NOVEL COMPOUNDS AND COMPOSITIONS FOR TREATING DISEASES ASSOCIATED WITH TRYPTASE ACTIVITYThe present invention relates to novel compounds which are typtase inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.A compound of Formula I :in which:X5 is (C3.14)cycloalkylene, hetero(C3.14)cycloalkylene, (C6.|4)arylene or hetero(C5-|4)arylene;X4 and X6 are independently (C0.2)alkylene;X' and X9 are independently a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(0)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R )C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C._3)alkyl or (C3.8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds; X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-,-S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)0-, wherein R3 is as defined above; X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)alkylene, -X'°-X'- or -X'-X,ϋ-, wherein X'° is (C0.4)alkylene or hetero(C3.4)alkylene and X' is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene; R' is R -X12- or R5-X'3-, wherein:R4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino, X12 is (C .6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X14-X,5-X16-, wherein X15 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene, X14 is (Cn,4)alkylene and X16 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yI, 1 -methylpiperid-3-yI, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piper.azin- 1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yI, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,4,5,6-tetrahydropyrimidin-4-yl and 1 ,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.14)cycloalkyl, (C6.I4)aryl, (C6.)4)aryl(C,.4)alkyl, (C|.8)alkanoyl, (C,.8)aIkyloxy, (C6.l4)aryloxy, (C3.14)cycloalkyloxy, (Cμ4)alkyloxy,(C,.8)alkylthio, (C3.14)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.14)cycloalkyl or (C6_M)aryl, and X'3 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X'7-X18-X'9-, wherein X'8 is as defined above for X'5, X,7 is (Cnl7)alkylene and X'8 is (Cn|8)alkylene, wherein the sum of nl7 and nl 8 is 0, 1 or 2; andR2 is R -X20- or R9-X2'-, wherein:R8 is amino, 1 -iminoethyl or methylamino, X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)a!kylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22 is (Cn22)alkylene and X24 is (Cn2 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R8 is amino then X22 is not (C4.6)alkylene or oxa(C4.6)alkylene and n22 is not 1 , 2, 3 or 4,R9 is as defined above for R5 and X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Ct.8)alkyl, (C3.,4)cycloalkyl, (C6.14)aryl, (C6.I4)aryl(CM)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.,4)cycloalkyloxy, (C )alkyloxy, (C,.8)aIkylthio, (C3.14)cycIoalkylthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R', X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
