Pyrrolidines as inhibitors of neuraminidasesDisclosed are compounds of formula (I) which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.The compound of following formula: or its pharmacy acceptable salt, ester or prodrug, wherein r 1be selected from: (a)-co 2h，(b)-ch 2co 2h，(c)-so 3h，(d)-ch 2so 3h，(e)-so 2h， (f)-ch 2so 2h，(g)-po 3h 2，(h)-ch 2po 3h 2，(i)-po 2h，(j)-ch 2po 2h， (k) tetrazyl, (l)-ch 2-tetrazyl, (m)-c (=o)-nh-s (o) 2-r 11, (n)-ch 2c (=o)-nh-s (o) 2-r 11, (o)-so 2n (t-r 11) r 12with (p)-ch 2so 2n(t-r 11)r 12， wherein t is selected from:(i) key, (ii)-c (=o)-, (iii)-c (=o) o-, (iv)-c (=o) s-,(v)-c (=o) nr 36-, (vi)-c (=s) o-, (vii)-c (=s) s-and (viii)-c(＝s)nr 36， r 11be selected from: (i) c 1-c 12alkyl, (ii) c 2-c 12alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl) alkyl,(v) (cycloalkyl) alkenyl, (vi) cycloalkenyl group, (vii) (cycloalkenyl group) alkyl,(viii) (cycloalkenyl group) alkenyl, (ix) aryl, (x) (aryl) alkyl, (xi)(aryl) alkenyl,(xii) heterocyclic radical, (xii) (heterocyclic radical) alkyl and(xiv) (heterocyclic radical) alkenyl; andr 12and r 36independently be selected from: (i) hydrogen, (ii) c 1-c 12alkyl, (iii) c 2-c 12alkenyl, (iv) cycloalkyl, (v) (cycloalkyl) alkyl, (vi) (cycloalkyl) alkenyl, (vii) cycloalkenyl group,(viii) (cycloalkenyl group) alkyl, (ix) (cycloalkenyl group) alkenyl, (x) aryl,(xi) (aryl) alkyl, (xii) (aryl) alkenyl, (xii) heterocyclic radical,(xiv) (heterocyclic radical) alkyl and (xv) (heterocyclic radical) alkenyl; x is selected from: (a)-c (=o)-n (r *)-, (b)-n (r *)-c (=o)-, (c)-c (=s)-n (r *)-, (d)-n (r *)-c (=s)-, (e)-n (r *)-so 2-and (f)-so 2-n (r *)-, be r wherein *be hydrogen, c 1-c 3low alkyl group or cyclopropyl; r 2be selected from: (a) hydrogen, (b) c 1-c 6alkyl, (c) c 2-c 6alkenyl, (d) c 3-c 6cycloalkyl, (e) c 5-c 6cycloalkenyl group, (f) halo c 1-c 6alkyl and (g) halo c 2-c 6alkenyl; or r 2-x-is y wherein 1for-ch 2-,-o-,-s-or-nh-and y 2for-c (=o)-or-c (r aa) (r bb)-, be r wherein aaand r bbindependently be selected from hydrogen, c 1-c 3low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, sulphomethyl, 