US 2003/0114448 A1Published application

Inhibitors of factor Xa

AssigneeMillennium Pharmaceuticals, Inc.

InventorsPenglie Zhang, Bing-Yan Zhu, Wenrong Huang, Robert M. Scarborough

Life of this patent

Estimating the term…

Abstract

Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.

Claims8

Dependent claims

A compound of the formula I:

69
wherein:
A is selected from the group consisting of:
(a) C1-C6-alkyl;
(b) C3-C8-cycloalkyl;
(c) —N(R,R1), (R,R1)N—C(═NR2)—, R1—C(═NR2)—, (R,R1)N—C(═NR2)—NR3—, R—C(—NR2)—N(R3)—;
(d) phenyl, which is independently substituted with 0-2 R1 substituents;
(e) naphthyl, which is independently substituted with 0-2 R1 substituents;
and (f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system is optionally substituted with 0-2 R1 substituents;
R and R1 are independently selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, —CN, —NO2, (CH2)mCON(R2,R3), (CH2)mCO2R2, (CH2)mN(R2,R3), (CH2)mSO2N(R2,R3), (CH2)mSO2R2, CF3, OR2, N(R2,R3), (R2,R3)N—C(═NR4)—, R2—C(—NR4)— and a 3-8 membered cyclic system containing from 0-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the ring system are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
and wherein R and R1 taken together may form a ring;
the subscript m is an integer of 0-4;
R2 and R3 are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, OH, NH2, OC1-4alkyl, N(C1-4alkyl,C1-4alkyl), C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
and wherein R2 and R3 taken together may form a ring;
Y is a member selected from the group consisting of a direct link, —C(═O)—, —CH2—, —N(R4)—CH2—, —CH2N(R4)—, —N(R4)—, —C(═O)—N(R4)—, —N(R4)—C(═O)—, —C(═NR4)—, —C(═NR4)—N(R)—, —C(═NR4)—CH2—, —C(═NR4)—N(R4a)—CH2—, —S(═O)2—, —S(═O)—, —O—, —S—, —SO2—N(R4)— and —N(R4)—SO2—;
R4 and R4a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
D is a member selected from the group consisting of (a) phenyl, which is independently substituted with 0-2 R1a substituents;
and (b) an aromatic five or six-membered heterocyclic ring having from 1-2 ring hetero atoms selected from oxygen, sulfur and nitrogen atoms, and wherein the ring atoms are optionally substituted with 0-2 R1a substituents;
wherein R1a is selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, (CH2)nN(R2a,R3a) (CH2)nSO2N(R2a,R3a), (CH2)nSO2R2a, (CH2)nOR2a, (CH2)nCON(R2a,R3a), (CH2)nCO2R2a, CF3, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 0-4 hydrogen atoms on the aromatic heterocyclic system is optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
the subscript n is an integer of 0-4;
and R2a and R3a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
X is a member selected from the group consisting of —C(R5,R5a)—C(═O)—, —C(R5,R5a)—C(═S)—, —C(R5,R5a)—, —C(R5,R5a)—C(R6,R6a), —C(R5,R5a)—C(R6,R6a) —C(R7,R7a)—, —C(═O)—, —S(═O)2—, —C(R5)═C(R6)—C(═O)—, —C(R5)═C(R6)—C(═S)—, —C(R5)═C(R6)—, —O—C(R5,R5a)—C(═O)—, —S(═O)—, —O—C(R5,R5a)—C(═S)—, —S—C(R5,R5a)—C(═O)—, —S—C(R5,R5a)—C(═S)—, N═C(R5)—C(═S)—, —N═C(R5)—C(═O)—, —O—C(R5,R5a)—C(R6,R6a)—, —N(R4)—C(R5,R5a)—C(R6,R6a)—, —N(R4)—C(R5,R5a)—, —O—C(R5,R5a)—, —N═C(R5)—;
—S(═O)—C(R5,R5a)—C(R6,R6a)—, —S(═O)2—C(R5,R5a)—C(R6,R6a)—, —C(═C(R5a,R5b))—C(═O)— and —C(═C(R5a,R5b))—C(═S)—;
wherein the first named atom of each X is directly attached to the D ring, and wherein D, X and the N atom attached to the last chain atom of X collectively form a bicyclic ring structure;
R5, R5a, R6, R6a, R7, and R7a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, NO2, CF3, (CH2)nOC1-4alkyl, (CH2)nN(C1-4alkyl, C1-4alkyl), (CH2)nCO2C1-4alkyl, (CH2)nCON(C1-4alkyl, C1-4alkyl), C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
where two alkyl groups may form a ring and the subscript n has the meaning defined above;