트립타아제활성관련질병을 치료하기 위한 화합물 및 조성물본 발명은 트립타아제 억제제인 신규 화합물, 이들의 약제학적으로 허용되는 염 및 N-옥사이드, 치료제로의 용도 및 이들의 제조 방법에 관한 것이다. 하기 화학식(I)의 화합물, 및 이의 약제학적으로 허용되는 염, N-옥사이드, 전구약물 유도체 및 보호된 유도체: (I) 상기 식에서 X5는 (C3-14)시클로알킬렌, 헤테로(C3-14)시클로알킬렌, (C6-14)아릴렌 또는 헤테로(C5-14)아릴렌이고; X4 및 X6는 독립적으로 (C0-2)알킬렌이고; X1 및 X9는 독립적으로 공유 결합, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- 또는 -OC(O)O-이고, 각각의 R3는 독립적으로 수소, (C1-3)알킬 또는 (C3-8)시클로알킬이나, 단 X1 및 X9는 둘다 공유결합은 아니고; X3 및 X7은 독립적으로 -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- 또는 -OC(O)O-이고, R3는 상기 정의된 바와 같으며; X2 및 X8은 독립적으로 (C1-8)알킬렌, 헤테로(C1-8)알킬렌, -X10-X11- 또는 -X11-X10-이고, X10은 (C0-4)알킬렌 또는 헤테로(C3-4)알킬렌이고, X11은 (C3-8)시클로알킬렌 또는 헤테로(C3-8)시클로알킬렌이며; R1은 R4-X12- 또는 R5-X13-이고, R4는 아미노, 아미디노, 구아니디노, 1-이미노에틸 또는 메틸아미노이고, X12는 (C4-6)알킬렌, 헤테로(C4-6)알킬렌, 헤테로옥소(C4-6)알킬렌, 옥소(C4-6)알킬렌 또는 -X14-X15-X16-이고, X15는 (C3-6)시클로알킬렌, 헤테로(C5-6)아릴렌, 헤테로(C3-6)시클로알킬렌 또는 페닐렌이고, X14는 (Cn14)알킬렌이고, X16은 (Cn16)알킬렌이고, n14와 n16의 합은 0, 1, 2, 3 또는 4이고, R5는 아제티딘-3-일, 벤조이미다졸-4-일, 벤조이미다졸-5-일, 이미다졸-1-일, 이미다졸-2-일, 이미다졸-4-일, 2-이미다졸린-2-일, 2-이미다졸린-3-일, 2-메틸이미다졸-1-일, 4-메틸이미다졸-1-일, 5-메틸이미다졸-1-일, 1-메틸피페리드-3-일, 1-메틸피페리드-4-일, 피페리드-3-일, 피페리드-4-일, 피페라진-1-일, 피페라진-2-일, 피리드-3-일, 피리드-4-일, 피리미딘-4-일, 피리미딘-5-일, 피롤리딘-3-일, 1,4,5,6-테트라히드로피리미딘-2-일, 1,4,5,6-테트라히드로피리미딘-4-일 및 1,4,5,6-테트라히드로피리미딘-5-일 및 이들의 모든 카르보시클릭 케톤 또는 티오케톤 유도체로부터 선택되는 기이고, 이들 기는 할로, 히드록시, 메르캅토, (C1-8)알킬, (C3-14)시클로알킬, (C6-14)아릴, (C6-14)아릴(C1-4)알킬, (C1-8)알카노일, (C1-8)알킬옥시, (C6-14)아릴옥시, (C3-14)시클로알킬옥시, (C1-4)알킬옥시, (C1-8)알킬티오, (C3-14)시클로알킬티오, (C6-14)아릴티오 및 -NR6R7(여기에서, R6 및 R7은 독립적으로 수소, (C1-8)알킬, (C1-8)알카노일, (C3-14)시클로알킬 또는 (C6-14)아릴로부터 선택된다)로부터 선택되는 하나 이상의 라디칼로 임의로 치환되고, X13은 (C0-6)알킬렌, 헤테로(C2-6)알킬렌, 헤테로옥소(C3-6)알킬렌, 옥소(C2-6)알킬렌 또는 -X17-X18-X19-이고, X18은 상기에서 X15에 대해 정의한 바와 같으며, X17은 (Cn17)알킬렌이고, X18은 (Cn18)알킬렌이고, n17와 n18의 합은 0, 1 또는 2이고; R2는 R8-X20- 또는 R9-X21-이고, R8은 아미노, 1-이미노에틸 또는 메틸아미노이고, X20은 (C4-6)알킬렌, 헤테로(C4-6)알킬렌, 헤테로옥소(C4-6)알킬렌, 옥소(C4-6)알킬렌 또는 -X22-X23-X24-이고, X23은 상기에서 X15에 대해 정의한 바와 같으며, X22는 (Cn22)알킬렌이고, X24는 (Cn24)알킬렌이고, n22와 n24의 합은 0, 1, 2, 3 또는 4이고, 단, R8이 아미노인 경우에 X22는 (C4-6)알킬렌 또는 옥사(C4-6)알킬렌이 아니며, n22는 1, 2, 3 또는 4가 아니고, R9는 상기에서 R5에 대해 정의된 바와 같으며, X21은 (C0-6)알킬렌, 헤테로(C2-6)알킬렌, 헤테로옥소(C3-6)알킬렌, 옥소(C2-6)알킬렌 또는 -X25-X26-X27-이고, X26은 상기에서 X15에 대해 정의한 바와 같으며, X25는 (Cn25)알킬렌이고, X27는 (Cn27)알킬렌이고, n25와 n27의 합은 0, 1 또는 2이며; 상기 정의된 바와 같이 각각의 알킬렌, 시클로알킬렌, 헤테로시클로알킬렌, 페닐렌, 아릴렌 및 헤테로아릴렌은 할로, 히드록시, 메르캅토, (C1-8)알킬, (C3-14)시클로알킬, (C6-14)아릴, (C6-14)아릴(C1-4)알킬, (C1-8)알카노일, (C1-8)알킬옥시, (C6-14)아릴옥시, (C3-14)시클로알킬옥시, (C1-4)알킬옥시, (C1-8)알킬티오, (C3-14)시클로알킬티오, (C6-14)아릴티오 및 -NR6R7(여기에서, R6 및 R7은 상기에서 정의된 바와 같다)로부터 선택되는 하나 이상의 라디칼로 임의로 치환되나, 단, R1, X2, X4, X6, X8 및 R2에 들어 있는 헤테로원자와 X3, X5, X7 및 X9에 들어 있는 헤테로원자 간에는 공유결합이 일어나지 않는다. 