US 7,253,180 B2 · Pre-organized tricyclic integrase inhibitor compounds

Abstract

Tricyclic compounds according to the structure below, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed. A1 and A2 are moieties forming a five, six, or seven membered ring. L is a bond or a linker connecting a ring atom of Ar to N. X is O, S, or substituted nitrogen. Ar is aryl or heteroaryl. Q is N, +NR, or CR4. The aryl carbons may be independently substituted with substituents other than hydrogen. The compounds may include prodrug moieties covalently attached at any site.

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Claims66

Dependent claims

A compound having the structure:

wherein:
A1 is independently selected from C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, and C(═NR),
A2 is independently selected from C(R2)2—C(R3)2, C(R2)═C(R3) and C(═O)C(R3)2;
Q is CR4;
L is selected from a bond, O, S, S—S, S(═O), S(═O)2, S(═O)2NR, NR, N—OR, C1-C12 alkylene, C1-C12 substituted alkylene, C2-C12 alkenylene, C2-C12 substituted alkenylene, C2-C12 alkynylene, C2-C12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH2)n, or (CH2CH2O)n, where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR2, N—CR2OR and N—CR2NR2;
Ar is selected from (a) a C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R2 or two R3 may form a spiro ring;
R1 is independently selected from CR3, NRSO2R, OC(═O)NR2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
RX2 is independently selected from H, C1-C8 alkyl, C1-C5 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group selected from benzyhydryl (CHPh2), trialkylsilyl (R3Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH2OR), and ester (C(═O)R);
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y═Z is C═C(OH), X is O, A1 is C(═O), A2 is C(R2)═C(R3), and Q is CH, then L is not a bond.

12 more elements

A compound having the structure:

wherein:
A1 is independently selected from C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, and C(═NR),
A2 is independently selected from C(R2)2—C(R3)2, C(R2)═C(R3), and C(═O)C(R3)2;
Q is CR4;
L is selected from a bond, O, S, S—S, S(═O), S(═O)2, S(═O)2NR, NR, N—OR, C1-C12 alkylene, C1-C12 substituted alkylene, C2-C12 alkenylene, C2-C12 substituted alkenylene, C2-C12 alkynylene, C2-C12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH2)2, or (CH2CH2O)2, where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR2, N—CR2OR and N—CR2NR2;
Ar is selected from (a) a C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
when taken together on a single carbon, two R2 or two R3 may form a spiro ring;
R1 is independently selected from CR3, NRSO2R, OC(═O)NR2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
R1 is independently selected from CR3, NRSO2R, OC(═O)OR, OC(═O)NR2 OC(+O)R, SR, H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
R is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
RX2 is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y═Z is C═C(OH), X is O, A1 is C(═O), A2 is C(R2)═C(R3), and Q is CH, then L is not a bond;
and
P is a protecting group selected from benzyhydryl (CHPh2), trialkylsilyl (R3Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH2OR), and ester (C(═O)R).

15 more elements

A process for preparation of a compound having the structure:

comprising reacting a succinimide compound having the structure:
with a heterocyclic compound having the structure:
and reacting with an acylation reagent having a formula selected from:
wherein:
A2 is selected from C(R2)2—C(R3)2, C(R2)═C(R3), and C(═O)C(R3)2;
Q is CR4;
L is selected from a bond, O, S, NR, N—OR, C1-C12 alkyldiyl, C1-C12 substituted alkyldiyl, C(═O)NH, C(═O), S(═O), S(═O)2, C(═O)NH(CH2)n, and (CH2CH2O)n, where n ranges from 1 to 6;
Ar is selected from (a) a C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R1 selected from R, OR, NR2, NHR, NHSO2R, and NRSO2R;
E is selected from Cl, imidazole, and hydroxybenzotriazole;
R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
and
R is selected from C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

