Substituted [1,2,4]triazolo[4,3-A]pyrazines as prolyl endopeptidase inhibitors

Patent metadata

Field	Value
Publication number	US-11337973-B2
Application number	US-201816761713-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	Nov 7, 2017
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

The invention relates to prolyl endopeptidase (PREP) inhibitors of formula (I) which contain a condensed 2,4-dihydro-3H-1,2,4-triazol-3-one ring system, methods for producing same, the use thereof alone or in combinations for treating and/or preventing diseases, and the use thereof for producing drugs for treating and/or preventing diseases, in particular for treating and/or preventing inflammatory lung diseases (COPD).

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
(i) A is —CD 2 - or —(C 1 -C 4 ) alkylene-, wherein the (C 1 -C 4 ) alkylene is optionally substituted by 1 or more substituents independently selected from the group consisting of F, OH, and O(C 1 -C 4 ) alkyl; or
(ii) A is:

wherein:
n is 0 or 1;
p is 0 or 1;
q is 1 or 2;
# 1 is the point of attachment to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring; and
* is the point of attachment to R 1 ;

X is —N(R 10 )—, —N[C(O)R 8 ]—, —N[C(O)NR 6 R 7 ]—, or —N[C(O)OR 9 ]—;
R 1 is (C 3 -C 7 ) cycloalkyl, phenyl, or 5- to 10-membered heteroaryl;
wherein the (C 3 -C 7 ) cycloalkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, (C 1 -C 4 ) alkyl, CF 3 , and O(C 1 -C 4 ) alkyl;
wherein the phenyl is substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, (C 1 -C 4 ) alkyl, CF 3 , C(O)NH 2 , C(O)NH(C 1 -C 4 ) alkyl, C(O)N[(C 1 -C 4 ) alkyl] 2 , C(O)NH(C 3 -C 5 ) cycloalkyl, C(O)OH, C(O)O(C 1 -C 4 ) alkyl, NH 2 , NH(C 1 -C 4 ) alkyl, N[(C 1 -C 4 ) alkyl] 2 , O(C 1 -C 4 ) alkyl, OCH 2 F, OCHF 2 , OCF 3 , S(C 1 -C 4 ) alkyl, S(O)(C 1 -C 4 ) alkyl, S(O) 2 (C 1 -C 4 ) alkyl, S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 4 ) alkyl, S(O) 2 N[(C 1 -C 4 ) alkyl] 2 , S(O) 2 (C 3 -C 4 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl, and (C 3 -C 5 ) cycloalkoxy;
wherein the 5- to 10-membered heteroaryl is substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, (C 1 -C 4 ) alkyl, CF 3 , C(O)NH 2 , C(O)NH(C 1 -C 4 ) alkyl, C(O)N[(C 1 -C 4 ) alkyl] 2 , C(O)NH(C 3 -C 5 ) cycloalkyl, C(O)OH, C(O)O(C 1 -C 4 ) alkyl, NH 2 , NH(C 1 -C 4 ) alkyl, N[(C 1 -C 4 ) alkyl] 2 , O(C 1 -C 4 ) alkyl, OCHF 2 , OCF 3 , OCH 2 CF 3 , S(C 1 -C 4 ) alkyl, S(O)(C 1 -C 4 ) alkyl, S(O) 2 (C 1 -C 4 ) alkyl, S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 4 ) alkyl, S(O) 2 N[(C 1 -C 4 ) alkyl] 2 , S(O) 2 (C 3 -C 4 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 5 ) cycloalkoxy, and phenyl; and
wherein each phenyl substituent of the 5- to 10-membered heteroaryl is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, CH 3 , CH 2 CH 3 , and OCH 3 ;

(iii) R 2 is:

wherein:
r is 0 or 1;
Z is —CR 13A R 13B —, —NR 14 —, —O—, —S—, —S(O)—, or —S(O) 2 —;
R 11 is H, CN, (C 1 -C 4 ) alkyl, C(O)H, or C(O)CH 3 ;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F and OH; and
wherein the C(O)CH 3 is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of F and OH;