1-thio-ethyl, 2-thio-ethyl, methoxymethyl, n-methylamino methyl and methylthiomethyl; r 3and r 4independently be selected from (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl group, (d) heterocyclic radical, (e) aryl and (f)-z-r 14wherein z is (i)-c(r 37a)(r 37b)-，(ii)-c(r 47)＝c(r 48)-，(iii)-c≡c-、(iv)-c(＝o)-， (v)-c(＝s)-，(vi)-c(＝nr 15)-，(vii)-c(r 37a)(or 37c)-，(viii) -c(r 37a)(sr 37c)-， (ix)-c(r 37a)(n(r 37b)(r 37c))-，(x)-c(r 37a)(r 37b)-o-， (xi)-c(r 37a)(r 37b)-n(r 37c)-，(xii)-c(r 37a)(r 37b)-n(o)(r 37c)-， (xiii)-c(r 37a)(r 37b)-n(oh)-，(xiv)-c(r 37a)(r 37b)-s-， (xv)-c(r 37a)(r 37b)-s(o)-，(xvi)-c(r 37a)(r 37b)-s(o) 2-， (xvii)-c(r 37a)(r 37b)-c(＝o)-，(xviii)-c(r 37a)(r 37b)-c(＝s)-， (xix)-c(r 37a)(r 37b)-c(＝nr 15)-，(xx)-c(r 37a)(or 37c)-c(＝o)-， (xxi)-c(r 37a)(sr 37c)-c(＝o)-，(xxii)-c(r 37a)(or 37c)-c(＝s)-， (xxiii)-c(r 37a)(sr 37c)-c(＝s)-，(xxiv)-c(＝o)-c(r 37a)(or 37c)-， (xxv)-c(＝o)-c(r 37a)(sr 37c)-，(xxvi)-c(＝s)-c(r 37a)(or 37c)-， (xxvii)-c(＝s)-c(r 37a)(sr 37c)-，(xxviii)-c(r 37a)(or 37c)-c(r 37a)(or 37c)- (xxix)-c(r 37a)(sr 37c)-c(r 37a)(or 37c)-， (xxx)-c(r 37a)(or 37c)-c(r 37a)(sr 37c)-， (xxxi)-c(r 37a)(sr 37c)-c(r 37a)(sr 37c)-，(xxxii)-c(＝o)-c(＝o)-， (xxxiii)-c(＝s)-c(＝s)-，(xxxiv)-c(＝o)-o-，(xxxv)-c(＝o)-s-，(xxxvi)-c(＝s)-o-，(xxxvii)-c(＝s)-s-，(xxxviii)-c(＝o)-n(r 37a)-， (xxxix)-c(＝s)-n(r 37a)-，(xl)-c(r 37a)(r 37b)-c(＝o)-n(r 37a)-， (xli)-c(r 37a)(r 37b)-c(＝s)-n(r 37a)-，(xlii)-c(r 37a)(r 37b)-c(＝o)-o-， (xliii)-c(r 37a)(r 37b)-c(＝o)-s-，(xliv)-c(r 37a)(r 37b)-c(＝s)-o-， (xlv)-c(r 37a)(r 37b)-c(＝s)-s-，(xlvi)-c(r 37a)(r 37b)-n(r 37b)-c(＝o)-， (xlvii)-c(r 37a)(r 37b)-n(r 37b)-c(＝s)-，(xlviii)-c(r 37a)(r 37b)-o-c(＝o)- ，(xlix)-c(r 37a)(r 37b)-s-c(＝o)-， (l)-c(r 37a)(r 37b)-o-c(＝s)-，(li)-c(r 37a)(r 37b)-s-c(＝s)-， (lii)-c(r 37a)(r 37b)-n(r 37b)-c(＝o)-n(r 37a)-， (liii)-c(r 37a)(r 37b)-n(r 37b)-c(＝s)-n(r 37a)-， (liv)-c(r 37a)(r 37b)-n(r 37b)-c(＝o)-o-， (lv)-c(r 37a)(r 37b)-n(r 37b)-c(＝o)-s-， (lvi)-c(r 37a)(r 37b)-n(r 37b)-c(＝s)-o-， (lvii)-c(r 37a)(r 37b)-n(r 37b)-c(＝s)-s-， (lviii)-c(r 37a)(r 37b)-o-c(＝o)-n(r 37a)-， (lix)-c(r 