Fused heterocyclic compounds
View Patent ↗This invention provides fused heterocyclic compounds, pharmaceutical compositions of the compounds, and methods of using the compounds for the treatment of, inter alia, IL-12 related disease and disorders.
1. A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof;
wherein:
U and V are N;
Ring D is a phenyl which may be further substituted with one or more substituents;
A 2 is —X—R′-L′-R″ and A 1 is a group represented by the following formula:
Z is N;
W is O;
u is 0, 1, 2, 3, or 4;
X is O, S, S(O), S(O) 2 , N(R k ), C(O), C(S), C(S)NR k , C(NR), C(NR)NR k , C(O)NR k , C(O)NR k NR k , C(O)ONR k , C(O)NR k O, C(O)O, OC(O), OC(O)O, (C(R g )(R g )) m , (C(R g )(R g )) m NR k , (C(R g )(R g )) m O, (C(R g )(R g )) m S(O) p , (C(R g )(R g )) m N═C(R g ), C(R g )═N, C(R g )═N—O, C(R g )═N—S(O) p , C(R g )═N—NR k , C(R g )═N—C(CR g ) 2 , (C(R g )(R g )) m C(R g )═N, (C(R g )(R g )) m N═N, (C(R g )(R g )) m C(R g )═C(R g ), C(R g )═C(R g ), N═C(R g ), N(R k )N═C(R g ), N(R k )C(R g )═N, N(R k )C(R g )═C(R g ), N═N, N(R k )N═N, NR k C(O)NR k , NR k C(S)NR k , NR k C(O), NR k C(O)O, NR k C(NR)NR k , NR k C(S)O, NR k S(O) p NR k , OC(O)NR k , OC(S)NR k , OC(NR)NR k , OS(O) p NR k , C(NR)O, S(O) p NR k , or S(O) p NR k NR k ;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —C(O)R c , —OR k , —SR k , —NR h R j , hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or —S(O) 2 R c ;
R′ is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L′ is O, S, S(O), S(O) 2 , N(R k ), C(O), C(S), C(S)NR k , C(NR), C(NR)NR k , C(O)NR k , C(O)NR k NR k , C(O)ONR k , C(O)NR k O, C(O)O, OC(O), OC(O)O, (C(R g )(R g )) m , (C(R g )(R g )) m NR k , (C(R g )(R g )) m O, (C(R g )(R g )) m S(O) p , (C(R g )(R g )) m N═C(R g ), C(R g )═N, C(R g )═N—O, C(R g )═N—S(O) p , C(R g )═N—NR k , C(R g )═N—C(CR g ) 2 , (C(R g )(R g )) m C(R g )(R g )═N, (C(R g )(R g )) m N═N, (C(R g )(R g )) m C(R g )═C(R g ), C(R g )═C(R g ), N═C(R g ), N(R k )N═C(R g ), N(R k )C(R g )═N, N(R k )C(R g )═C(R g ), N═N, N(R k )N═N, NR k C(O)NR k , NR k C(S)NR k , NR k C(O), NR k C(O)O, NR k C(NR)NR k , NR k C(S)O, NR k S(O) p NR k , OC(O)NR k , OC(S)NR k , OC(NR)NR k , OS(O) p NR k , C(NR)O, S(O) p NR k , S(O) p NR k NR k or absent; and
R″ is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R k )(CH 2 ) n R g , —OR k , —SR k , —NR h R j , hydroxylalkyl, —C(O)R c , —C(S)R c , —C(NR)R c , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, —S(O)R c , —S(O) 2 R c , —P(O)R c R c , —P(S)R c R c , or an optionally substituted alkylcarbonylalkyl;
R c is, independently for each occurrence, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
R g , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c ,—OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , —P(O)R c R c , halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
R h and R j , for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R h and R j taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
R k , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
m, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; and
p, for each occurrence, is independently 0, 1, or 2;
Y is (CH(R g )) m , C(O), C(NR), O, S, S(O), S(O) 2 , N(R k ), or absent;
R 3 is R g , —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , or —P(O)R c R c ;
R 2 and R 4 are, independently for each occurrence, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , —P(O)R c R c , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R 2 and R 4 taken together are ═O, ═S, or ═NR;
