Bridged bicyclic kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-10144746-B2
Application number	US-201715807331-A
Country	US
Kind code	B2
Filing date	Nov 8, 2017
Priority date	Jun 12, 2015
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

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

First claim

What is claimed:

1. A compound of Formula (I″), or a pharmaceutically acceptable salt thereof, having structure:

wherein:
one of A and B is O and the other of A and B is a bond;
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 hydrogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, 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 1 -C 6 alkyl, aminocarbonyl, amidinoC 1 -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 are hydrogen;
ring D is phenyl;
R 31 is 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, 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), —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 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 cycloalkyl, C 3 -C 6 cycloalkylC 1-6 alkoxy, C 3 -C 6 cycloalkylC 1-6 alkoxy, 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 alkyl-sulfonyl, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, aminocarbonyl, acyl, 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); and
R 30 is hydrogen; or
a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the carbon atom to which they are attached form C═O.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is NR 13 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —(CR 3 R 4 )—Z—X 1 — is —CONHCH 2 —.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with R e , R f , or R g independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, amino, aminomethyl, —CONH 2 , —CONHCH 3 , tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2,4-dihydrofuran-3-yl, tetrazol-1-yl, amidinoC 1 -C 6 alkyl, —C(═NR h )NHR i (where R h and R i are independently hydrogen, hydroxy, C 1 -C 6 alkoxy, acyl, —C(O)OC 1 -C 6 alkyl, a natural or an unnatural amino acid 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, and 1,2,4-oxadiazol-5(4H)-one-3-yl.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with R e and R f independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, —CONH 2 , —CONHCH 3 , tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl,2,4-dihydrofuran-3-yl, tetrazol-1-yl, and cyano wherein R e and R f are attached to the carbon atoms of the phenyl ring that are ortho to the carbon of the phenyl ring attached to X 1 , and is substituted with R g wherein R g is amino, aminomethyl, —C(═NR h )NHR i (where R h and R i are independently hydrogen, hydroxy, methoxy, ethoxy, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, a natural or an unnatural amino acid 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)), and 1,2,4-oxadiazol-5(4H)-one-3-yl and wherein R g is located at the carbon of the phenyl ring that is para to the carbon of the phenyl ring attached to X 1 .

7. The compound of claim 4 , or a pharmaceutical

Assignees

• Global Blood Therapeutics Inc

Inventors

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

Classifications

• C07D307/81

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D491/18

  Bridged systems · 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

• C07D401/12

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

• C07D471/08

  Bridged systems · CPC title