37a)(r 37b)-s-c(＝o)-n(r 37a)-， (lx)-c(r 37a)(r 37b)-o-c(＝s)-n(r 37a)-， (lxi)-c(r 37a)(r 37b)-s-c(＝s)-n(r 37a)-， (lxii)-c(r 37a)(r 37b)-o-c(＝o)-o-， (lxiii)-c(r 37a)(r 37b)-s-c(＝o)-o-，(lxiv)-c(r 37a)(r 37b)-o-c(＝o)-s-， (lxv)-c(r 37a)(r 37b)-s-c(＝o)-s-，(lxvi)-c(r 37a)(r 37b)-o-c(＝s)-o-， (lxvii)-c(r 37a)(r 37b)-s-c(＝s)-o-，(lxviii)-c(r 37a)(r 37b)-o-c(＝s)-s-， (lxix)-c (r 37a) (r 37b)-s-c (=s)-s-or (lxx)-c (r 37a) (r 37b)-c (r 37a) (or 37c)-; r 14for (i) hydrogen, (ii) c 1-c 12alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (the v) alkyl that replaces of thiol, (vi) r 37cthe alkyl that o-replaces, (vii) r 37cthe alkyl that s-replaces, (viii) aminoalkyl group, (ix) (r 37c) alkyl that replaces of nh-, (x) (r 37a) (r 37c) alkyl that replaces of n-, (xi) r 37athe alkyl that o-(o=) c-replaces, (xii) r 37as-(o=) c-replaces alkyl, (xiii) r 37athe alkyl that o-(s=) c-replaces, (xiv) r 37athe alkyl that s-(s=) c-replaces, (xv) (r 37ao) 2-p (=o)-and the alkyl that repl...
뉴라미니다제 억제제로서의 피롤리딘본 발명은 질환 유발 미생물로부터의 뉴라미니다제, 특히 인플루엔자 뉴라미니다제를 억제하는데 유용한 화학식 Ⅰ의 화합물을 기술하고 있다. 또한 본 발명은 뉴라미니다제를 갖는 미생물에 의해 유발되는 질환을 예방하고 치료하기 위한 조성물 및 방법, 상기 화합물을 제조하는 방법 및 상기 방법에 사용되는 합성 중간체를 기술하고 있다.화학식 Ⅰ화학식 Ⅰ의 화합물 또는 약제학적으로 허용되는 이의 염, 에스테르 또는 프로드럭. 화학식 Ⅰ [이미지] 상기식에서, R1은 (a) -CO2H, (b) -CO2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H, (f) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H, (k) 테트라졸릴, (l) -CH2-테트라졸릴, (m)-C(=O)-NH-S(O)2-R11, (n) -CH2C(=O)-NH-(SO)2-R11, (o) -SO2N(T-R11)R12 및 (p) -CH2SO2N(T-R11)R12[여기서, T는 (ⅰ) 결합, (ⅱ) -C(=O)-, (ⅲ) -C(=O)O-, (ⅳ) -C(=O)S-, (ⅴ) -C(=O)NR36-, (ⅵ) -C(=S)O-, (ⅶ) -C(=S)S- 및 (ⅷ) -C(=S)NR36-으로 이루어진 그룹으로부터 선택되고, R11은 (ⅰ) C1-C12 알킬, (ⅱ) C2-C12 알케닐, (ⅲ) 사이클로알킬, (ⅳ) (사이클로알킬)알킬, (ⅴ) (사이클로알킬)알케닐, (ⅵ) 사이클로알케닐, (ⅶ) (사이클로알케닐)알킬, (ⅷ) (사이클로알케닐)알케닐, (ⅸ) 아릴, (ⅹ) (아릴)알킬, (ⅹⅰ) (아릴)알케닐, (ⅹⅱ) 헤테로사이클릭, (ⅹⅲ) (헤테로사이클릭)알킬 및 (ⅹⅳ) (헤테로사이클릭)알케닐로 이루어진 그룹으로부터 선택되고, R12 및 R36은 독립적으로 (ⅰ) 수소, (ⅱ) C1-C12 알킬, (ⅲ) C2-C12 알케닐, (ⅳ) 사이클로알킬, (ⅴ) (사이클로알킬)알킬, (ⅵ) (사이클로알킬)알케닐, (ⅶ) 사이클로알케닐, (ⅷ) (사이클로알케닐)알킬, (ⅸ) (사이클로알케닐)알케닐, (ⅹ) 아릴, (ⅹⅰ) (아릴)알킬, (ⅹⅱ) (아릴)알케닐, (ⅹⅲ) 