G is:
Hydrazide;
Hydrazone;
Hydrazine;
Hydroxylamine;
Oxime;
Amide;
Ester;
Carbonate;
Carbamate;
Thiocarbamate;
—NR k —C(NR)—NR k —;
—NR k —C(O)—NR k —;
—NR k —C(S)—NR k —;
—NR k —S(O) 2 —NR k —;
Phosphoryl;
an optionally substituted -Cyclyl-;
an optionally substituted -Heterocyclyl-;
an optionally substituted -Aryl-;
an optionally substituted -Heteroaryl-;
an optionally substituted -Heteroarylalkyl-;
an optionally substituted -Heteroaryl-NR k —;
an optionally substituted -Heteroaryl-S—;
an optionally substituted -Heteroarylalkyl-O—;
—Si(OR k ) 2 —;
—B(OR k )—
—C(NR)—NR k —;
—N(R k )—CR g R g —C(O)—;
—C(O)—ON(R k )—;
—C(O)—N(R k )O—;
—C(S)—ON(R k )—;
—C(S)—N(R k )O—;
—C(N(R k ))—ON(R k )—;
—C(N(R k ))—NR k O—;
—OS(O) 2 —N(R k )N(R k )—;
—OC(O)—N(R k )N(R k )—;
—OC(S)—N(R k )N(R k )—;
—OC(N(R k ))—N(R k )N(R k )—;
—N(R k )N(R k )S(O) 2 O—;
—N(R k )N(R k )C(S)O—;
—N(R k )N(R k )C(N(R k ))O—;
—OP(O)(R c )O—;
—N(R k )P(O)(R c )O—;
—OP(O)(R c )N(R k )—;
—N(R k )P(O)(R c )N(R k )—;
—P(O)(R c )O—;
—P(O)(R c )N(R k )—;
—N(R k )P(O)(R c )—;
—OP(O)R c )—;
—O-alkyl-heterocyclyl-N(R k )—;
—N(R k )CHR g C(O)N(R k )CHR g C(O)—;
—N(R k )CHR g C(O)—;
—N(R k )C(O)CHR g —;
—C(O)N(R k )CHR g C(O)—;
or absent;
n, for each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, or 7; and
wherein when G is absent, R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , or NR h R j .
2. The compound of claim 1 , wherein the compound is represented by the following structural formula:
wherein:
X 1 , X 2 and X 3 are each, CR g .
3. The compound of claim 2 , wherein R′ and L′ are absent.
4. The compound of claim 3 , wherein R″ is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
5. The compound of claim 4 , wherein R″ is an optionally substituted aryl or an optionally substituted heteroaryl.
6. The compound of claim 5 , wherein R″ is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, —NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, —S(O) p R c , and —C(O)R c .
7. The compound of claim 4 , wherein Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is 0, 1, 2, 3, or 4.
8. The compound of claim 7 , wherein G is absent.
9. The compound of claim 7 , wherein G is >C═N—R, —NR k C(O)—, —C(O)NR k —, —OC(O)—, —C(O)O—, —OC(O)O—, —NR k C(O)O—, —OC(O)NR k —, —NR k C(S)O—, —OC(S)NR k —, —NR k C(NR)NR k —, —NR k C(O)NR k —, —NR k C(S)NR k —, —NR k S(O) 2 NR k —, —C(NR)NR k —, or —NR k CR g R g C(O)—.
10. The compound of claim 8 , wherein R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , or NR h R j .
11. The compound of claim 10 , wherein R 3 is optionally substituted aryl or optionally substituted heteroaryl.
12. The compound of claim 11 , wherein R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzo[1,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally, substituted triazinyl, an optionally substituted triazolyl an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
13. The compound of claim 10 , wherein R 3 is an optionally substituted heterocycloalkyl.
14. The compound of claim 13 , wherein R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [1,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
15. The compound of claim 10 , wherein R 3 is —OR k or —NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or —C(O)R c .
16. The compound of claim 8 , wherein R 3 is —C(O)OR k , —OC(O)R k , —C(O)NR h k j , —NR k C(O)R k , —C(S)OR k , —OC(S)R k , —NR k C(O)NR h R j , —NR k C(S)NR h R j , —C(O)NR h R j , —S(O) 2 R k , —S(O) 2 NR h R j , —OC(O)NR h R j , or —NR k C(O)OR k .
