Bridged bicyclic kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-2016362427-A1
Application number	US-201615177641-A
Country	US
Kind code	A1
Filing date	Jun 9, 2016
Priority date	Jun 12, 2015
Publication date	Dec 15, 2016
Grant date	—

Abstract

Provided herein are kallikrein modulating compounds, pharmaceutical compositions comprising the same, and uses thereof.

First claim

1 . A compound of formula (I):

wherein:
one of A and B is a bond, O, CO, S(O) p , NCOR b , NCONHR c , NSO 2 R d , or CR 8 R 9 and the other of A and B is a bond, NR a , or CR 10 R 11 , wherein p is 0, 1, or 2, R a is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy or C 3 -C 6 cycloalkyl, R b , R c and R d are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, or mono or bicyclic aryl (wherein aforementioned mono or bicyclic aryl, mono or bicyclic heteroaryl, and monocyclic heterocyclyl are optionally substituted with one, two, or three substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, and cyano) and R 8 , R 9 , R 10 and R 11 are independently hydrogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, and provided that both A and B are not bond or heteroatoms simultaneously;
ring C is phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, or C 5 -C 6 cycloalkyl, wherein ring C, in addition to —CR 3 R 4 —Z—X 1 —R 1 , is optionally substituted with one or two substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkyl-amino, diC 1 -C 6 alkylamino, and cyano;
R 3 and R 4 are independently hydrogen, fluoro, or C 1 -C 6 alkyl, or R 3 and R 4 together with the carbon they are attached form C═O, C═NR 12 (wherein R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy), or C 3 -C 6 cycloalkyl, provided that when R 3 and R 4 together form C═NR 12 then Z is NR 13 ;
Z is a bond, NR 13 , or CR 14 R 15 , wherein R 13 , R 14 , and R 15 are independently hydrogen or C 1 -C 6 alkyl;
X 1 is bond, C═NR 8 , CR 16 R 17 , O, or S(O) q , wherein q is 0, 1, or 2, R 8 is as defined above, and R 16 and R 17 are independently hydrogen, deuterium, or C 1 -C 6 alkyl, or R 16 and R 17 together with the carbon they are attached form C 3 -C 6 cycloalkyl, C═NH, or C═O, provided that when R 3 and R 4 together form C═O then X 1 is not O;
R 1 is mono or bicyclic aryl, mono or bicyclic heteroaryl, C 3 -C 6 cycloalkyl, monocyclic heterocyclyl, or fused heterocyclyl, wherein each of the aforementioned ring(s) is optionally substituted with R e , R f or R g independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, aminoC-C 6 alkyl, aminocarbonyl, amidinoC-C 6 alkyl, —C(═NR h )NHR i (where R h and R i are independently hydrogen, hydroxy, C 1 -C 6 alkoxy, benzyloxy, acyl, —C(O)OC 1 -C 6 alkyl, a natural or an unnatural amino acid residue, a dipeptidic residue, —CO(ethylene)SO 2 R u (where R u is C 1 -C 6 alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH 2 ) 2-3 OR v (where R v is hydrogen, C 1 -C 6 alkoxyC 1-3 alkyl, or optionally substituted monocyclic heterocyclyl)), cyano, monocyclic heteroaryl (wherein the monocyclic heteroaryl is optionally substituted with one, two or three substituents independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, and cyano), and monocyclic heterocyclyl (wherein the monocyclic heterocyclyl is optionally substituted with one, two or three substituents independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, and diC 1 -C 6 alkylamino);
R 5 and R 6 independently are hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, hydroxy, carboxy, C 1 -C 6 alkoxycarbonyl, or C 1 -C 6 alkoxy;
R 2 and R 7 are independently hydrogen, halo, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, cyano, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, fused heterocyclyl, mono or bicyclic arylC 1 -C 6 alkyl, mono or bicyclic heteroarylC 1 -C 6 alkyl, monocyclic heterocyclylC 1 -C 6 alkyl (wherein the alkylene chain in mono or bicyclic arylC 1 -C 6 alkyl, mono or bicyclic heteroarylC 1 -C 6 alkyl or monocyclic heterocyclylC 1 -C 6 alkyl is optionally substituted with deuterium), spiroheterocycloamino, bridged heterocycloamino, —NR 18 R 19 , —OR 20 , —CHFR 21 , —CF 2 R 22 , SR 23 , SOR 24 , SO 2 R 25 , —C(═O)R 26 ; —C(═O)NR 27 R 28 , or —NR 18 C(═O)R 29 wherein R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 29 are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, or monocyclic heterocyclyl; or R 18 and R 19 or R 27 and R 28 together with the nitrogen atom they are attached form heterocycloamino or mono or bicyclic heteroaryl, and wherein each of the aforementioned ring in R 2 and R 7 , by itself or as part of another group, is optionally substituted with R j , R k or R l independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, amino, C 1 -C 6 alkyl-amino, diC 1 -C 6 alkylamino, aminoC 1 -C 6 alkyl, cyano, monocyclic heteroaryl (wherein the monocyclic heteroaryl is optionally substituted with one, two or three substituents independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, and cyano), and monocyclic heterocyclyl (wherein the monocyclic heterocyclyl is optionally substituted with one, two or three substituents independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, and diC 1 -C 6 alkylamino); or
R 2 and R 7 together with the atoms they are attached form ring D:

where ring D is phenyl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, fused heterocyclyl, or C 5 -C 6 cycloalkyl; and
R 30 and R 31 are independently hydrogen, halo, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, cyano, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, fused heterocyclyl, mono or bicyclic arylC 1 -C 6 alkyl, mono or bicyclic heteroarylC 1 -C 6 alkyl monocyclic heterocyclylC 1 -C 6 alkyl (wherein the alkylene chain in mono or bicyclic arylC 1 -C 6 alkyl, mono or bicyclic heteroarylC 1 -C 6 alkyl or monocyclic heterocyclylC 1 -C 6 alkyl is optionally substituted with deuterium), spiro heterocycloamino, bridged heterocycloamino, —NR 32 R 33 , —OR 34 , —CHFR 35 , —CF 2 R 36 , SR 37 , SOR 38 , SO 2 R 39 , —C(═O)R 40 , —C(═O)NR 41 R 42 , or —NR 43 C(═O)R 44 , wherein R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , and R 44 are independently hydrogen, C 1 -C 6 alkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, or monocyclic heterocyclyl; or R 32 and R 33 or R 41 and R 42 together with the nitrogen atom they are attached form heterocycloamino or mono or bicyclic heteroaryl, and wherein each of the aforementioned ring in R 30 and R 31 , whether by itself or part of another group, is optionally substituted with R m , R n or R o independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cyc

Assignees

• Global Blood Therapeutics Inc

Inventors

• Li Zhe
• Zancanella Manuel
• Yu Chul
• Setti Lina
• Sham Hing
• Xu Qing
• Yee Calvin
• Yu Ming

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D519/00 Primary

  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

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D405/12

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

• C07D487/08

  Bridged systems · CPC title