IP Library Granted Patent US 9,522,894
Granted Patent B2
US 9,522,894 · App. 14/601,371 · Granted Dec 20, 2016

Certain (2

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Quick Facts
Patent No.
US 9,522,894
App. No.
14/601,371
Granted
Dec 20, 2016
Kind
B2
Abstract

The present disclosure relates to certain (2S)—N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof), that inhibit dipeptidyl peptidase 1 (DPP1) activity, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.

Claims (58)

1. A compound of formula (I)

wherein

R 1 is

R 2 is selected from hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl;

R 3 is selected from hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form a azetidine, pyrrolidine or piperidine ring; or

R 1 is selected from

X is selected from O, S or CF 2 ;

Y is selected from O or S;

Q is selected from CH or N;

R 6 is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran;

R 7 is selected from hydrogen, F, Cl or CH 3 ; or a pharmaceutically-acceptable salt thereof.

2. A compound according to claim 1 wherein

R 1 is

or a pharmaceutically acceptable salt thereof.

3. A compound according to either claim 1 or claim 2 wherein

X is O;

R 6 is C 1-3 alkyl; and

R 7 is hydrogen; or a pharmaceutically acceptable salt thereof.

4. A compound of the formula (I) according to claim 1 selected from:

(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate;

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2, 3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-2-(4′-Carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-1-Cyano-2-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-2-[4′-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;

(2S)—N-[(1S)-1-Cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;

(2S)—N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; and

(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts thereof.

5. A compound according to claim 1 which is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 which is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

7. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

8. A method of treating asthma or chronic obstructive pulmonary disease in a patient suffering from said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 .

Assignments (7)
PATENT SECURITY AGREEMENT Recorded Oct 20, 2022
From: INSMED INCORPORATED
To: BIOPHARMA CREDIT PLC
Reel/Frame 061735/0875 →
SECOND LIEN PATENT SECURITY AGREEMENT Recorded Oct 19, 2022
From: INSMED INCORPORATED
To: ORBIMED ROYALTY & CREDIT OPPORTUNITIES IV, LP
Reel/Frame 061727/0039 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2015
From: ASTRAZENECA UK LIMITED
To: ASTRAZENECA AB
Reel/Frame 035641/0258 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2015
From: DOYLE, KEVIN; VAN DE POEL, AMANDA; JONES, GRAHAM; WATSON, DAVID; MACRITCHIE, JAQUELINE; PALMER, NICHOLAS
To: BIOFOCUS DPI LTD
Reel/Frame 035641/0403 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2015
From: BIOFOCUS DPI LTD
To: ASTRAZENECA AB
Reel/Frame 035641/0472 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2015
From: CONNOLLY, STEPHEN; SWALLOW, STEVEN
To: ASTRAZENECA UK LIMITED
Reel/Frame 035641/0200 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2015
From: PONTEN, JOHN FRITIOF; LONN, HANS ROLAND; AURELL, CARL-JOHAN; KARLSSON, STAFFAN PO
To: ASTRAZENECA AB
Reel/Frame 035641/0104 →