17. A compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein,
Ring D is a phenyl which may be further substituted with one or more substituents;
U and V are each N;
Z is N;
W is O;
u is 0, 1, 2, 3, or 4;
X is O, S, S(O), S(O) 2 , N(R k ), C(O), C(S), C(S)NR k , C(NR), C(NR)NR k , C(O)NR k , C(O)NR k , C(O)NR k NR k , C(O)ONR k , C(O)NR k O, C(O)O, OC(O), OC(O)O, (C(R g )(R g )) m , (C(R g )(R g )) m NR k , (C(R g )(R g )) m O, (C(R g )(R g )) m S(O) p , (C(R g )(R g )) m N═C(R g ), C(R g )═N, C(R g )═N—O, C(R g )═N—S(O) p , C(R g )═N—NR k , C(R g )═N—C(CR g ) 2 , (C(R g )(R g )) m C(R g )═N, (C(R g )(R g )) m N═N, (C(R g )(R g )) m C(R g )═C(R g ), C(R g )═C(R g ), N═C(R g ), N(R k )N═C(R g ), N(R k )C(R g )═N, N(R k )C(R g )═C(R g ), N═N, N(R k )N═N, NR k C(O)NR k , NR k C(S)NR k , NR k C(O), NR k C(O)O, NR k C(NR)NR k , NR k C(S)O, NR k S(O) p NR k , OC(O)NR k , OC(S)NR k , OC(NR)NR k , OS(O) p NR k , C(NR)O, S(O) p NR k , or S(O) p NR k NR k ;
w is 0 or 1;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —C(O)R c , —OR k , —SR k , —NR h R j , hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or —S(O) 2 R c ;
R′ is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally Substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L′ is O, S, S(O), S(O) 2 , N(R k ), C(O), C(S), C(S)NR k , C(NR), C(NR)NR k , C(O)NR k , C(O)NR k NR k , C(O)ONR k , C(O)NR k O, C(O)O, OC(O), OC(O)O, (C(R g )(R g )) m , (C(R g )(R g )) m NR k , (C(R g )(R g )) m O, (C(R g )(R g )) m S(O) p , (C(R g )(R g )) m N═C(R g ), C(R g )═N, C(R g )═N—O, C(R g )═N—S(O) p , C(R g )═N—NR k , C(R g )═N—C(CR g ) 2 , (C(R g )(R g )) m C(R g )═N, (C(R g )(R g )) m N═N, (C(R g )(R g )) m C(R g )═C(R g ), C(R g )═C(R g ), N═C(R g ), N(R k )N═C(R g ) N(R k )C(R g )═N, N(R k )C(R g )═C(R g ), N═N, N(R k )N═N, NR k C(O)NR k , NR k C(S)NR k , NR k C(O), NR k C(O)O, NR k C(NR)NR k , NR k C(S)O, NR k S(O) p NR k , OC(O)NR k , OC(S)NR k , OC(NR)NR k , OS(O) p NR k , C(NR)O, S(O) p NR k , S(O) p NR k NR k or absent; and
R″ is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R k )(CH 2 ) n R g , —OR k , —SR k , —NR h R j , hydroxylalkyl, —C(O)R c , —C(S)R c , —C(NR)R c , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, —S(O)R c , —S(O) 2 R c , —P(O)R c R c , —P(S)R c R c , or an optionally substituted alkylcarbonylalkyl;
Y is (CH(R g )) m , C(O), C(NR), O, S, S(O), S(O) 2 , N(R k ), or absent,
R 3 is R g , —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , or —P(O)R c R c ;
R 2 and R 4 are, independently for each occurrence, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , —P(O)R c R c , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R 2 and R 4 taken together are ═O, ═S, or ═NR;
R c , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
R g , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R c , —OC(O)R c , —SC(O)R c , —NR k C(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NR k C(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NR k C(NR)R c , —SO 2 R c , —S(O)R c , —NR k SO 2 R c , —OS(O) 2 R c , —OP(O)R c R c , —P(O)R c R c , halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
R h and R j , for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R h and R j taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
R k , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl;
G is:
Hydrazide;
Hydrazone;
Hydrazine;
Hydroxylamine;
Oxime;
Amide;
Ester;
Carbonate;
Carbamate;
Thiocarbamate;
—NR k —C(NR)—NR k —;
—NR k —C(O)—NR k —;
—NR k —C(S)—NR k —;
—NR k —S(O) 2 —NR k —;
Phosphoryl;
an optionally substituted -Cyclyl-;
an optionally substituted -Heterocyclyl-;
an optionally substituted -Aryl-;
an optionally substituted -Heteroaryl-;
an optionally substituted -Heteroarylalkyl-;
an optionally substituted -Heteroaryl-NR k —;
an optionally substituted -Heteroaryl-S—;
an optionally substituted -Heteroarylalkyl-O—;
—Si(OR k ) 2 —;
—B(OR k )—
—C(NR)—NR k —;
—N(R k )—CR g R g —C(O)—;
—C(O)—ON(R k )—;
—C(O)—N(R k )O—;
—C(S)—ON(R k )—;
—C(S)—N(R k )O—;
—C(N(R k ))—ON(R k )—;
—C(N(R k ))—NR k O—;
—OS(O) 2 —N(R k )N(R k )—;
—OC(O)—N(R k )N(R k )—;
—OC(S)—N(R k )N(R k )—;
—OC(N(R k ))—N(R k )N(R k )—;
—N(R k )N(R k )S(O) 2 O—;
—N(R k )N(R k )C(S)O—;
—N(R k )N(R k )C(N(R k ))O—;
—OP(O)(R c )O—;
—N(R k )P(O)(R c )O—;
—OP(O)(R c )N(R k )—;
—N(R k )P(O)(R c )N(R k )—;
—P(O)(R c )O—;
—P(O)(R c )N(R k )—;
—N(R k )P(O)(R c )—;
—OP(O)(R c )—;
—O-alkyl-heterocyclyl-N(R k )—;
—N(R k )CHR g C(O)N(R k )CHR g C(O)—;
—N(R k )CHR g C(O)—;
—N(R k )C(O)CHR g —;
—C(O)N(R k )CHR g C(O)—;
or absent, each of which is optionally substituted;
m, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8;
n, for each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, or 7;
p, for each occurrence, is independently 0, 1, or 2;
wherein if w is 0 and R′ and L′ are absent, then R″ is an optionally substituted cycloalkyl, an optional substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
