of Celite® washing with EtOH (~ 900 mL). The solvent is removed under reduced pressure to afford (cis)-ethyl 4-ethylpyrrolidine-3 -carboxylate (8.69 g, 79%) as an oil: LC/MS (Table 1, Method a) Rt = 1.11 min; MS m/z: 172 (M+H)+.

Step D: (ds)-ethyl 4-ethylpyrrolidine-3-carboxylate to (ds)-l-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid

To a flask charged with (cis)-et yl 4-ethylpyrrolidine-3-carboxylate (8.69g, 50.7 mmol) is added aqueous HCl (6N, 130 mL, 782 mmol). The solution is heated at about 75°C for about 12 h. aqueous HCl (6N, 100 mL, 599 mmol) is added and stirred at about 80 °C for about 20 h. Aqueous HCl (6N, 100 mL, 599 mmol) is added and continued stirring at about 80 °C for about 20 h. The reaction mixture is cooled to ambient temperature and the solvent is removed under reduced pressure. 1,4-Dioxane (275 mL) and water (50 mL) are added followed by portionwise addition of Na2C03 (13.5 g, 127 mmol). Di-ie/t-butyl dicarbonate (13.3 g, 60.9 mmol) is added and the reaction mixture is stirred at ambient temperature for about 16 h. The solid is filtered and washed with EtOAc (250 mL). The aqueous layer is acidified with aqueous HCl (IN) to about pH 3-4. The layers are partitioned and the aqueous layer is extracted with EtOAc (3 x 100 mL). The combined organic layers are dried over anhydrous Na2S04, filtered and removed under reduced pressure. As the organic layer is almost fully concentrated (~ 10 mL remaining), a solid precipitated. Heptane (30 mL) is added and the solid is filtered washing with heptane to afford (cis)-l-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid (3.9 g, 32%) as an off white solid as product: LC/MS (Table 1, Method c) Rt = 0.57 min; MS m/z: 242 (M-H)~.

Synthesis of Intermediate benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-l-carboxylate

Acidic cleavage of a Boc-protected amine (e.g., l-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid to 4-ethylpyrrolidine-3-carboxylic acid

hydrochloride)

To a solution of a Boc-protected amine (preferably 1 equiv.) in an organic solvent (such as DCM, 1,4-dioxane, or MeOH) is added TFA or HC1 (preferably 4 N HC1 in 1,4-dioxane, 2-35 equiv., preferably 2-15 equiv.). The reaction is stirred at about 20-100 °C (preferably ambient temperature to about 60 °C) for about 1-24 h (preferably about 1-6 h). In any case where an additional acid labile group is present (for example, a t-butyl ester), this group may also be cleaved during the reaction. Optionally, additional TFA or HC1

(preferably 4 N HC1 in 1,4-dioxane solution, 2-35 equiv., preferably 2-15 equiv.) may be added to the reaction mixture in cases where the reaction does not proceed to completion as monitored by TLC, LC/MS, or HPLC. Once the reaction has proceeded to an acceptable level, the reaction mixture can be concentrated in vacuo to provide the amine as a salt.

Alternatively, the reaction may be partitioned between an organic solvent (such as EtOAc, DCM or 1,4-dioxane) and an aqueous base (such as saturated aqueous NaHC03 or saturated aqueous Na2C03, preferably saturated aqueous NaHC03). The aqueous layer can be optionally extracted with additional organic solvent such as EtOAc or DCM. The combined organic layers may optionally be washed with brine, dried over anhydrous Na2S04 or MgS04, then decanted or filtered, prior to concentrating under reduced pressure to give the target compound.

