Bridged heterocycles as HIV integrase inhibitorsThe disclosure generally relates to the novel compounds of formula I, including their salts, which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.Formula i compound or pharmaceutically acceptable salt thereof:whereinr 1be (ar 1) alkyl, alkyl, (cycloalkyl) alkyl, xenyl alkyl, phenoxyalkyl, (phenyl nh) alkyl, (methylpyrrole alkyl) alkyl, (imidazolyl) alkyl, (amido in penta) alkyl, (tetrahydrofuran base) alkyl, ((fluorine) (methyl) pyridyl) methyl, phenycyclopropyl or benzyl-pyrrole alkyl; r 2be hydrogen, alkyl, hydroxyl or alkoxyl group; r 3be hydrogen, halogen, hydroxyl, alkoxyl group, cyano group, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, n (r 8) (r 9), n (r 6) cor 7, n (r 6) so 2r 7, n (r 6) co 2r 7, n (r 6) so 2n (r 8) (r 9), co 2r 6, con (r 8) (r 9), sor 7, so 2r 7, so 2n (r 8) (r 9), po (or 6) 2, r 12or ar 2r 4be hydrogen, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy or n (r 6) (r 6); r 5be hydrogen, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy or n (r 6) (r 6); r 6be hydrogen, alkyl, haloalkyl or cycloalkyl; r 7be alkyl, haloalkyl or cycloalkyl; r 8be hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or dialkyl aminoalkyl; r 9be hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or dialkyl aminoalkyl; or n (r 8) (r 9) be azetidinyl together, pyrrolidyl, (r 10)-piperidyl, n-(r 11)-piperazinyl, morpholinyl, parathiazan base or dioxo thiazinyl; r 10be hydrogen, alkyl, hydroxyl or hydroxyalkyl; r 11be hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy alkoxy alkyl, phenyl, pyridyl, (methylimidazolyl) methyl, cor 6, co 2r 6, (hydroxyalkyl) co, (alkoxyalkyl) co, (tetrahydrofuran base) co, (methyl-isoxazole base) co, (thienyl) co, (furyl) co, (pyridyl) co, con (r 8) (r 9), so 2r 7, so 2n (r 8) (r 9), (dimethyl isoxazole base) so 2, ((ethoxycarbonyl) thienyl) so 2, (methylimidazolyl) so 2, r 12be the azetidine ketone group, pyrrolidone-base, penta interior amido, caprolactam base, maleimide amino, oxazolidine ketone group, imidazolidinonyl, triazole ketone group, n-(r 6)-dioxo thiazolidyl or dioxo thiazinyl, and be substituted with 0-2 and be selected from following substituting group: alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl and aminoalkyl group; r 13be hydrogen, alkyl, alkyl-carbonyl, alkoxy carbonyl, benzyl oxygen base carbonyl or alkyl sulphonyl; r 14be n (r 15) (r 15), n (r 15) (benzyl oxygen base carbonyl), n (r 15) (alkyl oxy carbonyl), n (r 15) ((hydroxyalkyl) oxygen base carbonyl), n (r 15) ((alkyl oxy) alkyl oxy carbonyl), n (r 15) co (r 16), n (r 15) ((co (n (r 15) 2) alkyl), n (r 15) ((co 2co (n (r 15) 2) alkyl), n (r 15) co ((n (r 15) 2) alkyl), n (r 15) co ((con (r 15) (r 