CYCLIC AMIDE DERIVATIVES INHIBITORS OF THE INHIBITOR OF APOPTOSIS PROTEINS, THEIR PREPARATION, AND THEIR USEThe present disclosure relates to XIAP inhibitor compounds of the formula (I)A compound of the formula (I): whereinR1 is H or CrC4alkyl;R2 is H, or Ci-C4alkyl which is unsubstituted or substituted by one or more substituents selected from halogen, -OH, -SH, -OCH3, -SCH3, -CN, -SCN and nitro;R3 is H, C1-C4 alkyl, -CF3, -C2F5, -CH2-Z or R2 and R3 together form with the nitrogen form a C3-C6 heteroaliphatic ring;Z is H, -OH1 F, Cl, -CH3; -CF3, -CH2CI, -CH2F or -CH2OH;X is a monocyclic or a bicyclic structure selected from the group consisting of: whereA iS -CH2, -CH-, N1 O, or S;X1 is 0, S, or NR3;R4, Ra and Rb are independently, H; C1-C16 straight or branched alkyl; C1-C16 alkenyl; C1-C16 alkynyl; or C1-C16 cycloalkyl; -(CH2)0-6-phenyl; (CH2)0-6-het; -0-C1-C16 straight or branched alkyl, -S-C1-C16 straight or branched alkyl; -N-C1-C16 straight or branched alkyl; - -0-C1-C16 alkenyl; -S-C1-C16 alkenyl; -N-C1-C16 alkenyl -0-C1-C16 cycloalkyl; -N-C1-C16 cycloalkyl; -S-C1- C16 cycloalkyl; -O-(CH2)0-6-phenyl; -N-(CH2)0.6-phenyl; -S-(CH2)0.6-phenyl; -O-(CH2)0.6-het; -N- (CH2)o-6-het or -S-(CH2)0-6-het wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R4 and R3 may form a ring;U is -R5; -CH(R5)(R6); -CO-N(R5)(R6); -CO-O(R5); -CO-S(R5); -CS-N(R5)(R6); -N(R5)-C0- N(R5)(R6); -C1-C5 alkyl-N(R5)(R6);-CrC5-alkyl-O(R6) or or -C1-C5 alkyl-S(O)n(R6) where n is O, 1 or 2; R5 is H; C1-C10 alkyl; C3-C7 cycloalkyl; -(CH2)L6-C3-C7 cycloalkyl; -C1-C10 alkyl-aryl; -(CH2W phenyl; -(CH2)O-6-C3-C7 cycloalkyl-(CH2)o.6-phenyl; -(CH2)o.4CH-((CH2)i.4-phenyl)2; -(CH2W CH(phenyl)2; -C(O)-C1-C10 alkyl; -C(O)-(CH2WC3-C7 cycloalkyl; -C(0)-(CH2)o-6-phenyl; -(CH2)1-6-het; -C(O)-(CH2)1.6-het; -(CR7R8)o-2-Aryl-V-Aryl; CHR6C(O)N(R12)(R13); C(O)-NH- CH(R11)(R14) or R5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted; or when U is -CO-N(R5)(R6); -CS-N(R5)(R6); -N(R5)-CO-N(R5)(R6); or N(R5)-CO-N(RS)(R6), R5 and R6 together with the N atom form an aromatic or alihpatic heterocycle;R7 and R8 are independently H, halogen; Ci-7 alkyl; -OC1-7 alkyl; C1-7 cycloalkyl; or -OC1-7 cycloalkyl wherein the alkyl, cycloalkyl substituents may be substituted or unsubstituted;V is R9; R10; CR9R10; -C(O)-; C(hal)2; -0-; -N(H)-; N(alkyl); N(aryl); S; SO; or S(O)2;R9 and R10 are independently H, halogen, C1-7 alkyl;-OC1-7 alkyl; C1-7 cycloalkyl; or -OC1-7 cycloalkyl wherein the alkyl, cycloalkyl substituents may be substituted or unsubstituted;R6 is H; -C1-C10 alkyl; -OH; -0-C1-C10 alkyl; -(CH2)O-6-C3-C7 cycloalkyl; -0-(CH2)o-6-aryl; -(CH2)0-6-aryl; phenyl; -(CH2)1-6-het; -O-(CH2)1-6-het; -N(R12)(R13); -CNOR12; -S-R12; -S(O)-R12; -S(O)2-R12; or -S(O)2-NR12R13 wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted;R12 and Ri3 are independently H; C1-C10 alkyl; -(CH2WC3-C7 cycloalkyl; -(CH2W (CH)0-1 (aryl)1-2; -C(O)-C1-C10 alkyl; -C(O)-(CH2WC3-C7 cycloalkyl; -C(0)-0-(CH2)o-6-aryl; -C(0)-(CH2)o-6-0-fluorenyl; -C(O)-NH-(CH2)0.6-aryl; -C(0)-(CH2)o-6-aryl; or -C(O)-(CH2)1-6-het, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted; or a substituent that facilitates transport of the molecule across a cell membrane, or R12 and Ri3 together with the nitrogen are het; where R11 and R14 are C1-7 alkyl; -(CH2)0-6-phenyl; or amide; aryl is phenyl, naphthyl, or indanyl which is unsubstituted or substituted; and pharmaceutically acceptable salts thereof.
