Chemical compounds

Patent metadata

Field	Value
Publication number	US-11254671-B2
Application number	US-201816770673-A
Country	US
Kind code	B2
Filing date	Dec 12, 2018
Priority date	Dec 15, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

The invention relates to compounds of formula (I):wherein R1, R2, R3, R4, L and A are as defined in the description and claims, or pharmaceutically acceptable salts thereof having mTOR kinase inhibitor activity. The invention also relates to pharmaceutical compositions including a compound of formula (I) or a pharmaceutically acceptable salt thereof, and to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy, including in the treatment of a disease or condition for which an mTOR kinase inhibitor activity is indicated, and in particular the treatment of idiopathic pulmonary fibrosis.

First claim

The invention claimed is:

1. A compound or pharmaceutically acceptable salt thereof, according to formula (I),

wherein:
A is

where ring A is attached via N;
X is O or NH;
L is (C 1 -C 3 )alkylene, (C 1 -C 3 )haloalkylene, (C 3 -C 5 )cycloalkylene or (C 2 -C 5 ) heterocycloalkylene;

R 1 is (C 1 -C 3 )alkyl, (C 3 -C 5 ) cycloalkyl, (C 1 -C 3 )alkoxy, or NR 2 R 3 ,
which (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl or (C 1 -C 3 )alkoxy is optionally substituted with NR 2 R 3 ;
R 2 and R 3 are each independently CH 3 or H;
R 4 is NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , (C 1 -C 3 )alkyl, NH 2 or OH;
R 5 is (C 1 -C 3 )alkyl or H;
m is 1 or 2; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt thereof, according to formula (Ia),

wherein:
A is

where ring A is attached via N;
X is O or NH;
L is (C 1 -C 3 )alkylene, (C 1 -C 3 )haloalkylene, (C 3 -C 5 )cycloalkylene or (C 2 -C 5 ) heterocycloalkylene;

R 1 is (C 1 -C 3 )alkyl, (C 3 -C 5 ) cycloalkyl, (C 1 -C 3 )alkoxy, or NR 2 R 3 ,
which (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl or (C 1 -C 3 )alkoxy is optionally substituted with NR 2 R 3 ;
R 2 and R 3 are each independently CH 3 or H;
R 4 is NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , (C 1 -C 3 )alkyl, NH 2 or OH;
R 5 (C 1 -C 3 )alkyl or H;
m is 1 or 2; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

3. The compound or pharmaceutically acceptable salt according to claim 1 wherein A is

4. The compound or pharmaceutically acceptable salt according to claim 1 wherein X is O.

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein L is methandiyl, propan-2,2-diyl, cyclopropan-1,1-diyl, difluoromethandiyl, tetrahydro-2H-pyran-4,4-diyl or piperidin-4,4-diyl.

6. The compound or pharmaceutically acceptable salt according to claim 5 wherein L is tetrahydro-2H-pyran-4,4-diyl.

7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is (C 1 -C 3 )alkyl, cyclopropyl or NR 2 R 3 .

8. The compound or pharmaceutically acceptable salt according to claim 7 , wherein R 1 is methyl, ethyl, cyclopropyl or N(CH 3 ) 2 .

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is NHCH 3 .

10. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is ethyl.

11. The compound or pharmaceutically acceptable salt according to claim 1 wherein m is 1.

12. A compound which is (S)-1-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine,

or a pharmaceutically acceptable salt thereof.

13. A compound which is (S)-1-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine,

14. A pharmaceutical composition comprising a) a compound or pharmaceutically acceptable salt thereof as defined in claim 1 , and b) a pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14 wherein said compound is (S)-1-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine

or a pharmaceutically acceptable salt thereof.

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Bravi Gianpaolo
• Hobbs Heather
• Inglis Graham George Adam
• Nicolle Simon
• Peace Simon

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title