Fused heterocyclic derivatives and methods of use
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.
1. A compound of formula I
an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof wherein
J is N:
W is CR 2b ;
Z is —O—, or —NR 5 ;
Z* is —O—, —S(O) v —, or —NR 5 —;
R a , R b , R c and R d are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, —NO 2 , —CN, —NR 5 R 5a , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 ; —C(═O)NR 5 R 5a , —N(R 5 )C(═O)NR 5 R 5a , —OC(═O)NR 5 R 5a , —S(O) v R 4 , —S(O) 2 NR 5 R 5a , —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;
or R a and R b together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R c and R d together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R a and/or R b may combine with any R c or R d to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R c and R d attached to the same carbon atom may combine to form a carbonyl group;
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 cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, any of which may be optionally independently substituted with one or more R 10 as allowed by valence,
R 2a , and 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 , —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 ;
or R 5 and R 5a may combine to form a heterocyclo ring optionally substituted with one or more R 10 ;
R 10 at each occurrence is 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 ;
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 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 ;
and further wherein any two R 10 groups attached to the same atom or attached to adjacent atoms may combine to form an optionally substituted 3- to 8 membered ring system;
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 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoismazolyl, 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 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, 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 2 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, 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, benzoffiranyl, 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.
5. A compound of claim 2 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
6. A compound of claim 3 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl, heteroaryl or heterocyelo ring system selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
7. A compound of claim 5 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl, heteroaryl or heterocyclo ring system selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
8. A compound of claim 1 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, having a formula IB
9. A compound of claim 8 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 groups are either unsubstituted or independently substituted as allowed by valence with one or more halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O)R 4 , -(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , or -(alkylene) m -N(R 5 )C(═O)OR 4 .
10. A compound ol' claim 9 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 groups are selected from
where R 10a , R 10b , R 10y and R 10z are independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O)R 4 , -(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , or -(alkylene) m -N(R 5 )C(═O)OR 4 ;
or where R 10a and R 10b combine to form an optionally substituted 3- to 8-membered ring system.
11. A compound of claim 10 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is
12. A compound of claim 1 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, having the following formula IF
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;
Z* is —O—, —S(O) v , or —NH;
R a , R b , R c and R d are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, —NO 2 , —CN, —NR 5 R 5a , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 ; —C(═O)NR 5 R 5a , —N(R 5 )C(═O)NR 5 R 5a , —OC(═O)NR 5 R 5a , —S(O) v R 4 ,
or R a and R b together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R c and R d together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R a and/or R b may combine with any R c or R d to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R c and R d attached to the same carbon atom may combine to form a carbonyl group;
R 2 is cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, any or which may be optionally independently substituted with one or more R 10 as allowed by valence;
R 2a and R 2b are independently selected from H, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy;
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 ;
or R 5 and R 5a may combine to form a heterocyclo ring optionally substituted with one or more R 10 ;
R 10 and 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 , 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 R 5a , -(alkylene) m -N(R)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 ;
v is 0, 1 or 2.
13. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, having formula IFi, IFii, IFiii or IFiv
14. A compound of claim 13 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 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, pyrazolopvridazinyl, 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.
15. A compound of claim 14 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl, heteroaryl or heterocyclo ring system selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
16. A compound of claim 15 , an enantiomer, a diastereomcr, or a pharmaceutically acceptable salt thereof, wherein R 10c at each occurrence is independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═O)OR 4 , -(alkylene) m -OC(═O)R 4 , -(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , or -(alkylene) m -N(R 5 )C(═O)OR 4 .
17. A compound of claim 12 , an enantiomer, a diastereomcr, or a pharmaceutically acceptable salt thereof, wherein n* is 0 or 1, and t* is 1.
18. A compound of claim 12 , an enantiomer, a diastereomcr, or a pharmaceutically acceptable salt thereof, wherein n* is 1 and t* is 0.