유기 화합물본 개시문은 하기 화학식 I의 XIAP 억제제 화합물에 관한 것이다. <화학식 I>  하기 화학식 I의 화합물 및 그의 제약상 허용되는 염. <화학식 I>  상기 식에서, R1은 H 또는 C1-C4알킬이고; R2는 H, 또는 비치환되거나 또는 할로겐, -OH, -SH, -OCH3, -SCH3, -CN, -SCN 및 니트로로부터 선택된 하나 이상의 치환기에 의해 치환된 C1-C4알킬이고; R3은 H, C1-C4알킬, -CF3, -C2F5, -CH2-Z이거나, 또는 R2 및 R3은 질소와 함께 C3-C6헤테로지방족 고리를 형성하고, Z는 H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F 또는 -CH2OH이고; X는  로 이루어진 군으로부터 선택된 모노시클릭 또는 바이시클릭 구조이고, 여기서, A는 -CH2, -CH-, N, O 또는 S이고, X1은 O, S 또는 NRa이고, R4, Ra 및 Rb는 독립적으로 H, 선형 또는 분지형 C1-C16알킬, C1-C16알케닐, C1-C16알키닐, C1-C16시클로알킬, -(CH2)0-6-페닐, (CH2)0-6-het, 선형 또는 분지형 -O-C1-C16알킬, 선형 또는 분지형 -S-C1-C16알킬, 선형 또는 분지형 -N-C1-C16알킬, -O-C1-C16알케닐, -S-C1-C16알케닐, -N-C1-C16알케닐, -O-C1-C16시클로알킬, -N-C1-C16시클로알킬, -S-C1-C16시클로알킬, -O-(CH2)0-6-페닐, -N-(CH2)0-6-페닐, -S-(CH2)0-6-페닐, -O-(CH2)0-6-het, -N-(CH2)0-6-het 또는 -S-(CH2)0-6-het (여기서, 알킬, 시클로알킬 및 페닐은 비치환되거나 치환됨)이거나, 또는 R4 및 Ra는 고리를 형성할 수 있고; U는 -R5, -CH(R5)(R6), -CO-N(R5)(R6), -CO-O(R5), -CO-S(R5), -CS-N(R5)(R6), -N(R5)-CO-N(R5)(R6), -C1-C5알킬-N(R5)(R6), -C1-C5-알킬-O(R6) 또는 -C1-C5알킬-S(O)n(R6) (여기서, n은 0, 1 또는 2임)이고, R5는 H, C1-C10알킬, C3-C7시클로알킬, -(CH2)1-6-C3-C7시클로알킬, -C1-C10알킬-아릴, -(CH2)0-6-페닐, -(CH2)0-6-C3-C7시클로알킬-(CH2)0-6-페닐, -(CH2)0-4-CH-((CH2)1-4-페닐)2, -(CH2)0-6-CH(페닐)2, -C(O)-C1-C10알킬, -C(O)-(CH2)1-6-C3-C7시클로알킬, -C(O)-(CH2)0-6-페닐, -(CH2)1-6-het, -C(O)-(CH2)1-6-het, -(CR7R8)0-2-아릴-V-아릴, CHR6C(O)N(R12)(R13), C(O)-NH-CH(R11)(R14)이거나 또는 R5는 아미노산 잔기이거나 (여기서, 알킬, 시클로알킬, 페닐 및 아릴 치환기는 비치환되거나 치환됨); 또는 U가 -CO-N(R5)(R6), -CS-N(R5)(R6), -N(R5)-CO-N(R5)(R6) 또는 N(R5)-CO-N(R5)(R6)인 경우에 R5 및 R6은 N 원자와 함께 방향족 또는 지방족 헤테로고리를 형성하고; R7 및 R8은 독립적으로 H, 할로겐, C1-7알킬, -OC1-7알킬, C1-7시클로알킬 또는 -OC1-7시클로알킬 (여기서, 알킬, 시클로알킬 치환기는 비치환되거나 치환될 수 있음)이고; V는 R9, R10, CR9R10, -C(O)-, C(hal)2, -O-, -N(H)-, N(알킬), N(아릴), S, SO 또는 S(O)2이고; R9 및 R10은 독립적으로 H, 할로겐, C1-7알킬, -OC1-7알킬, C1-7시클로알킬 또는 -OC1-7시클로알킬 (여기서, 알킬, 시클로알킬 치환기는 비치환되거나 치환될 수 있음)이고; R6은 H, -C1-C10알킬, -OH, -O-C1-C10알킬, -(CH2)0-6-C3-C7시클로알킬, -O-(CH2)0-6-아릴, -(CH2)0-6-아릴, 페닐, -(CH2)1-6-het, -O-(CH2)1-6-het, -N(R12)(R13), -CNOR12, -S-R12, -S(O)-R12, -S(O)2-R12 또는 -S(O)2-NR12R13 (여기서, 알킬, 시클로알킬 및 아릴 치환기는 비치환되거나 치환됨)이고; R12 및 R13은 독립적으로 H, C1-C10알킬, -(CH2)0-6-C3-C7시클로알킬, -(CH2)0-6-(CH)0-1(아릴)1-2, -C(O)-C1-C10알킬, -C(O)-(CH2)1-6-C3-C7시클로알킬, -C(O)-O-(CH2)0-6-아릴, -C(O)-(CH2)0-6-O-플루오레닐, -C(O)-NH-(CH2)0-6-아릴, -C(O)-(CH2)0-6-아릴 또는 -C(O)-(CH2)1-6-het (여기서, 알킬, 시클로알킬 및 아릴 치환기는 비치환되거나 치환됨)이거나 또는 세포막을 통한 분자의 수송을 용이하게 하는 치환기이거나, 또는 R12 및 R13은 질소와 함께 het이고; 여기서, R11 및 R14는 C1-7알킬, -(CH2)0-6-페닐 또는 아미드이고, 아릴은 비치환되거나 치환된 페닐, 나프틸 또는 인다닐이다.