Cbz-protection of an amine (e.g., 4-ethylpyrrolidine-3-carboxylic acid hydrochloride to l-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid)

A solution of an amine or an amine salt (preferably 1 equiv.) and a base (for example, Na2C03 or NaOH, 1-3 equiv., preferably Na2C03, 1.6 equiv.) in water or aqueous organic solvent (for example, water / 1,4-dioxane or water / acetonitrile (MeCN), preferably water/ 1,4-dioxane) is stirred at ambient temperature for about 1-10 min (preferably 5 min). A solution of benzyl 2,5-dioxopyrrolidin-l-yl carbonate (1-2 equiv., preferably 1.0 equiv.) in an organic solvent such as 1,4-dioxane or MeCN is added to the reaction. The reaction is stirred at ambient temperature for about 8-144 h (preferably about 72 h). Optionally, the reaction mixture is concentrated under reduced pressure. The resulting aqueous solution is diluted with an organic solvent (such as EtOAc or DCM). The organic extracts are optionally washed with water and/or brine, dried over anhydrous Na2S04 or MgS04, filtered or decanted, and concentrated under reduced pressure. Alternatively, the resulting aqueous solution is acidified by adding an acid such as aqueous NH4C1 or HC1 and is then extracted with an organic solvent (such as EtOAc or DCM).

Formation of a bromomethyl ketone from an acid (e.g., l-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid to benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-l-carboxylate)

To a solution of a carboxylic acid (preferably 1 equiv.) in an organic solvent (DCM or 1,2-dichloroethane (DCE), preferably DCM) is slowly added oxalyl chloride (1.2-3.0 equiv., preferably 2.2 equiv.) followed by dropwise addition of DMF (0.01-0.20 equiv., preferably about 0.15 equiv.). The reaction is stirred at about 0-40 °C (preferably ambient temperature) for about 3-24 h (preferably about 14 h) before it is concentrated under reduced pressure to a constant weight to give the crude acid chloride. A solution of a crude acid chloride

(preferably 1 equiv.) in an organic solvent (such as THF, MeCN, Et20, or THF/MeCN, preferably THF/MeCN) is added to trimethylsilyldiazomethane (2.0 M in Et20) or diazomethane solution in Et20 (prepared from DIAZALD® according to Aldrich protocol or J. Chromatogr. Sci. 1991, 29:8) (2-10 equiv., preferably 3.5 equiv. of

trimethylsilyldiazomethane) at about -20-20 °C (preferably about 0 °C) in a suitable organic solvent such as THF, MeCN, Et20, or THF/MeCN (preferably THF/MeCN). The reaction mixture is stirred for about 0.5-5 h (preferably about 3 h) at about -20-20 °C (preferably about 0 °C) before the dropwise addition of 48% aqueous HBr (5-40 equiv., preferably about 10 equiv.). After about 0-30 min, (preferably about 5 min) the reaction mixture can be concentrated to dryness to give the desired product, neutralized by a dropwise addition of saturated aqueous NaHC03 or is optionally washed with brine after optional addition of an organic solvent (such as EtOAc or DCM, preferably EtOAc). In cases where the reaction mixture is subjected to an aqueous work-up, the organic layer is dried over anhydrous Na2S04 or MgS04 (preferably MgS04), filtered, and concentrated under reduced pressure.

Synthesis of Intermediate tert-butyl (5-tosyl-5H-pyrrolo[2,3-Z>]pyrazin-2-yl)carbamate

Step A: 3,5-dibromopyrazin-2-amine to 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF (1255 mL) is added

PdCl2(PPh3)2 (3.47 g, 4.94 mmol). The reaction mixture is cooled at about -5-0°C and a solution of (trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) is added dropwise over about 15 min. The reaction mixture is stirred at about -5-0°C for about 1.5 h and then allowed to warm to room temperature (RT) overnight. The reaction mixture is then filtered through a CELITE® pad and washed with THF until no further product eluted. The filtrate is concentrated under reduced pressure to give a brown-orange solid. The solid is triturated and sonicated with warm petroleum ether (b.p. 30-60°C, 400 mL), cooled to RT, collected, washed with petroleum ether (b.p. 30-60°C; 2 x 60 mL), and dried to give 5-bmmo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b) Rt = 2.51 min; MS m/z: 270, 272 (M+H)+.

Step B: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine to 2-bromo-5-tosyl-5H-pyrrolo[2,3-Z>]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00g, 11.1 mmol) in DMF (60 mL) at about 0 °C is added NaH (60% dispersion in mineral oil, 0.577g, 14.4 mmol) in three portions. After about 15 min, p-toluenesulfonyl chloride (2.75g, 14.4 mmol) is added and the reaction is allowed to warm slowly to ambient temperature. After about 16 h, the reaction mixture is poured onto ice-cold water (120 mL) and the precipitate is collected by vacuum filtration. The crude solid is dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-bjpyrazine (2.16 g, 52%): LC/MS (Table 1, Method c) Rt = 1.58 min; MS m/z: 352, 354 (M+H)+.