19. A compound of claim 1 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, having the following formula IFA
wherein
q is 0, 1, 2 or 3;
n* is 0, 1 or 2;
t* is 0 or 1
U 1 U 2 and U 3 are each independently C, or N;
Z* is —O—, —S(O) v —, or —NH—;
R a , R b , R c and R d are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, —NO 2 , —CN, —NR 5 R 5a , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 ; —C(═O)NR 5 R 5a , —N(R 5 )C(═O)NR 5 R 5a , —OC(═O)NR 5 R 5a , —S(O) v R 4 , —S(O) 2 NR 5 R 5a , —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;
or R a and R b together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R c and R d together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R a and/or R b may combine with any R c or R d to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R 10 groups as allowed by valence;
or R C and R d attached to the same carbon atom may combine to form a carbonyl group;
R 2 is
cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, any of which may be optionally independently substituted with one or more R 10 as allowed by valence,
R a and R 2b are independently selected from H, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy;
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 ;
or R 5 and R 5a may combine to form a heterocyclo ring optionally substituted with one or more R 10 ;
R 10 and 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 5 a, -(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 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)SO 2 NR 5 R 5a , -(alkylene) m -N(R)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.
20. A compound of claim 19 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, having formula IFAi, IFAii or IFAiii
21. A compound of claim 20 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinvl, pyridazinyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofururanyl, 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 henzoisothiazolyl any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence.
22. A compound of claim 21 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl, heteroaryl or heterocyclo ring system selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
23. A compound of claim 22 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 10c at each occurrence is independently H, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene) m -OR 4 , -(alkylene) m -NR 5 R 5a , -(alkylene) m -C(═O)R 4 , -(alkylene) m -C(═O)R 4 , -(alkylene) m -OC(═O)R 4 , -(alkylene) m -C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)NR 5 R 5a , -(alkylene) m -N(R 5 )C(═O)R 4 , -(alkylene) m -OC(═O)NR 5 R 5a , or -(alkylene) m -N(R 5 )C(═O)OR 4 .
24. A compound of claim 19 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein n* is 0 or 1, and t* is 1.
25. A compound of claim 19 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein n* is 1 and t* is 0.
26. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable vehicle or carrier.
27. A method of treating cancer, wherein cancer is glioma, or gastric cancer in a subject, said method comprising administering an effective amount of a compound as in claim 1 , or a pharmaceutically acceptable salt thereof.
28. A compound of claim 1 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
29. A compound of claim 28 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
30. A compound of claim 28 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 10 is alkyl.
31. A compound of claim 30 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 2b is halo.
32. A compound of claim 31 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently alkyl.
33. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
34. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
35. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
36. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
37. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
38. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
39. A compound of claim 12 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
40. A pharmaceutical composition comprising a compound as in any one of claims 33 - 39 together with a pharmaceutically acceptable vehicle or carrier.
41. A method of treating cancer, wherein cancer is glioma, or gastric cancer in a subject, said method comprising administering an effective amount of a compound as in any one of claims 33 - 39 , or a pharmaceutically acceptable salt thereof
42. A compound of claim 19 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of
43. A compound of claim 42 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
44. A pharmaceutical composition comprising the compound of claim 43 together with a pharmaceutically acceptable vehicle or carrier.
45. A method of treating cancer, wherein cancer is glioma, or gastric cancer in a subject, said method comprising administering an effective amount of the compound of claim 43 or a pharmaceutically acceptable salt thereof
46. A compound of claim 42 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
47. A pharmaceutical composition comprising the compound of claim 46 together with a pharmaceutically acceptable vehicle or carrier.
48. A method of treating cancer, wherein cancer is glioma, or gastric cancer in a subject, said method comprising administering an effective amount of the compound of claim 46 or a pharmaceutically acceptable salt thereof
49. A compound of claim 42 , an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, that is
50. A pharmaceutical composition comprising the compound of claim 49 together with a pharmaceutically acceptable vehicle or carrier.
51. A method of treating cancer, wherein cancer is glioma, or gastric cancer in a subject, said method comprising administering an effective amount of the compound of claim 49 or a pharmaceutically acceptable salt thereof