IP Library › Granted Patent US 9,066,954

Granted Patent B2

US 9,066,954 · App. 13/916,984 · Granted Jun 30, 2015

Fused heterocyclic derivatives and methods of use

Inventors: Brian K. Albrecht (Cambridge, MA); David Bauer (Sudbury, MA); Steven Bellon (Wellesley, MA); Christiane M. Bode (Somerville, MA); Shon Booker (Thousand Oaks, CA); Alessandro Boezio (Somerville, MA); Deborah Choquette (Medford, MA); Derin D'Amico (Newbury Park, CA); Jean-Christophe Harmange (Andover, MA); Satoko Hirai (Brookline, MA); Randall W. Hungate (Camarillo, CA); Tae-Seong Kim (Thousand Oaks, CA); Richard T. Lewis (Farmingham, MA); Longbin Liu (Thousand Oaks, CA); Julia W. Lohman (San Francisco, CA); Mark H. Norman (Thousand Oaks, CA); Michele Potashman (Cambridge, MA); Aaron C. Siegmund (Ventura, CA); Stephanie K. Springer (Cambridge, MA); Markian Stec (Moorpark, CA); Ning Xi (Thousand Oaks, CA); Kevin Yang (San Gabriel, CA)

Assignee: Amgen Inc.

A61K31/538 C07D403/12 C07D471/04 C07D487/04 C07D493/04 C07D495/04 C07D498/04 C07D519/00 A61K31/437 A61K31/497 A61K31/5025 A61K31/506 A61K31/52 A61K31/5377 A61K45/06 C07D473/34

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Quick Facts

Patent No.: US 9,066,954
App. No.: 13/916,984
Granted: Jun 30, 2015
Kind: B2

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Abstract

Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Claims (43)

1. A compound of formula II

or a pharmaceutically acceptable salt thereof wherein

J is N;

W is CR 2b ;

Z and Z* are independently —O— or —NR 5 —;

R a , R b , R c and R d are each independently H, halo, alkyl, any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence;

R 1 is aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence;

R 2 is

(i) halo, cyano, nitro, or

(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —OR 4 , any of which may be optionally independently substituted with one or more R 10 as allowed by valence,

R 2a , R 2b and R 3 are independently selected at each occurrence from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,

heterocycloalkyl, —OR 4 , —S(O) v R 4 , —NR 5 R 5a , —C(═O)R 4 , —C(═S)R 4 , —C(═O)OR 4 , —C(═S)OR 4 , —C(═O)NR 5 R 5a , —C(═S)NR 5 R 5a , —N(R 5 )C(═O)NR 5 R 5a , —N(R 5 )C(═S)NR 5 R 5a , —N(R 5 )C(═O)R 4 , —N(R 5 )C(═S)R 4 , —OC(═O)NR 5 R 5a , —OC(═S)NR 5 R 5a , —SO 2 NR 5 R 5a , —N(R 5 )SO 2 R 4 , —N(R 5 )SO 2 NR 5 R 5a , —N(R 5 )C(═O)OR 4 , —N(R 5 )C(═S)OR 4 , —N(R 5 )SO 2 R 4 , any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence;

R 4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valence with one or more R 10 groups;

R 5 and R 5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valence with one or more R 10 ;

R 10 at each occurrence is independently, halo, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,

heterocycloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -S(O) v R 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═S)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O) R 4 , -(alkylene) m -C(═S)OR 4 , -(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -N(R 5 )C(═S)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , -(alkylene) m -OC(═S)NR 5 R 5a , -(alkylene) m -SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )SO 2 R 4 , -(alkylene) m -N(R 5 )SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)OR 4 , -(alkylene) m -N(R 5 )C(═S)OR 4 ,

or -(alkylene) m -N(R 5 )SO 2 R 4 ;

wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -OR 4 , -(alkylene) m -S(O) v R 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═S)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O)R 4 , -(alkylene) m -C(═S)OR 4 ,

-(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -C(═S)NR 5 O, -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -N(R 5 ) C(═S)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , -(alkylene) m -OC(═S)NR 5 R 5a , -(alkylene) m -SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )SO 2 R 4 , -(alkylene) m -N(R 5 )SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )C (═O)OR 4 , -(alkylene) m -N(R 5 )C(═S)OR 4 , or -(alkylene) m -N(R 5 )SO 2 R 4 ;

m is 0 or 1;

n is 0, 1 or 2;

q and t are each independently 0 or 1;

v is 0, 1 or 2.

2. A compound of claim 1 wherein R 1 is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence.

3. A compound of claim 1 wherein R 2 is phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence.

4. A compound of claim 1 having the following formula IIC

enantiomers, diastereomers, or a pharmaceutically acceptable salt thereof wherein

q is 0, 1, 2 or 3;

n* is 0, 1 or 2;

t* is 0 or 1

U 1 , U 2 , U 3 and U 4 are each independently C, or N;

R 10c at each occurrence are independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,

heterocycloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -S(O) v R 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m —C(═O)R 4 , -(alkylene) m -C(═S)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O) R 4 , -(alkylene) m -C(═S)OR 4 ,

-(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -N(R 5 ) C(═S)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , -(alkylene) m -OC(═S)NR 5 R 5a , -(alkylene) m -SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )SO 2 R 4 , -(alkylene) m -N(R 5 )SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )C (═O)OR 4 , -(alkylene) m -N(R 5 )C(═S)OR 4 , or -(alkylene) m -N(R 5 )SO 2 R 4 ;

more -(alkylene) m -OR 4 , -(alkylene) m -S(O) v R 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylenc) m -C(═S)R 4 , -(alkylenc) m -C(═O)OR 4 , -(alkylene) m -OC(═O)R 4 , -(alkyl ene) m -C(═S)OR 4 ,

-(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -C(═S)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═S)NR 5 R 5a , -(alkylcne) m -N(R 5 )C(═O)R 4 , -(alkylene) m -N(R 5 ) C(═S)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , -(alkylene) m -OC(═S)NR 5 R 5a , -(alkylene) m -SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )SO 2 R 4 , -(alkylene) m -N(R 5 )SO 2 NR 5 R 5a , -(alkylene) m -N(R 5 )C (═O)OR 4 , -(alkylene) m -N(R 5 )C(═S)OR 4 , or -(alkylene) m -N(R 5 )SO 2 R 4 ;

v is 0, 1 or 2.

5. A compound of claim 4 wherein n* is 0 or 1, and t* is 1.

6. A compound of claim 4 wherein n* is 1 and t* is 0.

7. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable vehicle or carrier.

8. A method of treating cancer in a subject, said method comprising administering an effective amount of a compound as in claim 1 , wherein cancer is adenocarcinoma, gastric cancer or glioma.

9. A compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the compound is

Continuity (5)

Division 13309488 · Dec 1, 2011

Division 12009123 · Jan 15, 2008

Continuation In Part 11879034 · Jul 13, 2007

Provisional Application 60830882 · Jul 14, 2006

Related Publication 20130303529A1 · Nov 14, 2013