18. The compound of claim 17 , wherein w is 0, and R′ and L′ are absent.
19. The compound of claim 18 , wherein R″ is an optionally substituted aryl or an optionally substituted heteroaryl.
20. The compound of claim 19 , wherein R″ is substitituted with one or more substituents selected from the group consisting of a lower alkyl, cyano, halo, nitro, —NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, —S(O) p R c , and —C(O)R c .
21. The compound of claim 18 , wherein Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is 0, 1, 2, 3, or 4.
22. The compound of claim 21 , wherein G is absent.
23. The compound of claim 21 , wherein G is >C═N—R, —NR k C(O)—, —C(O)NR k —, —OC(O)—, —C(O)O—, —OC(O)O—, —NR k C(O)O—, —OC(O)NR k —, —NR k C(S)O—, —OC(S)NR k —, —NR k C(NR)NR k —, —NR k C(O)NR k —, —NR k C(S)NR k —, —NR k S(O) 2 NR k —, —C(NR)NR k —, or —NR k CR g R g C(O)—.
24. The compound of claim 22 , wherein R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , or NR h R j .
25. The compound of claim 24 , wherein R 3 is optionally substituted aryl or optionally substituted heteroaryl.
26. The compound of claim 25 , wherein R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzo[1,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an Optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
27. The compound of claim 24 , wherein R 3 is an optionally substituted heterocycloalkyl.
28. The compound of claim 27 , wherein R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [1,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
29. The compound of claim 24 , wherein R 3 is —OR k or —NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or —C(O)R c .
30. The compound of claim 22 , wherein R 3 is —C(O)OR k , —OC(O)R k , —C(O)NR h R j , —NR k C(O)R k , —C(S)OR k , —OC(S)R k , —NR k C(O)NR h R j , —NR k C(S)NR h R j , —C(O)NRhRj, —S(O) 2 R k , —S(O) 2 NR h R j , —OC(O)NR h R j , or —NR k C(O)OR k .
31. The compound of claim 17 , wherein:
w is 1;
X is O, S, or NR k ; and
R′ and L′ are absent.
32. The compound of claim 31 , wherein R″ is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
33. The compound of claim 32 , wherein R″ is an optionally substituted aryl or an optionally substituted heteroaryl.
34. The compound of claim 33 , wherein R″ is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, —NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, or —C(O)R y , wherein R y is a lower alkyl.
35. The compound of claim 32 , wherein Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is 0, 1, 2, 3, or 4.
36. The compound of claim 35 , wherein G is absent.
37. The compound of claim 35 , wherein G is >C═N—R, —NR k C(O)—, —C(O)NR k —, —OC(O)—, —C(O)O—, —OC(O)O—, —NR k C(O)O—, —OC(O)NR k —, —NR k C(S)O—, —OC(S)NR k —, —NR k C(NR)NR k —, —NR k C(O)NR k —, —NR k C(S)NR k —, —NR k S(O) 2 NR k —, —C(NR)NR k —, or —NR k CR g R g C(O)—.
38. The compound of claim 36 , wherein R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , or NR h R j .
39. The compound of claim 38 , wherein R 3 is optionally substituted aryl or optionally substituted heteroaryl.
40. The compound of claim 39 , wherein R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzo[1,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
41. The compound of claim 38 , wherein R 3 is an optionally substituted heterocycloalkyl.
42. The compound of claim 41 , wherein R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [1,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
43. The compound of claim 38 , wherein R 3 is —OR k or —NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or —C(O)R c .