Q is O, or Q and the carbon atom to which it is attached is —CH2—;
E is a member selected from the group consisting of a direct link, —C(R8,R8a)—, —C(R8,R8a)C(R9,R9a)—, —C(R8,R8a)C(R9,R9a)C(R10,R10a)— and —C(═O)—;
wherein R8, R8a, R9, R9a, R10 and R10a are each independently a member selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, —C0-4alkylCO2R11, —C0-4alkylC(═O)N(R11,R11a), —C0-4alkylOC0-4alkylR11;
—CH2—CH2—O—R11, —N(—CH2—CH2—O—R11)2, —C0-4alkylN(R11)C(═O)R12, —C0-4alkylN(R11)SO2R12, C0-4alkylOH, C0-4alkylNR11R11a, C0-4alkylOC1-4alkyl, C0-4alkylN(C1-4alkyl, C1-4alkyl) and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, —CN and —NO2;
R8 and R9, or R9 and R10, or R8 and R8a, or R9 and R9a taken together may form a ring;
R11, R11a and R12 are independently selected from the group consisting of H, C1-4alkyl, C0-4alkylCON(R13,R14), C0-4alkylCOR13, C0-4alkylN(R13,R14) and C0-4alkylOR13;
and wherein R11 and R11a, taken together with N, optionally form a 5-8 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
R13 and R14 are independently selected from the group consisting of H and C1-4alkyl;
or R13 and R14 taken together with N form a 5-8 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
G is a member selected from the group consisting of a direct link, —O—, —O—C(R15,R15a)—, —N(R15)—, —N(R15)—C(R15a,R15b)—, —S—, —N(R15)—S(═O)—, —N(R15)—S(═O)2—, —S(═O)—N(R15)—, —S(═O)2N(R15)—, —N(R15)—C(═O)—, —C(═O)—N(R15)—, —N(R15)—C(═O)—N(R15a)— and a monocyclic aromatic or non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein 0-4 ring atoms of the ring system are selected from N, O and S;
R15, R15a and R15b are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alky1C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheteroaryl, C1-4alkylCO2H, C1-4alkylCO2C1-4alkyl, C1-4alkylCONH2, C1-4alkylCON(C1-4alkyl, C1-4alkyl), C2-4alkylOH, C2-4alkylNH2, C2-4alkylOC1-4alkyl and C2-4alkylN(C1-4alkyl, C1-4alkyl), wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
J is a member selected from the group consisting of a direct link, —O—, —S—, —N(R16)—, —N(R16)—C(═O)—, —C(═O)—N(R16)—, —N(R16)—CH2—, —S(═O)2, —S(═O)— and —OCH2—;
R16 is a member selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, —CH2CO2C1-4alkyl-, CH2CO2H, CH2CON(C1-4alkyl, C1-4alkyl), CH2CONH2, C(═O)C1-4alkyl, SO2C1-4alkyl, CH2CO2—C1-4alkylphenyl and CH2CO2C1-4alkylnaphthyl;
Z is a member selected from the group consisting of (a) phenyl, which is independently substituted with 0-2 R1b substituents;
(b) naphthyl, which is independently substituted with 0-2 R1b substituents;
and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system is optionally substituted from 0-2 R1b substituents;
R1b is selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynl, C3-8cycloalkyl, C0-4alkylC;
C3-8cycloalkyl, —CN, —NO2, N(R2b,R3b), SO2N(R2b,R3b), SO2R2b, CO2N(R2b,R3b), CO2R2b, CF3, OR2b, O—CH2—CH2—OR2b, O—CH2—CH2—N(R2b,R3b), O—CH2—CON(R2b,R3b), O—CH2—CH2—N(R2b,R3b), O—CH2—COOR2b, N(R2b)—CH2—CH2—OR3b, N(—CH2—CH2—O2b)2, N(R2b)—C(═O)R3b, N(R2b)—SO2—R3b and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
R2b and R3b are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
L is selected from the group consisting of H, —CN, C(═O)N(R17,R17a), (CH2)nN(R17, R17aR), C(═NR17)N(R17a,R17b), OR17, —NR17C(═NR17a)N(R17b,R17c) and NR17C(═NR17a)—R17b;
R17, R17a, R17b, and R17c are independently selected from the group consisting of H, —OR18, —NR18R18a, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, COOC1-4alkyl, COO—C0-4alkylphenyl and COO—C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
R18 and R18a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

