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 having the following formula IG
an enantiomer, a diastereomer, or a pharmaceutically acceptable salts thereof wherein a is a bond or is absent;
U 5 is C or N;
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 valance;
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 valance;
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 valance;
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 valance;
or R a and R b may combine to form a carbonyl group;
or R c and R d attached to the same carbon atom may combine to form a carbonyl group; provided that when q is 1, R a and R b are independently other than halo, —NO 2 , —CN, —NR 5 R 5a , —OR 4 , —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 :
R 2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —OR 4 , —NR 5 R 5a , —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 as allowed by valance,
R 2a and R 2b 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 valance;
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 valance 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 valance 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 10d 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;
n+ is 0, 1, 2 or 3;
q is 0 or 1;
v is 0, 1 or 2.
2. A compound of claim 1 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof wherein q and n are each zero, and a is a bond.
3. A compound of claim 1 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof wherein R 2 is H, halo, cyano, alkynyl, —NR 5 R 5a , —C(═O)NR 5 R 5a , —N(R 5 )C(═O)R 4 , —N(R 5 )C(═O)OR 4 , 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 3 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof wherein R 2 is
(a) halo, alkynyl, —C(═O)NR 5 R 5a , —N(R 5 )C(═O)R 4 or —N(R 5 )C(═O)OR 4 any of which may be optionally independently substituted with one or more R 10 groups as allowed by valence or
(b) an aryl, heteroaryl or heterocyclo ring system selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
5. A compound or a pharmaceutically acceptable salt thereof selected from:
6. A compound of claim 2 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently H and alkyl.
7. A compound of claim 6 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein alkyl is methyl.
8. A compound of claim 4 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
9. A compound of claim 8 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein R 10 is alkyl and m* is 1.
10. A compound of claim 9 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected at each occurrence from H, halo and alkyl.
11. A compound of claim 10 , an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof, wherein U 5 is C.
12. A pharmaceutical composition comprising a compound according to claim 1 or 5 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable vehicle or carrier.
13. A method of treating cancer, wherein cancer is glioma, adenocarcinoma, breast or gastric cancer in a subject, said method comprising administering an effective amount of a compound according to claim 1 or 5 , or a pharmaceutically acceptable salt thereof.
14. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
15. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
16. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
17. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
18. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
19. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
20. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
21. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
22. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
23. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
24. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
25. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
26. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
27. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
28. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
29. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
30. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
31. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
32. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
33. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
34. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
35. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
36. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, that is
37. A pharmaceutical composition comprising a compound according to any one of claims 14 - 36 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable vehicle or carrier.
38. A method of treating cancer, wherein the cancer is glioma, adenocarcinoma, breast or gastric cancer in a subject, said method comprising administering an effective amount of a compound according to any one of claims 14 - 36 , or a pharmaceutically acceptable salt thereof.