Shionogi Company Limited

Viiv Healthcare Company

Glaxosmithkline LLC

Masahiro Fuji

Yasuhiko Kanda

Toshio Fujishita

Yukio Tada

Ryuichi Kiyama

Shozo Takechi

Takashi Kawasuji

Yoshiyuki Taoda

Brian Alvin Johns

Hiroshi Yoshida

Tsutomu Iwaki

Teruhiko Taishi

Daiki Nagamatsu

Yoshinori Tamura

Toshiyuki Akiyama

Tomokazu Yoshinaga

Kenji Tomita

Masafumi Iwatsu

Shuichi Sugiyama

Daisuke Taniyama

Substituted 1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2&#x2032;:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidines having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a pharmaceutical composition containing the same, particularly an anti-HIV pharmaceutical composition.

Substituted 1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2&#x2032;:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidines having HIV integrase inhibitory activity

The present invention is directed to N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide of the formula: or a pharmaceutically acceptable salt or stereoisomer thereof, and pharmaceutical compositions comprising the same. The present invention has HIV integrase inhibitory activity.

N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3] oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide having HIV integrase inhibitory activity

The present invention provides the following compound having anti-HIV activity of formula: wherein, Ais C, CRor N;

Tricyclic heterocycle derivatives having HIV replication inhibitory effect

The present invention provides an integrase inhibitor. The inventors have found the following compound of formula (I) possessing an integrase inhibitory activity.  

Antiviral agent

The invention is a process for the preparation of a compound of the following formula (I): wherein R is &#x2014;CHO, &#x2014;CH(OH)or &#x2014;CH(OH)(OR); Pis H or a hydroxyl protecting group; Pis H or a carboxy protecting group; Ris H, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, etc.; Ris H, halogen or R&#x2014;X&#x2014;NR&#x2014;C(O)&#x2014;; etc. as defined in the specification. The compounds are useful as intermediates in synthesizing compounds having HIV integrase inhibitory activity.

Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates

The present invention is directed to a class of substituted pyrido[1'2&#x2032;:4,5]pyrazino[1,2-a]-pyrimidines useful as intermediates in the production of anti-HIV agents. The compounds have the formula (I-24b): wherein Ris one or two halogen; Ris Calkyl; Ris hydrogen, Ccycloalkyl, heterocyclyl, or Calkyl optionally substituted with hydroxy, Ccycloalkyl, alkoxy, heterocyclyl, heteroaryl, Caryl, or amino, wherein said amino may be optionally substituted with &#x2014;C(O)Calkyl or Calkyl; and Pis CarylCalkyl; or a pharmaceutically acceptable salt thereof.

Substituted pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidines as HIV integrase inhibitors

A synthesis approach providing an early ring attachment via a bromination to compound 1-1 yielding compound II-II, whereby a final product such as AA can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q. 

The present invention is to provide a novel compound (I) shown below, having the anti-virus activity; particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein

Substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1h-pyrido[1,2-a]pyrrolo[1',2&#x2032;:3,4]imidazo[1,2-d]pyrazine-8-carboxamides

The present invention is directed to a class of substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2&#x2032;:3,4]imidazo[1,2-d]pyrazine-8-carboxamides useful as anti-HIV agents. The compounds have the formula (I-1-1): wherein ring A is an optionally substituted hexahydro-1H-pyrrolo[1,2-c]-imidazole; Rand Rare independently hydrogen or optionally substituted lower alkyl; Ris selected from various groups; Ris hydrogen or lower alkyl; R is halogen; m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

[object Object]

A synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II:  

A synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II: whereby a final product such as AA: can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.

The present invention is directed to a substituted 2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2 -a]pyrido[1,2-d]pyrazine-5,7-dione useful as an anti-HIV agent, which has the formula: as well as pharmaceutically acceptable salts thereof, compostions thereof, and methods of use thereof.

(3S,11aR)-N-[2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide useful as anti-HIV agent

Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and a pharmaceutical composition, particularly an anti-HIV agent. (wherein When Bis NR, Rand Rmay be connected together to form an optionally substituted heterocycle; When Bis CHR, Rand Rmay be connected together to form an optionally substituted heterocycle. Alternatively, Band Bare independently C, CRor N and, in this case, Band Bmay be taken together to form a heterocycle. R, R, Rand Rare independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl etc.)

Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity

The present invention is directed to a class of substituted 5-hydroxy-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-6,10-diones useful as anti-HIV agents. The compounds have the formula: Z&#x2550;O; R, R, R, R, Rand Rindependently are hydrogen, C-Calkyl, (C-C)aryl-(C-C)alkyl, C-Caryl, or alkoxy; the stereochemistry of an asymmetric carbon represented by * shows R- or S-configuration, or a mixture thereof; Ris hydrogen; Ris hydrogen or optionally substituted lower alkyl; Ris hydrogen; Ris hydrogen or lower alkyl; R is halogen; and m is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness

Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. A compound represented by the formula: (wherein

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Osaka, Japan

Takashi Kawasuji