Bridged bicyclic kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-9815853-B2
Application number	US-201615177641-A
Country	US
Kind code	B2
Filing date	Jun 9, 2016
Priority date	Jun 12, 2015
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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):

wherein:
one of A and B is O and the other of A and B is a bond;
ring C is phenyl, 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 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 atom 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 cyclo-alkyl, 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 (wherein 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 ((wherein 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 (wherein 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;
R 2 and R 7 together with the atoms they are attached form ring D:

wherein ring D is phenyl; and
R 30 is C 3 -C 6 cycloalkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, fused heterocyclyl, spiro heterocycloamino or bridged heterocycloamino, and wherein each of the aforementioned ring in R 30 , 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);
R 31 is hydrogen; or
a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl optionally substituted, in addition to —CR 3 R 4 —Z—X 1 —R 1 , with a substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, and halo.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having structure (I″)

4. The compound of claim 3 , 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.

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Z is NR 13 , and X 1 is CR 16 R 17 where R 16 and R 17 are independently hydrogen, deuterium, or C 1 -C 6 alkyl.

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

7. The compound of claim 6 , 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.

8. The compound of claim 6 , 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

Assignees

• Global Blood Therapeutics Inc

Inventors

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

Classifications

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D405/12

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

• C07D401/12

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

• C07B59/002

  Heterocyclic compounds · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title