10 more elements

A compound having the structure:

wherein:
A1 is independently selected from C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, and C(═NR),
A2 is independently selected from C(R2)2—C(R3)2, C(R2)—C(R3) and C(═O)C(R3)2;
Q is CR4;
L is selected from a bond, O, S, S—S, S(═O), S(═O)2, S(═O)2NR, NR, N—OR, C 1-C12 alkylene, C1-C12 substituted alkylene, C2-C12 alkenylene, C2-C12 substituted alkenylene, C2-C12 alkynylene, C2-C12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH2)n, or (CH2CH2O)n, where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR2, N—CR2OR and N—CR2NR2;
Ar is selected from (a) a C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
when taken together on a single carbon, two R2 or two R3 may form a spiro ring;
R1 is independently selected from CR3, NRSO2R, OC(═O)NR2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
R is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, and phosphate;
RX2 is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a protecting group selected from benzyhydryl (CHPh2), trialkylsilyl (R3Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH2OR), and ester (C(═O)R);
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y═Z is C═C(OH), X is O, A1 is C(═O), A2 is C(R2)═C(R3), and Q is CH, then L is not a bond.

12 more elements

Dependencies are inferred from the claim text.

Description73,691 words

Summary1,867 words

#The invention relates generally to compounds with antiviral activity and more specifically with HIV-integrase inhibitory properties.

#Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. A virally encoded integrase protein mediates specific incorporation and integration of viral DNA into the host genome. Integration is necessary for viral replication. Accordingly, inhibition of HIV integrase is an important therapeutic pursuit for treatment of HIV infection of the related diseases.

#Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, etal N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). There is a need for new agents directed against alternate sites in the viral life cycle. Integrase has emerged as an attractive target, because it is necessary for stable infection and homologous enzymes are lacking in the human host (LaFemina, etal J. Virol. (1992) 66:7414-7419). The function of integrase is to catalyze integration of proviral DNA, resulting from the reverse transcription of viral RNA, into the host genome, by a stepwise fashion of endonucleolytic processing of proviral DNA within a cytoplasmic preintegration complex (termed 3′-processing or “3′-P”) with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, followed by translocation of the complex into the nuclear compartment where integration of 3′-processed proviral DNA into host DNA occurs in a “strand transfer” (ST) reaction (Hazuda, etal Science (2000) 287:646-650; Katzman, etal Adv. Virus Res. (1999) 52:371-395; Asante-Applah, etal Adv. Virus Res. (1999) 52:351-369). Although numerous agents potently inhibit 3′-P and ST in extracellular assays that employ recombinant integrase and viral long-terminal-repeat oligonucleotide sequences, often such inhibitors lack inhibitory potency when assayed using fully assembled preintegration complexes or fail to show antiviral effects against HIV-infected cells (Pommier, etal Adv. Virus Res. (1999) 52:427-458; Farnet, etal Proc. Natl. Acad. Sci. U.S.A. (1996) 93:9742-9747; Pommier, etal Antiviral Res. (2000) 47:139-148.

Detailed description71,824 words

#Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying descriptions, structure and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

#Definitions

#Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

Facts

Application

10/687,373Filed 16 Oct 2003 · us provisional application

Priority

16 Oct 2002

Published

US 2004/0167124 A126 Aug 2004

Granted

7 Aug 2007

Term ended

16 Oct 2023

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification8 codes

C07D 207/404
2,5-Pyrrolidine-diones: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon…
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/18
For RNA viruses: for HIV
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Timeline

16 Oct 2002Priority claimedParent application 60/418,963
16 Oct 2003Application filedUS 10/687,373
17 Mar 2004Assigned to Gilead Sciences, Inc.assignment of assignor's interest
26 Aug 2004PublishedUS 2004/0167124 A1
7 Aug 2007GrantedUS 7,253,180 B2
16 Oct 2023Term endedEstimated

Pre-organized tricyclic integrase inhibitor compounds

Life of this patent

Pre-organized tricyclic integrase inhibitor compounds

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Abstract

Drawings

Drawings

Claims66

Description73,691 words

Drawings

Classification8 codes

Life of this patent

Description73,691 words