Human plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-10689346-B2
Application number	US-201916400798-A
Country	US
Kind code	B2
Filing date	May 1, 2019
Priority date	Mar 7, 2014
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Disclosed are compounds of formula I

as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also disclosed are pharmaceutical compositions comprising at least one such compound, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

First claim

What is claimed is:

1. A method of treating a disease or condition characterized by unwanted plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof:

wherein:
X represents CH, C(OH), C(O(C 1 -C 6 )alkyl), —C(NH 2 ), —C(NR a R b ), —C(N 3 ), —C(CN), —C(NO 2 ), —C(S(O) n R a ), —C[—C(═O)R c ], —C[—C(═O)NR c R d ], —C[—C(═O)SR c ], —C[—S(O)R c ], —C[—S(O) 2 R c ], —C[S(O)(OR c )], —C[—S(O) 2 (OR c )], —C[—SO 2 NR c R d ], —C(halogen), —C[(C 1 -C 5 )alkyl], —C[(C 4 -C 5 )carbocyclyl], —C[(C 1 -C 8 )substituted alkyl], —C[(C 2 -C 8 )alkenyl], —C[(C 2 -C 8 )substituted alkenyl], —C[(C 2 -C 8 )alkynyl], —C[(C 2 -C 8 )substituted alkynyl], —C[aryl(C 1 -C 5 )alkyl] or N;
—Y—R 4 represents —((C 1 -C 6 )alkyl)-R 4 , —CH 2 C(O)—R 4 , —CH 2 NH-R 4 , —CH 2 N((C 1 -C 6 )alkyl)-R 4 , —CR a R b —R 4 , —NH—R 4 , —NHCH 2 —R 4 , —NHC(O)—R 4 , —N((C 1 -C 6 )alkyl)-R 4 , —N((C 1 -C 6 )alkyl)CH 2 —R 4 , —N((CH 2 ) 2 OH)—R 4 , —N[(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl]R 4 , -heterocyclyl-R 4 , —OR 4 , —OCH 2 —R 4 , —OC(O)—R 4 , —SCH 2 R 4 , or —SR 4 , wherein the (C 1 -C 6 )alkyl moiety of —((C 1 -C 6 )alkyl)-R 4 is optionally substituted;
Z is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, —CF 3 , —OCF 3 , (C 1 -C 6 )alkoxy, aryl, aryloxy, amino, amino(C 1 -C 6 )alkyl, —C(O)NH 2 , cyano, —NHC(O)(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 NH 2 , (C 3 -C 5 )cycloalkyl, (CH 2 ) r OR a , N 02 , (CH 2 ) r NR a R b , (CH 2 ) r C(O)R a , NR a C(O)R b , C(O)NR c R d , NR a C(O)NR c R d , —C(═NR a )NR c R d , NHC(═NR a )NR c R d , NR a R b , SO 2 NR c R d , NR a SO 2 NR c R d , NR a SO 2 -(C 1 -C 6 )alkyl, NR a SO 2 R a , S(O) p R a , (CF 2 ) r CF 3 , NHCH 2 R a , OCH 2 R a , SCH 2 R a , NH(CH 2 ) 2 (CH 2 ) r R a , O(CH 2 ) 2 (CH 2 ) r R a , and S(CH 2 ) 2 (CH 2 ) r R a ; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R 1c represents halo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, cyano, —C(═NH)NH 2 , —CONR a R b , —(C 1 -C 6 )alkylCONR a R b , —SO 2 CH 3 , formyl, acyl, —NH 2 , —C(═NH)NH(OH), —C(═NH)NH(C(O)O—(C 1 -C 6 )alkyl), —C(═NH)NH(C(O)O—(C 1 -C 6 )haloalkyl), —C(═NH)NH(C(O)S—(C 1 -C 6 )alkyl), —C(═NH)NH(C(O)(OCH(C 1 -C 6 )alkyl)OC(O)(C 1 -C 6 )alkyl), optionally substituted aryl, or optionally substituted heteroaryl;
R 2 represents halo, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, —OCH 3 , —Si(CH 3 ) 3 , —CONH 2 , —C(O)OH, cyano, or phenyl;
R 3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;
R 3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, —CF 3 , —OCF 3 , (C 1 -C 6 )alkoxy, aryl, aryloxy, amino, amino(C 1 -C 6 )alkyl, —C(O)NH 2 , cyano, —NHC(O)(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 NH 2 , (C 3 -C 8 )cycloalkyl, (CH 2 ) r OR a , NO 2 , (CH 2 ) r NR a R b , (CH 2 ) r C(O)R a , NR a C(O)R b , C(O)NR c R d , NR a C(O)NR c R d , —C(═NR a )NR c R d , NHC(═NR a )NR c R d , NR a R b , SO 2 NR c R d , NR a SO 2 NR c R d , NR a SO 2 -(C 1 -C 6 )alkyl, NR a SO 2 R a , S(O) p R a , (CF 2 ) r CF 3 , NHCH 2 R a , OCH 2 R a , SCH 2 R a , NH(CH 2 ) 2 (CH 2 ) r R a , O(CH 2 ) 2 (CH 2 ) r R a , or S(CH 2 ) 2 (CH 2 ) r R a ; or alternatively R 3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R 4 represents hydrogen, hydroxy, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, heterocyclyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —CH 2 OH, —CH((C 1 -C 6 )alkyl)OH, —CH(NH 2 )CH((C 1 -C 6 )alkyl) 2 , optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, heteroaryl, optionally substituted heteroaryl(C 1 -C 6 )alkyl, —CH 2 S(C 1 -C 6 )alkyl, amino, or cyano;
each R a and R b is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 3 -C 8 )carbocyclyl, —C(═O)R c , —C(═O)OR c , —C(═O)NR c R d , —C(═O)SR c , —S(O)R c , —S(O) 2 R c , —S(O)(OR c ), or —SO 2 NR c R d ;
each R c and R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 ) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O)n(C 1 -C 8 )alkyl, or aryl(C 1 -C 8 )alkyl; or when R and R d are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NR a —;
n is 2 or 3;
r is independently for each occurrence 0, 1, 2, or 3;
p is independently for each occurrence 0, 1, or 2; and
the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.

