(2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepan-2-carboxamide as a dipeptidyl peptidase 1 inhibitor

Abstract

To provide compounds that inhibit dipeptidyl peptidase 1 (DPP1) activity.SOLUTION: The present disclosure provides certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof) that inhibit DPP1 activity, their utility in treating and / or preventing clinical conditions including respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), their use in therapy, pharmaceutical compositions containing them, and processes for preparing such compounds.SELECTED DRAWING: None

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R 1 teeth, 【Chemistry 2】 And; R 2 These are hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 It is alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring or a piperidine ring); or R 1 teeth, 【Transformation 3】 And; X is O, S, or CF 2 And; Y is either O or S; Q is CH; R 6 C 1-3 It is alkyl (where C 1-3 The alkyl group may be substituted with 1, 2, or 3 F atoms, and also OH,OC 1-3 Alkyl, N(C) 1-3 Alkyl) 2 (may be substituted with one substituent selected from cyclopropyl and tetrahydropyran); R 7 is hydrogen, F, Cl, or CH 3 [is] A pharmaceutical composition for the treatment of airway obstructive disease in a patient requiring treatment of airway obstructive disease, comprising a compound represented by or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the pharmaceutically acceptable adjuvant, diluent or carrier comprises a cellulose derivative.

2. R 1 but, 【Chemistry 4】 And; X is O, S or CF 2 And; Y is either O or S; Q is CH; R 6 However, C 1-3 It is alkyl (where C 1-3 The alkyl group may be substituted with 1, 2, or 3 F atoms, and also OH,OC 1-3 Alkyl, N(C) 1-3 Alkyl) 2 (may be substituted with one substituent selected from cyclopropyl and tetrahydropyran); R 7 However, hydrogen, F, Cl or CH 3 That is, The pharmaceutical composition according to claim 1.

3. R 1 but, 【Transformation 5】 And; X is O, S or CF 2 And; Y is either O or S; R 6 However, C 1-3 It is alkyl (where C 1-3 The alkyl group may be substituted with 1, 2, or 3 F atoms, and also OH,OC 1-3 Alkyl, N(C) 1-3 Alkyl) 2 (may be substituted with one substituent selected from cyclopropyl and tetrahydropyran); R 7 However, hydrogen, F, Cl or CH 3 That is, The pharmaceutical composition according to claim 1 or 2.

4. R 1 but 【Transformation 6】 That is, A pharmaceutical composition according to any one of claims 1 to 3.

5. X is O; R 6 C 1-3 It is alkyl (where the C1-3 alkyl is unsubstituted); R 7 That is hydrogen. The pharmaceutical composition according to claim 4.

6. R 1 but, 【Transformation 7】 And; X is O; R 6 However, C 1-3 It is alkyl (where C 1-3 The alkyl group may be substituted with one, two, or three F atoms; R 7 However, it is hydrogen. The pharmaceutical composition according to claim 1.

7. The pharmaceutical composition comprises a compound represented by formula (I), R 1 but, 【Transformation 8】 And; X is O; R 6 However, C 1-3 It is alkyl (where the C1-3 alkyl is unsubstituted); R 7 However, it is hydrogen. The pharmaceutical composition according to claim 1.

8. The compound represented by formula (I) (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridine-3-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiadin-6-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl}phenyl)ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinoline-7-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazole-5-yl]phenyl}ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-2-[4'-(azetidine-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepan-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepan-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-benzothiazole-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepan-2-carboxamide; and (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepan-2-carboxamide The pharmaceutical composition according to claim 1, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

9. The compound represented by formula (I) 【Chemistry 9】 The pharmaceutical composition according to claim 1, wherein the composition is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}1,4-oxazepan-2-carboxamide, or a pharmaceutically acceptable salt thereof.

10. The compound represented by formula (I) 【Chemistry 10】 The pharmaceutical composition according to claim 1, wherein the compound is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl)phenyl]ethyl}-1,4-oxazepan-2-carboxamide.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is bronchiectasis.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is cystic fibrosis.

13. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is asthma.

14. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is chronic obstructive pulmonary disease (COPD).

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is administered orally to the patient.

16. The pharmaceutical composition according to claim 15, wherein the daily dose of the compound represented by formula (I) administered orally to the patient is 0.01 μg (μg / kg) to 100 mg (mg / kg) per kg of body weight.

17. A pharmaceutical composition according to any one of claims 1 to 16, wherein the dosage form is a tablet, capsule, syrup, liquid, suspension, powder, or granule.

18. The pharmaceutical composition according to claim 17, in tablet form.

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