15) alkyl), n (r 15) coco 2(r 15), n (r 15) co ((co 2(r 15) alkyl), n (r 15) cocon (r 15) (r 15), n (r 15) coco ((n (r 15) (r 15)) alkyl), n (r 15) co (n (r 15) 2), n (r 15) so 2r 16, n (r 15) so 2(n (r 15) 2) or n (r 15) coar 3or r 14be hydroxyl, alkoxyl group, (hydroxyl) alkoxyl group, (alkoxyl group) alkoxyl group, (r 16co 2) alkoxyl group or (phenyl co 2) alkoxyl group; or r 14be n (r 15) cocon (r 15) (alkoxyalkyl), n (r 15) cocon (r 15) (hydroxyalkyl), n (r 15) cocon (r 15) ((tetrahydrofuran base) methyl), n (r 15) cocon (r 15) ((n, n-dimethyl pyrazole base) methyl) or n (r 15) co ((ar 4) alkyl); or r 14be or r 14be r 15be hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl or cycloalkyl; or n (r 15) (r 15) be azetidinyl together, pyrrolidyl, (r 10)-piperidyl, n-(r 11)-piperazinyl, morpholinyl or parathiazan base, and be substituted with 0-2 and be selected from following substituting group: halogen, hydroxyl, alkoxyl group, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy alkoxy alkyl, kharophen, co 2r 6and con (r 8) (r 9); r 16be alkyl, haloalkyl, cycloalkyl, (cycloalkyl) alkyl, hydroxyalkyl, alkoxyalkyl, thp trtrahydropyranyl or ar 3r 17be hydrogen, alkyl, alkyl co, cycloalkyl co, alkyl oxy co, con (r 15) (r 15), cocon (r 15) (r 15), coar 3, alkyl so 2, cycloalkyl so 2, furyl so 2, triazolyl so 2or n-methylpyrrole base so 2ar 1be ar 2be tetrazyl, triazolyl ， oxadiazole base, thiadiazolyl group, pyrazolyl, imidazolyl ， oxazolyl, thiazolyl isoxazolyl, isothiazolyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridyl or hydroxy-pyridyl, and be substituted with 0-3 and be selected from following substituting group: oxo, halogen, cyano group, benzyl, alkyl, alkoxyl group, n (r 8) (r 9), co 2r 6and con (r 8) (r 9); ar 3be tetrazyl, triazolyl ， oxadiazole base, thiadiazolyl group, pyrazolyl, imidazolyl ， oxazolyl, thiazolyl ， isoxazolyl, isothiazolyl, furyl, thienyl, pyrryl, pyridyl, pyrimidyl, pyrazinyl, imidazopyridyl, quinolyl, isoquinolyl or phenyl, and be substituted with 0-3 and be selected from following substituting group: oxo, halogen, alkoxyl group, halogenated alkoxy, cyano group, benzyl, alkyl, haloalkyl, n (r 8) (r 9) and n (r 15) co (r 16); ar 4be pyrazolyl or triazolyl, and be substituted with the individual co that is selected from of 0-1 2r 6and con (r 8) (r 9) substituting group; with x-y-z is
