Tricyclic janus kinase 1 inhibitors, and compositions and methods thereof
A compound and cycloalkyl technology, applied in the field of safe and effective inhibitors and new therapeutic agents, can solve problems such as less side effects
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[0318] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacy. In general, these methods of preparation involve bringing into association a compound described herein ("active ingredient") with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, bringing into association the product The step of shaping and / or packaging in the desired single-dose or multi-dose unit.
[0319] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient will generally be equal to the dose of the active agent to be administered to the subject and / or a convenient fraction of such a dose, eg, one-half or one-third of such a dose.
[0320] Solid dosage f...
Embodiment 1
[0365]
[0366] Step 1. 4-Chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1b)
[0367] Compound 1a (30 g, 0.2 mol) and TsCl (45 g, 0.24 mol) were dissolved in a mixture of acetone and water (600 mL, V:V=5:1), then NaOH (11.8 g, 0.29 mmol) was added at 0 °C ). After stirring for 1 h at RT, the mixture was concentrated to 100 mL of solvent and cooled with ice water. The resulting solid was filtered and dried to give the title product as a white solid (52 g, 86% yield). 1 H NMR (400MHz, CDCl 3 )δ8.30(d,J=5.6Hz,1H),8.05(d,J=8.4Hz,2H),7.76(d,J=4.0Hz,1H),7.27(d,J=8.4Hz,2H) , 7.18 (d, J=5.2Hz, 1H), 6.69 (d, J=4.0Hz, 1H), 2.37 (s, 3H).
[0368] Step 2. 4-Chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1c)
[0369] To a mixture of compound lb (5.0 g, 16.3 mmol) and 75 mL of DCM was added tetrabutylammonium nitrate (2.9 g, 21.3 mmol) in portions at 0 °C followed by trifluoroacetic anhydride (3.14 mL, 22.2 mmol) slowly. After stirring at RT for 16 hrs, another po...
Embodiment 2
[0387]
[0388] Step 1. tert-Butyl (cis-3-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclobutyl)carbamate ( 2a)
[0389] Using a similar preparation procedure to the third step of Example 1, using compound 1c (300 mg, 0.85 mmol) and tert-butyl (cis-3-aminocyclobutyl)carbamate (191 mg, 1.02 mmol) as starting materials, Compound 2a (380 mg) was synthesized in 89% yield. 1 HNMR (400MHz, CDCl 3 )δ9.09(s,1H),9.04(d,J=6.8Hz,1H),8.06(d,J=8.4Hz,2H),7.60(d,J=4.4Hz,1H),7.30(d, J=8.4Hz, 2H), 6.75(d, J=4.4Hz, 1H), 4.73(br s, 1H), 4.07(br s, 1H), 3.04-2.92(m, 2H), 2.41(s, 3H) ), 2.03-1.94 (m, 2H), 1.40 (s, 9H).
[0390] Step 2. tert-Butyl (cis-3-((5-amino-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclobutyl)carbamate (2b )
[0391] Using compound 2a (380 mg, 0.76 mmol) as starting material, compound 2b (300 mg) was synthesized in 84% yield using a similar preparation procedure to the fourth step of Example 1 . LC-MS (Method 1): t R =1.63min, m / z(...
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