2. The method of claim 1 , wherein X represents CH, C(OH), C(O(C 1 -C 6 )alkyl), —C(NH 2 ), —C(NR a R b ), —C(halogen), —C[(C 2 -C 8 )alkenyl], —C[(C 2 -C 8 )substituted alkenyl], or N.

3. The method of claim 1 , wherein X represents CH.

4. The method of claim 1 , wherein —X—Y— represents —CHNHCH 2 —, —C(OH)CH 2 CH 2 —, or —CHOCH 2 —.

5. The method of claim 1 , wherein R 3 represents phenylene-R 3a .

6. The method of claim 1 , wherein —R 3 —R a represents

7. The method of claim 1 , wherein R 4 is cyclopropyl.

8. The method of claim 1 , wherein R 3 is phenyl, and R 3a is ortho, meta, or para —OH.

9. The method of claim 1 , wherein R 3 is phenyl, and R 3a is meta or para —NH 2 .

10. The method of claim 1 , wherein R 3 is phenyl, and R 3a is meta or para —CN.

11. The method of claim 1 , wherein Z is absent, or represents fluoro or chloro.

12. The method of claim 1 , wherein Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C 3 -C 8 )cycloalkyl.

13. The method of claim 1 , wherein R 1c represents aminomethyl.

14. The method of claim 1 , wherein R 1c represents cyano.

15. The method of claim 1 , wherein R 1c represents —SO 2 CH 3 .

16. The method of claim 1 , wherein R 2 is —CH 3 , —CF 3 , tert-butyl, cyclopropyl, —OCH 3 , —Si(CH 3 ) 3 , —CONH 2 , cyano, or phenyl.

17. The method of claim 1 , wherein the compound of formula (II) is selected from the group consisting of:

18. The method of claim 1 , wherein the compound of formula (II) has the structure:

Assignees

• Biocryst Pharm Inc

Inventors

• Kotian Pravin L
• Babu Yarlagadda S
• Wu Minwan
• Chintareddy Venkat R
• Kumar V Satish
• Zhang Weihe

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title