ＨＩＶ 인테그라제 억제제로서의 가교 헤테로사이클본 개시내용은 일반적으로 HIV 인테그라제를 억제하고, 인간 DNA로의 바이러스성 통합을 방지하는 하기 신규한 화학식 I의 화합물 (그의 염 포함)에 관한 것이다. 상기 작용은 HIV 감염 및 AIDS 치료에 유용한 화합물을 제조한다. 또한, 본 발명은 HIV에 감염된 것을 치료하기 위한 제약 조성물 및 방법을 포함한다. <화학식 I> 하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염.<화학식 I>[이미지]상기 식에서,R1은 (Ar1)알킬, 알킬, (시클로알킬)알킬, 디페닐알킬, 페녹시알킬, (PhNH)알킬, (메틸피롤리디닐)알킬, (이미다졸릴)알킬, (발레로락타밀)알킬, (테트라히드로푸라닐)알킬, ((플루오로)(메틸)피리디닐)메틸, 페닐시클로프로필 또는 벤질피롤리디닐이고;R2는 수소, 알킬, 히드록시 또는 알콕시이고;R3은 수소, 할로, 히드록시, 알콕시, 시아노, 알킬, 시클로알킬, 할로알킬, 히드록시알킬, 알콕시알킬, 알콕시, 할로알콕시, N(R8)(R9), N(R6)COR7, N(R6)SO2R7, N(R6)CO2R7, N(R6)SO2N(R8)(R9), CO2R6, CON(R8)(R9), SOR7, SO2R7, SO2N(R8)(R9), PO(OR6)2, R12 또는 Ar2이고;R4는 수소, 할로, 히드록시, 시아노, 알킬, 알콕시, 할로알킬, 할로알콕시 또는 N(R6)(R6)이고;R5는 수소, 할로, 히드록시, 시아노, 알킬, 알콕시, 할로알킬, 할로알콕시 또는 N(R6)(R6)이고;R6은 수소, 알킬, 할로알킬 또는 시클로알킬이고;R7은 알킬, 할로알킬 또는 시클로알킬이고;R8은 수소, 알킬, 할로알킬, 히드록시알킬, 알콕시알킬 또는 디알킬아미노알킬이고;R9는 수소, 알킬, 할로알킬, 히드록시알킬, 알콕시알킬 또는 디알킬아미노알킬이거나; 또는N(R8)(R9)는 함께 아제티디닐, 피롤리디닐, (R10)-피페리디닐, N-(R11)-피페라지닐, 모르폴리닐, 티오모르폴리닐 또는 디옥소티아지닐이고;R10은 수소, 알킬, 히드록시 또는 히드록시알킬이고;R11은 수소, 알킬, 시클로알킬, 히드록시알킬, 알콕시알킬, 히드록시알콕시알킬, 페닐, 피리디닐, (메틸이미다졸릴)메틸, COR6, CO2R6, (히드록시알킬)CO, (알콕시알킬)CO, (테트라히드로푸라닐)CO, (메틸이속사졸릴)CO, (티에닐)CO, (푸라닐)CO, (피리디닐)CO, CON(R8)(R9), SO2R7, SO2N(R8)(R9), (디메틸이속사졸릴)SO2, ((카르보에톡시)티에닐)SO2, (메틸이미다졸릴)SO2, [이미지]이고;R12는 아제티디노닐, 피롤리디노닐, 발레로락타밀, 카프로락타밀, 말레이미도, 옥사졸리디노닐, 이미다졸리디노닐, 트리아졸로닐, N-(R6)-디옥소티아졸리디닐 또는 디옥소티아지닐이며, 알킬, 히드록시알킬, 할로알킬, 알콕시알킬 및 아미노알킬로 이루어진 군으로부터 선택된 0 내지 2개의 치환기로 치환되고;R13은 수소, 알킬, 알킬카르보닐, 알콕시카르보닐, 벤질옥시카르보닐 또는 알킬술포닐이고;R14는 N(R15)(R15), N(R15)(벤질옥시카르보닐), N(R15)(알킬옥시카르보닐), N(R15)((히드록시알킬)옥시카르보닐), N(R15)((알킬옥시)알킬옥시카르보닐), N(R15)CO(R16), N(R15)(CO(N(R15)2)알킬), N(R15)(CO2CO(N(R15)2)알킬), N(R15)CO((N(R15)2)알킬), N(R15)CO(CON(R15)(R15)알킬), N(R15)COCO2(R15), N(R15)CO(CO2(R15)알킬), N(R15)COCON(R15)(R15), N(R15)COCO((N(R15)(R15))알킬), N(R15)CO(N(R15)2), N(R15)SO2R16, N(R15)SO2(N(R15)2) 또는 N(R15)COAr3이거나; 또는R14는 히드록시, 알콕시, (히드록시)알콕시, (알콕시)알콕시, (R16CO2)알콕시 또는 (PhCO2)알콕시이거나; 또는R14는 N(R15)COCON(R15)(알콕시알킬), N(R15)COCON(R15)(히드록시알킬), N(R15)COCON(R15)((테트라히드로푸라닐)메틸), N(R15)COCON(R15)((N,N-디메틸피라졸릴)메틸) 또는 N(R15)CO((Ar4)알킬)이거나; 또는R14는 [이미지]이거나; 또는R14는 [이미지]이고;R15는 수소, 알킬, 히드록시알킬, 알콕시알킬, 할로알킬 또는 시클로알킬이거나; 또는N(R15)(R15)는 함께 아제티디닐, 피롤리디닐, (R10)-피페리디닐, N-(R11)-피페라지닐, 모르폴리닐 또는 티오모르폴리닐이며, 할로, 히드록시, 알콕시, 알킬, 히드록시알킬, 알콕시알킬, 히드록시알킬옥시알킬, 아세트아미도, CO2R6 및 CON(R8)(R9)로부터 선택된 0 내지 2개의 치환기로 치환되고;R16은 알킬, 할로알킬, 시클로알킬, (시클로알킬)알킬, 히드록시알킬, 알콕시알킬, 테트라히드로피라닐 또는 Ar3이고;R17은 수소, 알킬, 알킬CO, 시클로알킬CO, 알킬옥시CO, CON(R15)(R15), COCON(R15)(R15), COAr3, 알킬SO2, 시클로알킬SO2, 푸라닐SO2, 트리아졸릴SO2 또는 N-메틸피롤릴SO2이고;Ar1은 [이미지]이고;Ar2는 테트라졸릴, 트리아졸릴, 옥사디아졸릴, 티아디아졸릴, 피라졸릴, 이미다졸릴, 옥사졸릴, 티아졸릴, 이속사졸릴, 이소티아졸릴, 푸라닐, 티에닐, 피롤릴, 피리미디닐, 피라지닐, 피리디닐 또는 히드록시피리디닐이며, 옥소, 할로, 시아노, 벤질, 알킬, 알콕시, N(R8)(R9), CO2R6 및 CON(R8)(R9)로 이루어진 군으로부터 선택된 0 내지 3개의 치환기로 치환되고;Ar3은 테트라졸릴, 트리아졸릴, 옥사디아졸릴, 티아디아졸릴, 피라졸릴, 이미다졸릴, 옥사졸릴, 티아졸릴, 이속사졸릴, 이소티아졸릴, 푸라닐, 티에닐, 피롤릴, 피리디닐, 피리미디닐, 피라지닐, 이미다조피리디닐, 퀴놀리닐, 이소퀴놀리닐 또는 페닐이며, 옥소, 할로, 알콕시, 할로알콕시, 시아노, 벤질, 알킬, 할로알킬, N(R8)(R9) 및 N(R15)CO(R16)으로 이루어진 군으로부터 선택된 0 내지 3개의 치환기로 치환되고;Ar4는 피라졸릴 또는 트리아졸릴이며, CO2R6 및 CON(R8)(R9)로부터 선택된 0 내지 1개의 치환기로 치환되고;X-Y-Z는 [이미지]이다.