R 12 is H, F, or (C 1 -C 4 ) alkyl;
R 13A is H, halogen, CN, (C 1 -C 4 ) alkyl, CH 2 F, CHF 2 , CF 3 , OH, O(C 1 -C 4 ) alkyl, OCHF 2 , OCF 3 , OCH 2 CF 3 , (C 3 -C 6 ) cycloalkyl, or (C 3 -C 5 ) cycloalkoxy:
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of NH 2 , NH(C 1 -C 4 ) alkyl, N[(C 1 -C 4 ) alkyl] 2 , and OH;

R 13B is H, F, or (C 1 -C 4 ) alkyl,
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 F substituents; or

R 11 and R 12 , together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl;
wherein the cyclopropyl or cyclobutyl is optionally substituted by 1 or 2 F substituents; or

R 12 and R 13A , together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl;
wherein the cyclopropyl or cyclobutyl is optionally substituted by 1 or 2 F substituents; or

R 13A and R 13B , together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl;
wherein the cyclopropyl or cyclobutyl is optionally substituted by 1 or 2 F substituents;

R 14 is H or CH 3 ; and
# 2 is the point of attachment to —C(O)—; or

(iv) R 2 is:

wherein:
Y is —CR 16A R 16B —, —NR 15 —, —O—, or —S—;
R 15 is H or CH 3 ;
R 16A is H or CH 3 ;
R 16B is H or CH 3 ; and
# 3 is the point of attachment to —C(O)—;

R 3 is H;
R 4 is H or (C 1 -C 4 ) alkyl;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, NH(C 1 -C 4 ) alkyl, N[(C 1 -C 4 ) alkyl] 2 , OH, and O(C 1 -C 4 ) alkyl;

R 5 is H;
R 6 is (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
wherein the (C 1 -C 6 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, CN, OH, and O(C 1 -C 4 ) alkyl; and
wherein the (C 3 -C 6 ) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , (C 1 -C 4 ) alkyl, and O(C 1 -C 4 ) alkyl;

R 7 is H or (C 1 -C 4 ) alkyl;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 F substituents;

R 8 is (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, CN, OH, and O(C 1 -C 4 ) alkyl; and
wherein the (C 3 -C 6 ) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , (C 1 -C 4 ) alkyl, and O(C 1 -C 4 ) alkyl;

R 9 is (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, or phenyl;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 F substituents; and
wherein the (C 3 -C 6 ) cycloalkyl or phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , (C 1 -C 4 ) alkyl, and O(C 1 -C 4 ) alkyl; and

R 10 is H, (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, or phenyl;
wherein the (C 1 -C 4 ) alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, CN, OH, O(C 1 -C 4 ) alkyl, and (C 3 -C 6 ) cycloalkyl; and
wherein the (C 3 -C 6 ) cycloalkyl or phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , (C 1 -C 4 ) alkyl, and O(C 1 -C 4 ) alkyl;

with the provisos that:
(1) if R 11 is H, then at least one of R 12 , R 13A , or R 13B is not H; and
(2) if R 11 is CN, (C 1 -C 4 ) alkyl, C(O)H, or C(O)CH 3 , then R 12 , R 13A , and R 13B are H.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is —(C 1 -C 4 ) alkylene-;
X is —N(R 10 )—, —N[C(O)R 8 ]—, —N[C(O)NR 6 R 7 ]—, or —N[C(O)OR 9 ]—;
R 1 is phenyl or 6-membered heteroaryl;
wherein the phenyl or 6-membered heteroaryl is substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, CN, CH 3 , CF 3 , CH 2 CH 3 , C(O)NHCH 3 , C(O)N(CH 3 ) 2 , C(O)OH, C(O)OCH

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Biber Nicole
• Brockschnieder Damian
• Kölling Florian
• Meding Jörg
• Miyatake Ondozabal Hideki
• Neubauer Thomas
• Schäfer Martina
• Zubov Dmitry
• Terjung Carsten

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title