44. The compound of claim 36 , wherein R 3 is —C(O)OR k , —OC(O)R k , —C(O)NR h R j , —NR k C(O)R k , —C(S)OR k , —OC(S)R k , —NR k C(O)NR h R j , —NR k C(S)NR h k j , —C(O)NRhRj, —S(O) 2 R k , —S(O) 2 NR h R j , —OC(O)NR h R j , or —NR k C(O)OR k .
45. A compound selected from the group consisting of:
N-(6,7-Dimethoxy-4-morpholin-4-yl-quinazolin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine;
(6,7-Dimethoxy-4-morpholin-4-yl-quinazolin-2-yl)-(2,3-dimethyl-1H-indol-5-yl)-amine;
2-(2-Methoxy-ethoxy)-4-morpholin-4-yl-6-m-tolyl-quinazoline;
[4-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-quinazolin-6-yl]-phenyl-amine;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-m-tolyl-quinazoline;
4-Morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-6-m-tolyl-quinazoline;
2-Methyl-1-(4-morpholin-4-yl-6-m-tolyl-quinazolin-2-yloxy)-propan-2-ol;
2-(4-Morpholin-4-yl-6-m-tolyl-quinazolin-2-yloxy)-ethanol;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-phenyl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-(3-trifluoromethyl-phenyl)-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-p-tolyl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-(5-methyl-thiophen-2-yl)-4-morpholin-4-yl-quinazoline;
3-{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazolin-6-yl}-benzonitrile
3-{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazolin-6-yl}-benzamide;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-(3-methoxy-phenyl)-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-(3,4-dimethyl-phenyl)-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-(3,5-dimethyl-phenyl)-4-morpholin-4-yl-quinazoline;
6-Benzofuran-2-yl-2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-phenoxy-quinazoline;
6-(4-Chloro-phenyl)-2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-(4-methoxy-phenyl)-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-(4-trifluoromethyl-phenyl)-quinazoline;
6-(4-Fluoro-phenyl)-2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazoline;
6-(2-Chloro-phenoxy)-2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazoline;
6-(3-Chloro-phenoxy) -2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazoline;
2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-6-p-tolyloxy-quinazoline;
4-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-p-tolyl-quinazoline;
6-(4-Fluoro-phenyl)-4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-quinazoline;
{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazolin-6-yl}-m-tolyl-amine;
{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazolin-6-yl}-p-tolyl-amine;
{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-quinazolin-6-yl}-o-tolyl-amine;
Methyl-[2-(4-morpholin-4-yl-6-naphthalen-2-yl-quinazolin-2-yloxy)-ethyl]-amine;
4-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-naphthalen-2-yl-quinazoline;
6-(1H-Indol-3yl)-4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-quinazoline;
4-Chloro-2-{2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-morpholin-4-yl-quinazolin-6-yl}-phenol;
4-Chloro-2-{2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-morpholin-4-yl-quinazolin-6-yl}-phenol;
6-(3-Chloro-phenyl)-2-(3-methoxy-propyl)-4-morpholin-4-yl-quinazoline;
6-(1,5-Dimethyl-1H-imidazol-2-yl)-2-(2-methoxy-ethoxy)-4-morpholin-4-yl-quinazoline;
[2-(2-Methoxy-ethoxy)-4-morpholin-4-yl-quinazolin-6-yl]-methyl-pyridin-2-yl-amine;
(2,3-Dimethyl-1H-indol-6-yl)-[2-(2-methoxy-ethoxy)-4-morpholin-4-yl-quinazolin-6-yl]-amine;
1-(4-Morpholin-4-yl-6-m-tolylamino-quinazolin-2-yl)-3-phenyl-urea;
N-Benzylidene-N′-[4-morpholin-4-yl-6-(toluene-3-sulfonyl)-quinazolin-2-yl]-hydrazine;
N-(3-Methyl-benzylidene)-N′-(4-morpholin-4-yl-6-m-tolyloxy-quinazolin-2-yl)-hydrazine;
N-(4-Morpholin-4-yl-6-m-tolyloxy-quinazolin-2-yl)-2-phenyl-acetamide;
6-(4,5-Dimethyl-imidazol-1-yl)-4-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-quinazoline;
3-[2-(6-Benzofuran-3-yl-4-morpholin-4-yl-quinazolin-2-yloxy)-ethyl]-oxazolidin-2-one;
3-{2-[6-(1H-Indol-4-yloxy)-4-morpholin-4-yl-quinazolin-2-yloxy]-ethyl}-oxazolidin-2-one; and
pharmaceutically acceptable salts thereof.
46. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , 17 , or 45 .