헤테로사이클릭, (ⅹⅳ) (헤테로사이클릭)알킬 및 (ⅹⅴ) (헤테로사이클릭)알케닐로 이루어진 그룹으로부터 선택된다]로 이루어진 그룹으로부터 선택되고; X는 (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-SO2- 및 (f) -SO2-N(R*)-(여기서, R*는 수소, C1-C3 저급 알킬 또는 사이클로프로필이다)로 이루어진 그룹으로부터 선택되고; R2는 (a) 수소, (b) C1-C6 알킬, (c) C2-C6 알케닐, (d) C3-C6 사이클로알킬, (e) C5-C6 사이클로알케닐, (f) 할로 C1-C6 알킬 및 (g) 할로 C2-C6 알케닐로 이루어진 그룹으로부터 선택되거나 R2-X는 [이미지][여기서, Y1은 -CH2-, -O-, -S- 또는 -NH-이고, Y2는 -C(=O)- 또는 -C(Raa)(Rbb)-이고, Raa 및 Rbb는 독립적으로 수소, C1-C3 저급 알킬, 하이드록시메틸, 1-하이드록시에틸, 2-하이드록시에틸, 아미노메틸, 1-아미노에틸, 2-아미노에틸, 티올메틸, 1-티올에틸, 2-티올에틸, 메톡시메틸, N-메틸아미노메틸 및 메틸티오메틸로 이루어진 그룹으로부터 선택된다]이고; R3 및 R4는 독립적으로 (a) 수소, (b) 사이클로알킬, (c) 사이클로알케닐, (d) 헤테로사이클릭, (e) 아릴 및 (f) -Z-R14로 이루어진 그룹으로부터 선택되고, Z는 (ⅰ) -C(R37a)(R37b)-, (ⅱ) - C(R47)=C(R48)-, (ⅲ) -C≡C-, (ⅳ) -C(=O)-, (ⅴ) -C(=S)-, (ⅵ) -C(=NR15)-, (ⅶ) -C(R37a)(OR37c)-, (ⅷ) -C(R37a)(SR37c)-, (ⅸ) -C(R37a)(N(R37b)(R37c))-, (ⅹ) -C(R37a)(R37b)-O-, (ⅹⅰ) -C(R37a)(R37b)-N(R37c)-, (ⅹⅱ) -C(R37a)(R37b)-N(O)(R37c)-, (ⅹⅲ) -C(R37a)(R37b)-N(OH)-, (ⅹⅳ) -C(R37a)(R37b)-S-, (ⅹⅴ) -C(R37a)(R37b)-S(O)-, (ⅹⅵ) -C(R37a)(R37b)-S(O)2-, (ⅹⅶ) -C(R37a)(R37b)-C(=O)-, (ⅹⅷ) -C(R37a)(R37b)-C(=S)-, (ⅹⅸ) -C(R37a)(R37b)-C(=NR15)-, (ⅹⅹ) -C(R37a)(OR37c)-C(=O)-, (ⅹⅹⅰ) -C(R37a)(SR37c)-C(=O)-, (ⅹⅹⅱ) -C(R37a)(OR37c)-C(=S)-, (ⅹⅹⅲ) -C(R37a)(SR37c)-C(=S)-, (ⅹⅹⅳ) -C(=O)-C(R37a)(OR37c)-, (ⅹⅹⅴ) -C(=O)-C(R37a)(SR37c)-, (ⅹⅹⅵ) -C(=S)-C(R37a)(OR37c)-, (ⅹⅹⅶ) -C(=S)-C(R37a)(SR37c)-, (ⅹⅹⅷ) -C(R37a)(OR37c)-C(R37a)(OR37c)-, (ⅹⅹⅸ) -C(R37a)(SR37c)-C(R37a)(OR37c)-, (ⅹⅹⅹ) -C(R37a)(OR37c)-C(R37a)(SR37c)-, (ⅹⅹⅹⅰ) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (ⅹⅹⅹⅱ) -C(=O)-C(=O)-, (ⅹⅹⅹⅲ) -C(=S)-C(=S)-, (ⅹⅹⅹⅳ) -C(=O)-O-, (ⅹⅹⅹⅴ) -C(=O)-S-, (ⅹⅹⅹⅵ) -C(=S)-O-, (ⅹⅹⅹⅶ) -C(=S)-S-, (ⅹⅹⅹⅷ) -C(=O)-N(R37a)- (ⅹⅹⅹⅸ) -C(=S)-N(R37a)-, (ⅹⅠ) -C(R37a)(R37b)-C(=O)-N(R37a)-, (ⅹⅠⅰ) -C(R37a)(R37b)-C(=S)-N(R37a)-, (ⅹⅠⅱ) -C(R37a)(R37b)-C(=O)-O-, (ⅹⅠⅲ) -C(R37a)(R37b)-C(=O)-S-, (ⅹⅠⅳ) -C(R37a)(R37b)-C(=S)-O-, (ⅹⅠⅴ) -C(R37a)(R37b)-C(=S)-S-, (ⅹⅠⅵ) -C(R37a)(R37b)-N(R37b)-C(=O)-, (ⅹⅠⅶ) -C(R37a)(R37b)-N(R37b)-C(=S)-, (ⅹⅠⅷ) -C(R37a)(R37b)-O-C(=O)-, (ⅹⅠⅸ) -C(R37a)(R37b)-S-C(=O)-, (Ⅰ) -C(R37a)(R37b)-O-C(=