	US 7,615,552 B2
	Fused heterocyclic compounds
Mitsunori Ono, Lexington, Mass. (US); Lijun Sun, Harvard, Mass. (US); Yumiko Wada, Billerica, Mass. (US); Teresa Przewloka, Tewksbury, Mass. (US); Hao Li, Brookline, Mass. (US); Zachary Demko, Somerville, Mass. (US); and Dinesh Chimmanamada, Waltham, Mass. (US)
Assigned to Synta Pharmaceuticals Corp., Lexington, Mass. (US)
Filed on Nov. 10, 2004, as Appl. No. 10/985,627.
Claims priority of provisional application 60/518788, filed on Nov. 10, 2003.
Prior Publication US 2005/0250770 A1, Nov. 10, 2005
Int. Cl. A61K 31/517 (2006.01); A61K 31/5377 (2006.01); C07D 265/30 (2006.01); C07D 413/04 (2006.01)

U.S. Cl. 514—231.5 [544/116]

46 Claims

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;

A₂is —X—R′-L′-R″ and A₁is 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^kNR^k, C(O)ONR^k, C(O)NR^kO, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_m, (C(R^g)(R_g))_mNR^k, (C(R^g)(R^g))_mO, (C(R^g)(R^g))_mS(O)_p, (C(R^g)(R^g))_mN═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))_mC(R^g)═N, (C(R^g)(R^g))_mN═N, (C(R^g)(R^g))_mC(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^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(O)_pNR^k, or S(O)_pNR^kNR^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^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or —S(O)₂R^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^kNR^k, C(O)ONR^k, C(O)NR^kO, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_m, (C(R^g)(R_g))_mNR^k, (C(R^g)(R^g))_mO, (C(R^g)(R^g))_mS(O)_p, (C(R^g)(R^g))_mN═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))_mC(R^g)(R^g)═N, (C(R^g)(R^g))_mN═N, (C(R^g)(R^g))_mC(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^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(O)_pNR^k, S(O)_pNR^kNR^kor 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)(CH₂)_nR^g, —OR^k, —SR^k, —NR^hR^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)₂R^c, —P(O)R^cR^c, —P(S)R^cR^c, or an optionally substituted alkylcarbonylalkyl;

R^cis, 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^hR^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^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R^c, —OC(O)R^c, —SC(O)R^c, —NR^kC(O)R^c, —C(S)R^c,—OC(S)R^c, —SC(S)R^c, —NR^kC(S)R^c, —C(NR)R^c, —OC(NR)R^c, —SC(NR)R^c, —NR^kC(NR)R^c, —SO₂R^c, —S(O)R^c, —NR^kSO₂R^c, —OS(O)₂R^c, —OP(O)R^cR^c, —P(O)R^cR^c, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R^hand 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^hand R^jtaken 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;

R₃is R^g, —C(O)R^c, —OC(O)R^c, —SC(O)R^c, —NR^kC(O)R^c, —C(S)R^c, —OC(S)R^c, —SC(S)R^c, —NR^kC(S)R^c, —C(NR)R^c, —OC(NR)R^c, —SC(NR)R^c, —NR^kC(NR)R^c, —SO₂R^c, —S(O)R^c, —NR^kSO₂R^c, —OS(O)₂R^c, —OP(O)R^cR^c, or —P(O)R^cR^c;

R₂and R₄are, independently for each occurrence, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, —OR^k, —SR^k, —NR^hR^j, hydroxylalkyl, —C(O)R^c, —OC(O)R^c, —SC(O)R^c, —NR^kC(O)R^c, —C(S)R^c, —OC(S)R^c, —SC(S)R^c, —NR^kC(S)R^c, —C(NR)R^c, —OC(NR)R^c, —SC(NR)R^c, —NR^kC(NR)R^c, —SO₂R^c, —S(O)R^c, —NR^kSO₂R^c, —OS(O)₂R^c, —OP(O)R^cR^c, —P(O)R^cR^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 R₂and R₄taken 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^gR^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^kO—;

—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)₂O—;

—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^gC(O)N(R^k)CHR^gC(O)—;

—N(R^k)CHR^gC(O)—;

—N(R^k)C(O)CHR^g—;

—C(O)N(R^k)CHR^gC(O)—;

or absent;

n, for each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, or 7; and

wherein when G is absent, R₃is 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^hR^j.