46 more elements

A compound having a formula selected from the group consisting of:

(a) compounds of formulae Ia, Ib, Ic and Id,
76
wherein:
A is a member selected from the group consisting of:
77
and Y is a member selected from the group consisting of:
a direct link, —O—, —S—, —SO2—, —SO—, —C(═O)—, —CH2—, —NH—CH2—, —NMe-CH2—, —CH2N(R4)—, —C(═NH)—, —C(═NH)—CH2—, —C(═NMe)-CH2—, —C(═NMe)-, —NH—, —NMe-, —C(═O)—NH—, —NH—C(═O)—, —C(═NH)—NH—, —C(═NH)—NMe- and —C(═NMe)—NH—;
(b) compounds of formulae IIa, IIb, IIc and IId,
78
wherein:
R1b is a member selected from the group consisting of:
H, F, Cl, Br I, Me, OH, OMe, OPh, OBn, NH2, OCH2CH2NH2, OCH2CH2OH, CONH2, NO2, SO2Me, SO2NH2, CN, CH2OH, CH2NH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
R5 and R6 are independently a member selected from the group consisting of:
H, Me, Et, CF3, Ph, Bn, CO2H, CO2Me, CONH2, CONMe2, NH2, OH, CH2NH2, CH2OH, CH2CO2H, CH2CO2Me, CH2CONH2 and CH2CONMe2;
and
R8 is a member selected from the group consisting of:
H, Me, Et, Ph, Bn, cyclohexyl, CH2cyclohexyl, CH2NH2, CH2OH, CONMe2, CONH2, CH2CONMe2, CH2CONH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, naphthyl, CH2naphthyl, CONMe2 and CH2CONMe2;
(c) compounds of formulae IIIa, IIIb, IIIc and IIId,
79
wherein:
R1b is a member selected from the group consisting of:
H, F, Cl, Br I, Me, OH, OMe, OPh, OBn, NH2, OCH2CH2NH2, OCH2CH2OH, CONH2, NO2, SO2Me, SO2NH2, CN, CH2OH, CH2NH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
and
R8 is a member selected from the group consisting of:
H, Me, Et, Ph, Bn, cyclohexyl, CH2cyclohexyl, CH2NH2, CH2OH, CONMe2, CONH2, CH2CONMe2, CH2CONH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, aryl, CH2aryl, CONMe2 and CH2CONMe2;
(d) compounds of formulae IVa, IVb, IVc, IVd and IVe,
80
wherein:
R1b is a member selected from the group consisting of:
H, F, Cl, Br, I, Me, OH, OMe, OPh, OBn, NH2, OCH2CH2NH2, OCH2CH2OH, CONH2, NO2, SO2Me, SO2NH2, CN, CH2OH, CH2NH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
R8 is a member selected from the group consisting of:
H, Me, Et, Ph, Bn, cyclohexyl, CH2cyclohexyl, CH2NH2, CH2OH, CONMe2, CONH2, CH2CONMe2, CH2CONH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
and
R16 is a member selected from the group consisting of:
H, Me, Et, Ph, and Bn;
(e) compounds of formulae Va, Vb, Vc, Vd, Ve and Vf,
81
wherein:
R1b, R1c and R1d are individually a member selected from the group consisting of:
H, F, Cl, Br, I, Me, OH, OMe, OPh, OBn, NH2, OCH2CH2NH2, OCH2CH2OH, CONH2, NO2, SO2Me, SO2NH2, CN, CH2OH, CH2NH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
R8 is a member selected from the group consisting of:
H, Me, Et, Ph, Bn, cyclohexyl, CH2cyclohexyl, CH2NH2, CH2OH, CONMe2, CONH2, CH2CONMe2, CH2CONH12, CO2H, CO2Me, CH2CO2H, CH2CO2Me, naphthyl, CH2naphthyl, CONMe2 and CH2CONMe2;
R15 is a member selected from the group consisting of:
H, Me, Et, Ph, and Bn;
(f) compounds of formulae VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj, VIk and VIl,
82
wherein:
R1b is a member selected from the group consisting of:
H, F, Cl, Br, I, Me, OH, OMe, OPh, OBn, NH2, OCH2CH2NH2, OCH2CH2OH, CONH2, NO2, SO2Me, SO2NH2, CN, CH2OH, CH2NH2, CO2H, CO2Me, CH2CO2H, CH2CO2Me, CONMe2 and CH2CONMe2;
and
(g) compounds of formula VIIa, VIIb and VIIc,
83
wherein:
R1b is a member selected from the group consisting of:
H, OH, NH2, NO2, F, SO2Me, CN, CONH2 and SO2NH2;
R8 is a member selected from the group consisting of:
H, Me, Et, Ph, Bn, CO2H and CO2Me;
and
R15 is a member selected from the group consisting of:
H, Me, Et and Bn.