S)-, (Ⅰⅰ) -C(R37a)(R37b)-S-C(=S)-, (Ⅰⅱ) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-, (Ⅰⅲ) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-, (Ⅰⅳ) -C(R37a)(R37b)-N(R37b)-C(=O)-O-, (Ⅰⅴ) -C(R37a)(R37b)-N(R37b)-C(=O)-S-, (Ⅰⅵ) -C(R37a)(R37b)-N(R37b)-C(=S)-O-, (Ⅰⅶ) -C(R37a)(R37b)-N(R37b)-C(=S)-S-, (Ⅰⅷ) -C(R37a)(R37b)-O-C(=O)-N(R37a)-, (Ⅰⅸ) -C(R37a)(R37b)-S-C(=O)-N(R37a)-, (Ⅰⅹ) -C(R37a)(R37b)-O-C(=S)-N(R37a)-, (Ⅰⅹⅰ) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (Ⅰⅹⅱ) -C(R37a)(R37b)-O-C(=O)-O-, (Ⅰⅹⅲ) -C(R37a)(R37b)-S-C(=O)-O-, (Ⅰⅹⅳ) -C(R37a)(R37b)-O-C(=O)-S-, (Ⅰⅹⅴ) -C(R37a)(R37b)-S-C(=O)-S-, (Ⅰⅹⅵ) -C(R37a)(R37b)-O-C(=S)-O-, (Ⅰⅹⅶ) -C(R37a)(R37b)-S-C(=S)-O-, (Ⅰⅹⅷ) -C(R37a)(R37b)-O-C(=S)-S-, (Ⅰⅹⅸ) -C(R37a)(R37b)-S-C(=S)-S- 또는 (Ⅰⅹⅹ) -C(R37a)(R37b)-C(R37a)(OR37c)-이고, R14는 (ⅰ) 수소, (ⅱ) C1-C12 알킬, (ⅲ) 할로알킬, (ⅳ) 하이드록시알킬, (ⅴ) 티올-치환된 알킬, (ⅵ) R37cO-치환된 알킬, (ⅶ) R37cS-치환된 알킬, (ⅷ) 아미노알킬, (ⅸ) (R37c)NH-치환된 알킬, (ⅹ) (R37a)(R37c)N-치환된 알킬, (ⅹⅰ) R37aO-(O=)C-치환된 알킬, (ⅹⅱ) R37aS-(O=)C-치환된 알킬, (ⅹⅲ) R37aO-(S=)C-치환된 알킬, (ⅹⅳ) R37aS-(S=)C-치환된 알킬, (ⅹⅴ) (R37aO)2-P(=O)-치환된 알킬,(ⅹⅵ) 시아노알킬, (ⅹⅶ) C2-C12 알케닐, (ⅹⅷ) 할로알케닐, (ⅹⅸ) C2-C12 알키닐, (ⅹⅹ) 사이클로알킬, (ⅹⅹⅰ) (사이클로알킬)알킬, (ⅹⅹⅱ) (사이클로알킬)알케닐, (ⅹⅹⅲ) (사이클로알킬)알키닐, (ⅹⅹⅳ) 사이클로알케닐, (ⅹⅹⅴ) (사이클로알케닐)알킬, (ⅹⅹⅵ) (사이클로알케닐)알케닐, (ⅹⅹⅶ) (사이클로알케닐)알키닐, (ⅹⅹⅷ) 아릴, (ⅹⅹⅸ) (아릴)알킬, (ⅹⅹⅹ) (아릴)알케닐, (ⅹⅹⅹⅰ) (아릴)알키닐, (ⅹⅹⅹⅱ) 헤테로사이클릭, (ⅹⅹⅹⅲ) (헤테로사이클릭)알킬, (ⅹⅹⅹⅳ) (헤테로사이클릭)알케닐 또는 (ⅹⅹⅹⅴ) (헤테로사이클릭)알키닐이고, 단 R14가 수소가 아닌 경우, Z는 -C(R37a)(R37b)-N(R37b)-C(=O)-O-, -C(R37a)(R37b)-N(R37b)-C(=S)-O-, -C(R37a)(R37b)-N(R37b)-C(=O)-S-, -C(R37a)(R37b)-N(R37b)-C(=S)-S-, -C(R37a)(R37b)-O-C(=O)-O-, -C(R37a)(R37b)-O-C(=S)-O-, -C(R37a)(R37b)-S-C(=O)-O-, -C(R37a)(R37b)-S-C(=S)-O-, -C(R37a)(R37b)-O-C(=O)-S-, -C(R37a)(R37b)-O-C(=S)-S-, -C(R37a)(R37b)-S-C(=O)-S- 또는 -C(R37a)(R37b)-S-C(=S)-S-이고, R37a, R37b, R47 및 R48은 각각 독립적으로 (ⅰ) 수소, (ⅱ) C1-C12 알킬, (ⅲ) 할로알킬, (ⅳ) 하이드록시알킬, (ⅴ) 알콕시알킬, (ⅵ) C2-C12 알케닐, (ⅶ) 할로알케닐, (ⅷ) C2-C12 알키닐, (ⅸ) 사이클로알킬, (ⅹ)(사이클로알킬)알킬, (ⅹⅰ) (사이클로알킬)알케닐, (ⅹⅱ) (사이클로알킬)알키닐, (ⅹⅲ) 사이클로알케닐, (ⅹⅳ) (사이클로알케닐)알킬, (ⅹⅴ) (사이클로알케닐)알케닐, (ⅹⅵ) (사이클로알케닐)알키닐, (ⅹⅶ) 아릴, (ⅹⅷ) (아릴)알킬, (ⅹⅸ)...