Step C: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine to methyl 5-tosyl-5H-pyrrolo[2,3-Z>]pyrazine-2-carboxylate

CO is bubbled into an orange solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50. Og, 142 mmol) in DMF (2.50 L) within a 5 L round bottom flask for about 2 min.

Bis(triphenylphosphine)-palladium(II) dichloride (9.96g, 14.2 mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) are added and the flask is fitted with a balloon of CO. The mixture is heated at about 95°C under an atmosphere of CO (1 atmosphere). After stirring overnight, the reaction mixture is cooled to ambient temperature overnight and poured into ice water (3.2 L). The mixture is stirred for about 10 min and the precipitate is collected by filtration, while washing with water, and dried for 1 h. The crude material is dissolved in DCM, separated from residual water, dried over anhydrous MgS04, filtered, added silica gel, and concentrated under reduced pressure to prepare for chromatography. The crude material is purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol% DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a) Rt = 2.35 min;

MS m/z 332 (M+H)+.

Step D: methyl 5-tosyl-5H-pyrrolo[2,3-Z>]pyrazine-2-carboxylate to 5-tosyl-5H-pyrrolo[2,3-/>]pyrazine-2-carboxylic acid

HC1 (6 N aqueous, 714 mL) is added to a yellow solution of methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8g, 53.6 mmol) in 1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixture is heated at about 60°C for about 16 h. The reaction mixture is cooled to ambient temperature. The organic solvent is removed under reduced pressure and the precipitate is collected, washed with water, and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) Rt = 1.63 min; MS m/z 316 (Μ-Η)“.

Step E: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid to tert-butyl 5-tosyl-5H-pyrrolo[2,3-Z>]pyrazin-2-ylcarbamate

In a 500 mL round bottom flask, 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3 mmol), diphenylphosphoryl azide (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100 mmol) in ie/t-butanol (i-BuOH) (200 mL) are added to give an orange suspension. The mixture is heated at about 70°C for about 16 h, cooled to ambient temperature and the insoluble material is removed by filtration. The solvent is removed under reduced pressure and the crude material is purified by silica gel column chromatography eluting with 25-60% EtOAc in heptane to yield tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as an off-white solid: LC/MS (Table 1, Method a) Rt = 2.79 min; MS m/z 389 (M+H)+.

PATENT

WO2011068881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011068881&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel Tricyclic Compounds [US2011311474]

2011-12-22

PATENT

http://www.google.com/patents/US20110311474

Preparation #F.1.1: 8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

• 
• To a solution of (cis)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (0.838 g, 1.541 mmol, prepared using E from Example #36 Step D with TFA, N, R, S.1 with Example #3 Step E, and T with Lawesson’s reagent) was added a solution of HBr (2.50 mL, 15.19 mmol, 33% in acetic acid). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction was diluted with Et2O (50 mL) and water (20 mL). The layers were stirred for about 3 min and the organic layer was decanted then the procedure was repeated 5 times. The aqueous layer was cooled to about 0° C. was basified with saturated aqueous NaHCO3solution (10 mL) to about pH 7. The aqueous layer was extracted with EtOAc (3×50 mL), combined, and dried over anhydrous Na2SO4, filtered and concd to give a brown solid. The solid was dissolved in DCM (50 mL) and washed with water (3×20 mL), dried over anhydrous Na2SO4, filtered and coned to afford 8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.453, 61%) as a brown residue: LC/MS (Table 1, Method a) Rt=1.73 min; MS m/z: 410 (M+H)+.

SEE…………..1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.609 mmol, Example #36, step F)

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c21cnc4c(n1c(cn2)[C@@H]3[C@@H](CN(C3)C(=O)NCC(F)(F)F)CC)ccn4

OR

CC[C@@H]1CN(C[C@@H]1c4cnc3cnc2nccc2n34)C(=O)NCC(F)(F)F

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