57 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/171,804Filed 28 May 2002
Priority: 31 May 2001
Published: 19 Jun 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
C07D 209/46
Iso-indoles; Hydrogenated iso-indoles: with an oxygen atom in position 1
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links

Family

Application60/294,273Us provisional application · filed 31 May 2001
US 2003/0114448 A1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of the formula I:

69
wherein:
A is selected from the group consisting of:
(a) C1-C6-alkyl;
(b) C3-C8-cycloalkyl;
(c) —N(R,R1), (R,R1)N—C(═NR2)—, R1—C(═NR2)—, (R,R1)N—C(═NR2)—NR3—, R—C(—NR2)—N(R3)—;
(d) phenyl, which is independently substituted with 0-2 R1 substituents;
(e) naphthyl, which is independently substituted with 0-2 R1 substituents;
and (f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system is optionally substituted with 0-2 R1 substituents;
R and R1 are independently selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, —CN, —NO2, (CH2)mCON(R2,R3), (CH2)mCO2R2, (CH2)mN(R2,R3), (CH2)mSO2N(R2,R3), (CH2)mSO2R2, CF3, OR2, N(R2,R3), (R2,R3)N—C(═NR4)—, R2—C(—NR4)— and a 3-8 membered cyclic system containing from 0-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the ring system are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
and wherein R and R1 taken together may form a ring;
the subscript m is an integer of 0-4;
R2 and R3 are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, OH, NH2, OC1-4alkyl, N(C1-4alkyl,C1-4alkyl), C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
and wherein R2 and R3 taken together may form a ring;
Y is a member selected from the group consisting of a direct link, —C(═O)—, —CH2—, —N(R4)—CH2—, —CH2N(R4)—, —N(R4)—, —C(═O)—N(R4)—, —N(R4)—C(═O)—, —C(═NR4)—, —C(═NR4)—N(R)—, —C(═NR4)—CH2—, —C(═NR4)—N(R4a)—CH2—, —S(═O)2—, —S(═O)—, —O—, —S—, —SO2—N(R4)— and —N(R4)—SO2—;
R4 and R4a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
D is a member selected from the group consisting of (a) phenyl, which is independently substituted with 0-2 R1a substituents;
and (b) an aromatic five or six-membered heterocyclic ring having from 1-2 ring hetero atoms selected from oxygen, sulfur and nitrogen atoms, and wherein the ring atoms are optionally substituted with 0-2 R1a substituents;
wherein R1a is selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, (CH2)nN(R2a,R3a) (CH2)nSO2N(R2a,R3a), (CH2)nSO2R2a, (CH2)nOR2a, (CH2)nCON(R2a,R3a), (CH2)nCO2R2a, CF3, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 0-4 hydrogen atoms on the aromatic heterocyclic system is optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
