# US 7,745,453 B2 · Hydroxypyrimidinone derivatives having inhibitory activity against HIV integrase

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- Number: US 7,745,453 B2
- Document ID: US7745453B2
- Status: Granted
- Kind: B2
- Application number: 10/583,796
- Filed: 2004-12-21
- Published: 2007-06-28
- Granted: 2010-06-29
- Earliest claimed: 2003-12-22
- Assignees: Shionogi & Co., Ltd.
- Inventors: Hidenori Mikamiyama; Minamo Iwata; Yoshiyuki Taoda
- Web page: https://patentgrep.com/patent/US7745453B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of Formula (1), pharmaceuticals containing the same, especially anti-HIV agents having anti viral activity, especially inhibitory activity against HIV integrase, wherein X represents either one of the following groups: (wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one atom in atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; R10 is hydrogen or lower alkyl; D ring is aryl or heteroaryl) Z1 and Z3 each is independently a single bond, O, S, S(═O) or SO2; Z2 is a single bond, lower alkylene or lower alkenylene; Ar is optionally substituted aryl or optionally substituted heteroaryl; R1 is lower alkyl, substituted lower alkyl or the like; R2 is a hydrogen atom or optionally substituted lower alkyl; or R1 and R2 may form, together with an adjacent atom, an optionally substituted heterocyclic ring, a pharmaceutically acceptable salt or a solvate thereof.

## Claims

### Claim 1

A compound of the formula:
(wherein:
X represents either one of the following groups:
(wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one of atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; R10 is hydrogen or lower alkyl; D ring is aryl or heteroaryl, wherein “heteroaryl” means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group, said monocyclic aromatic heterocyclic group means a group, which is derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom and which may have a bonding position at any substitutable position, said condensed aromatic heterocyclic group means a group, wherein a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom is condensed with 1 to 4 of 5- to 8-membered aromatic carbon cycle or the other 5- to 8-membered aromatic heterocyclic ring and which may have a bonding position at the any substitutable position)
Z1 and Z3 each is a single bond;
Z2 is lower alkylene;
Ar is aryl optionally substituted with halogen;
R1 is lower alkyl, substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 5- or 6-membered nitrogen containing heterocyclic group, or optionally substituted 5- or 6-membered nitrogen containing heterocyclic lower alkyl;
R2 is a hydrogen atom or optionally substituted lower alkyl; or
R1 and R2 may form, together with an adjacent atom, an optionally substituted heterocyclic ring, provided that
1) when X is a group shown by (a), R1 is not lower alkyl
2) when X is a group shown by (b), R1 and R2 form, together with an adjacent atom, a heterocyclic ring shown by the (d) as follows:
(wherein, R11, R12, R14, R15, R16, and R17 each is independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted hydroxy, optionally substituted thiol, optionally substituted sulfonyl or optionally substituted carbamoyl, or
R11 and R12, R14 and R15, and R16 and R17 may together form “═O”;
R13 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted carbamoyl, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heteroarylcarbonyl;
m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; provided that 1≦m+n≦3)),
or a pharmaceutically acceptable salt thereof,
wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring,
wherein “optionally substituted amino” and “optionally substituted carbamoyl” mean substituted by alkyl, benzyl, carbamoylalkyl, mono or di alkylcarbamoyl alkyl, hydroxyalkyl, heterocycle alkyl, alkoxycarbonyl alkyl, mono or di alkylamino alkyl, alkoxyalkyl, acyl, arylcarbonyl, aralkyl, hydroxy, alkyl sulfonyl, arylsulfonyl optionally substituted with alkyl or halogen, cycloalkyl, aryl optionally substituted with alkyl, alkylamino sulfonyl, alkylaminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, sulfamoyl, alkyl carbonylamino, heterocycle and amino.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein —Z1—Z2—Z3—Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1 represented by the formula:
(wherein each symbol has the same meanings as claim 1), or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein C ring represented by the formula:
is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein C ring is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 is substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted 5- or 6-membered nitrogen containing heterocyclic lower alkyl, optionally substituted aryl or optionally substituted 5- or 6-membered nitrogen containing heterocyclic group, and each substituent is selected from the group consisting of —NR3R4, —C(═O)R3, —C(═O)NR3R4 (wherein, R3 and R4 each is independently, hydrogen atom, hydroxy, alkoxy, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted lower alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, lower alkoxycarbonylcarbonyl, carboxycarbonyl, lower alkoxycarbonyl, optionally substituted heterocyclic carbonyl, lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, or optionally substituted lower alkylsulfonyl), oxo and halogen,
or a pharmaceutically acceptable salt thereof,
wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring,
wherein “optionally substituted amino,” “optionally substituted carbamoyl” and “optionally substituted carbamoylcarbonyl” mean substituted by alkyl, benzyl, carbamoylalkyl, mono or di alkylcarbamoyl alkyl, hydroxyalkyl, heterocycle alkyl, alkoxycarbonyl alkyl, mono or di alkylamino alkyl, alkoxyalkyl, acyl, arylcarbonyl, aralkyl, hydroxy, alkyl sulfonyl, arylsulfonyl optionally substituted with alkyl or halogen, cycloalkyl, aryl optionally substituted with alkyl, alkylamino sulfonyl, alkylaminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, sulfamoyl, alkyl carbonylamino, heterocycle and amino.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1 is a group selected from the group consisting of:
[Formula 8]
(wherein, R3 and R4 are the same meanings as above), or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein Ar is phenyl optionally substituted with halogen; X is a group represented by (a); C ring is a group selected from the group consisting of:
and R1 is substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted 5- or 6-membered nitrogen containing heterocyclic lower alkyl, optionally substituted aryl or optionally substituted 5- or 6-membered nitrogen containing heterocyclic group, and each substituent is selected from the group consisting of —NR3R4, —C(═O)R3, —C(═O)NR3R4 (wherein, R3 and R4 each is independently, hydrogen atom, hydroxy, alkoxy, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted lower alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, lower alkoxycarbonylcarbonyl, carboxycarbonyl, lower alkoxycarbonyl, optionally substituted heterocyclic carbonyl, lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, or optionally substituted lower alkylsulfonyl), oxo and halogen,
or a pharmaceutically acceptable salt thereof,
wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring,
wherein “optionally substituted amino,” “optionally substituted carbamoyl” and “optionally substituted carbamoylcarbonyl” mean substituted by alkyl, benzyl, carbamoylalkyl, mono or di alkylcarbamoyl alkyl, hydroxyalkyl, heterocycle alkyl, alkoxycarbonyl alkyl, mono or di alkylamino alkyl, alkoxyalkyl, acyl, arylcarbonyl, aralkyl, hydroxy, alkyl sulfonyl, arylsulfonyl optionally substituted with alkyl or halogen, cycloalkyl, aryl optionally substituted with alkyl, alkylamino sulfonyl, alkylaminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, sulfamoyl, alkyl carbonylamino, heterocycle and amino.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

### Claim 11 (depends on 9)

The compound according to claim 9, wherein C ring is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 9)

The compound according to claim 9, wherein R1 is a group selected from the group consisting of:
[Formula 8]
(wherein, R3 and R4 are the same meanings as above), or a pharmaceutically acceptable salt thereof.