US2012107275A1PendingUtilityA1
Fused heterocyclic derivatives and methods of use
Est. expiryJul 14, 2026(~0 yrs left)· nominal 20-yr term from priority
Inventors:Brian K. AlbrechtDavid BauerSteven BellonChristiane M. BodeShon BookerAlessandro BoezioDeborah ChoquetteDerin D'AmicoJean-Christophe HarmangeSatoko HiraiRandall W. HungateTae-Seong KimRichard T. LewisLongbin LiuJulia LohmanMark H. NormanMichele PotashmanAaron C. SiegmundStephanie SpringerMarkian StecNing XiKevin Yang
A61P 37/00A61P 5/00C07D 495/04C07D 498/04C07D 519/00A61P 3/00A61P 35/00C07D 471/04A61P 31/00C07D 487/04C07D 493/04
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Claims
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
exact text as granted — not AI-modified1 . A compound of formula I, II, III, IV, V, VI or VII
or an enantiomer, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof
wherein
J is N or CR 3 ;
W is N or CR 2b ;
W* is N or CR 2b ;
X is O or S;
Z and Z* are independently —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 3-10membered 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 3-10membered 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;
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 valance;
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 , —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,
provided that in compounds of formula I when W and J are both N, R 2 is other than
(c) —NR 5 R 5a where R 5 and R 5a are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl; and
(d) phenyl substituted with a group
where G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
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, —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 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 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 valance.
3 . A compound of claim 2 wherein R 2 is H, halo, cyano, alkynyl, —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 valance.
4 . A compound of claim 1 wherein R 1 is selected from
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
5 . A compound of claim 3 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 valance; 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.
6 . A compound of any of claim 1 having a formula IA, IB, IC, ID, or IIA
or an enantiomer, a diastereomer, a pharmaceutically acceptable salt or solvate thereof
7 . A compound of claim 6 wherein R 1 groups are either unsubstituted or independently substituted as allowed by valance 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 .
8 . A compound of claim 7 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.
9 . A compound of claim 8 wherein R 1 is
10 . A compound having the following formula IE, IF, IIB or IIC
or an enantiomer, a diastereomer, a pharmaceutically acceptable salt or solvate 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;
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 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 3-10membered 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 3-10membered 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;
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 , —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 as allowed by valance,
provided that in compounds of formula IE, R 2 is not a phenyl substituted with a group
where G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
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 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 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 ;
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 ;
v is 0, 1 or 2.
11 . A compound of claim 10 having formula IEi, IEii, IEiii, IEiv, IFi, IFii, IFiii or IFiv
or an enantiomer, a diastereomer, a pharmaceutically acceptable salt or solvate thereof.
12 . A compound of claim 11 wherein R 2 is H, halo, cyano, alkynyl, —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 valance.
13 . A compound of claim 11 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 valance; 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.
14 . A compound of claim 13 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 .
15 . A compound of claim 10 wherein n* is 0 or 1 and t* is 1;
16 . A compound of claim 10 wherein n* is 1 and t* is 0.
17 . A compound of claim 10 selected from
or a pharmaceutically acceptable salt thereof.
18 . A compound of claim 10 selected from
or a pharmaceutically acceptable salt thereof.
19 . A compound of claim 1 having the following formula IEA or IFA
or an enantiomer, a diastereomer 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;
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 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 3-10membered 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 3-10membered 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;
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 , —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 as allowed by valance,
provided that in compounds of formula IEA, R 2 is not a phenyl substituted with a group
where G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
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 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 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 ;
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 ;
v is 0, 1 or 2.
20 . A compound of claim 19 having formula IEAi, IEAii, IEAiii, IFAi, IFAii or IFAiii
or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof.
21 . A compound of claim 20 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 valance; 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.
22 . A compound of claim 21 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)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 .
23 . A compound of claim 19 wherein n* is 0 or 1 and t* is 1;
24 . A compound of claim 19 wherein n* is 1 and t* is 0.
25 . A compound of claim 19 selected from
or a pharmaceutically acceptable salt thereof.
26 . A compound of claim 19 having a formula IG or IH
wherein
U is CR 10c or N;
Z* is absent, CH 2 , —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 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 3-10membered 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 3-10membered 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;
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 , —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 as allowed by valance,
provided that in compounds of formula IG R 2 is not phenyl substituted with a group
where G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
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 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 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 ;
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 ;
R 10 , R 10b and R 10c are each 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)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 ; and
v is 0, 1 or 2.
27 . A compound of claim 26 selected from
or a pharmaceutically acceptable salt thereof.
28 . A compound of claim 26 selected from
or a pharmaceutically acceptable salt thereof.
29 . A compound of claim 6 selected from
or a pharmaceutically acceptable salt thereof.
30 . A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable vehicle or carrier.
31 . A method of treating cancer in a subject, said method comprising administering an effective amount of a compound as in claim 1 .
32 . The method of claim 31 wherein said compound of claim 1 is administered in combination with at least one compound selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and miscellaneous agents.
33 . A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound as in claim 1 .
34 . A compound of claim 1 wherein R 1 is an oxo-substituted heteroaryl or oxo-substituted heterocyclo selected from naphthyridinonyl, dihydronaphthyridinonyl, pyridopyrimidinonyl, dihydropyridopyrimidinonyl, imidazopyridinonyl, dihydroimidazopyridinonyl, oxazolopyridinonyl, dihydrooxazolopyridinonyl, thiazolopyridinonyl, dihydrothiazolopyridinonyl, pyrazolopyrazinonyl, dihydropyrazolopyrazinonyl, triazolopyrazinonyl, dihydrotriazolopyrazinonyl, triazolopyridinonyl or dihydrotriazolopyridinonyl any of which may be optionally further independently substituted with one or more R 10 groups as allowed by valance.
35 . A compound of claim 34 wherein R 1 is
a is a bond or is absent;
U 5 is C or N;
U 6 is NH, O or S;
m+ is 0,1, 2 or 3.
36 . A compound of claim 35 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 , —N(R 5 )C(═O)NR 5 R 5a , 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 valance.
37 . A compound of claim 35 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 valance; 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.
38 . A compound of claim 35 having the following formula IG
or an enantiomer, a diastereomer or a pharmaceutically acceptable salt 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 3-10membered 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 3-10membered 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.
39 . A compound of claim 38 wherein q and n are each zero, and a is a bond.
40 . A compound of claim 39 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 valance; 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.
41 . A compound of claim 35 having the following formula IH
or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof wherein
a is a bond or is absent;
U 6 is NH, O or S;
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 3-10membered 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 3-10membered 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, —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 1 is aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted with one or more R 10 groups as allowed by valance;
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 10z ;
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.
42 . A compound of claim 41 wherein q and n are each zero, and a is a bond.
43 . A compound of claim 41 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 valance.
44 . A compound of claim 43 selected from
44 . A compound of claim 6 selected from
45 . A compound of claim 1 having formula VII selected fromCited by (0)
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