the subscript n is an integer of 0-4;
and R2a and R3a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
X is a member selected from the group consisting of —C(R5,R5a)—C(═O)—, —C(R5,R5a)—C(═S)—, —C(R5,R5a)—, —C(R5,R5a)—C(R6,R6a), —C(R5,R5a)—C(R6,R6a) —C(R7,R7a)—, —C(═O)—, —S(═O)2—, —C(R5)═C(R6)—C(═O)—, —C(R5)═C(R6)—C(═S)—, —C(R5)═C(R6)—, —O—C(R5,R5a)—C(═O)—, —S(═O)—, —O—C(R5,R5a)—C(═S)—, —S—C(R5,R5a)—C(═O)—, —S—C(R5,R5a)—C(═S)—, N═C(R5)—C(═S)—, —N═C(R5)—C(═O)—, —O—C(R5,R5a)—C(R6,R6a)—, —N(R4)—C(R5,R5a)—C(R6,R6a)—, —N(R4)—C(R5,R5a)—, —O—C(R5,R5a)—, —N═C(R5)—;
—S(═O)—C(R5,R5a)—C(R6,R6a)—, —S(═O)2—C(R5,R5a)—C(R6,R6a)—, —C(═C(R5a,R5b))—C(═O)— and —C(═C(R5a,R5b))—C(═S)—;
wherein the first named atom of each X is directly attached to the D ring, and wherein D, X and the N atom attached to the last chain atom of X collectively form a bicyclic ring structure;
R5, R5a, R6, R6a, R7, and R7a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, NO2, CF3, (CH2)nOC1-4alkyl, (CH2)nN(C1-4alkyl, C1-4alkyl), (CH2)nCO2C1-4alkyl, (CH2)nCON(C1-4alkyl, C1-4alkyl), C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
where two alkyl groups may form a ring and the subscript n has the meaning defined above;
Q is O, or Q and the carbon atom to which it is attached is —CH2—;
E is a member selected from the group consisting of a direct link, —C(R8,R8a)—, —C(R8,R8a)C(R9,R9a)—, —C(R8,R8a)C(R9,R9a)C(R10,R10a)— and —C(═O)—;
wherein R8, R8a, R9, R9a, R10 and R10a are each independently a member selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, —C0-4alkylCO2R11, —C0-4alkylC(═O)N(R11,R11a), —C0-4alkylOC0-4alkylR11;
—CH2—CH2—O—R11, —N(—CH2—CH2—O—R11)2, —C0-4alkylN(R11)C(═O)R12, —C0-4alkylN(R11)SO2R12, C0-4alkylOH, C0-4alkylNR11R11a, C0-4alkylOC1-4alkyl, C0-4alkylN(C1-4alkyl, C1-4alkyl) and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, —CN and —NO2;
R8 and R9, or R9 and R10, or R8 and R8a, or R9 and R9a taken together may form a ring;
R11, R11a and R12 are independently selected from the group consisting of H, C1-4alkyl, C0-4alkylCON(R13,R14), C0-4alkylCOR13, C0-4alkylN(R13,R14) and C0-4alkylOR13;
and wherein R11 and R11a, taken together with N, optionally form a 5-8 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
R13 and R14 are independently selected from the group consisting of H and C1-4alkyl;
or R13 and R14 taken together with N form a 5-8 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
G is a member selected from the group consisting of a direct link, —O—, —O—C(R15,R15a)—, —N(R15)—, —N(R15)—C(R15a,R15b)—, —S—, —N(R15)—S(═O)—, —N(R15)—S(═O)2—, —S(═O)—N(R15)—, —S(═O)2N(R15)—, —N(R15)—C(═O)—, —C(═O)—N(R15)—, —N(R15)—C(═O)—N(R15a)— and a monocyclic aromatic or non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein 0-4 ring atoms of the ring system are selected from N, O and S;
R15, R15a and R15b are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alky1C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheteroaryl, C1-4alkylCO2H, C1-4alkylCO2C1-4alkyl, C1-4alkylCONH2, C1-4alkylCON(C1-4alkyl, C1-4alkyl), C2-4alkylOH, C2-4alkylNH2, C2-4alkylOC1-4alkyl and C2-4alkylN(C1-4alkyl, C1-4alkyl), wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
J is a member selected from the group consisting of a direct link, —O—, —S—, —N(R16)—, —N(R16)—C(═O)—, —C(═O)—N(R16)—, —N(R16)—CH2—, —S(═O)2, —S(═O)— and —OCH2—;
R16 is a member selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, —CH2CO2C1-4alkyl-, CH2CO2H, CH2CON(C1-4alkyl, C1-4alkyl), CH2CONH2, C(═O)C1-4alkyl, SO2C1-4alkyl, CH2CO2—C1-4alkylphenyl and CH2CO2C1-4alkylnaphthyl;
Z is a member selected from the group consisting of (a) phenyl, which is independently substituted with 0-2 R1b substituents;
(b) naphthyl, which is independently substituted with 0-2 R1b substituents;
and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system is optionally substituted from 0-2 R1b substituents;
R1b is selected from the group consisting of H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynl, C3-8cycloalkyl, C0-4alkylC;
C3-8cycloalkyl, —CN, —NO2, N(R2b,R3b), SO2N(R2b,R3b), SO2R2b, CO2N(R2b,R3b), CO2R2b, CF3, OR2b, O—CH2—CH2—OR2b, O—CH2—CH2—N(R2b,R3b), O—CH2—CON(R2b,R3b), O—CH2—CH2—N(R2b,R3b), O—CH2—COOR2b, N(R2b)—CH2—CH2—OR3b, N(—CH2—CH2—O2b)2, N(R2b)—C(═O)R3b, N(R2b)—SO2—R3b and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
R2b and R3b are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
L is selected from the group consisting of H, —CN, C(═O)N(R17,R17a), (CH2)nN(R17, R17aR), C(═NR17)N(R17a,R17b), OR17, —NR17C(═NR17a)N(R17b,R17c) and NR17C(═NR17a)—R17b;
R17, R17a, R17b, and R17c are independently selected from the group consisting of H, —OR18, —NR18R18a, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, COOC1-4alkyl, COO—C0-4alkylphenyl and COO—C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
R18 and R18a are independently selected from the group consisting of H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties are optionally independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

46 more elements

Facts

Application

10/171,804Filed 28 May 2002

Priority

31 May 2001

Published

19 Jun 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
C07D 209/46
Iso-indoles; Hydrogenated iso-indoles: with an oxygen atom in position 1
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links