MACROCYCLIC BROAD SPECTRUM ANTIBIOTICSProvided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.A compound of Formula (I) :wherein:R1 and R2 are each independently H, - (C1-C6) alkyl, - (C1-C6) alkyl-OR23, -CH2CH (OH) CH2NH2, -CH2CH (heterocycloalkyl) CH2NH2, -CH2C (O) NH2, -CH2C (O) N (H) CH2CN, - (C1-C6) alkyl-C (O) OR23, - (C1-C6) alkyl-NR21R22, - (C1-C6) alkyl-C (O) NR25R26, - (C1-C6) alkyl-N (R23) C (O) (C1-C6) alkylNR21R22, or - (C1-C6) alkyl-C (O) N (R23) (C1-C6) alkyl, or optionally substituted heterocycloalkyl；R6, R7, and R8 are each independently H, or - (C1-C6) alkyl；R9 is H, - (C1-C6) alkyl, - (C1-C6) haloalkyl, or - (C3-C6) cycloalkyl；R10 is H, or - (C1-C6) alkyl；R11 and R12 are each independently H, -NH2, - (C1-C6) alkyl, - (C1-C6) alkyl-OR23, - (C1-C6) alkyl-SR23, - (C1-C6) alkyl-C (O) OR23, - (C1-C6) alkyl-NR21R22, - (C1-C6) alkyl-CN, - (C1-C6) alkyl-C (O) NR25R26, - (C1-C6) alkyl-S (O) - (C1-C6) alkyl, - (C1-C6) alkyl-N (H) CH＝NH, - (C1-C6) alkyl-N (H) C (NH) NH2, - (C1-C6) alkyl-heterocycloalkyl, optionally substituted - (C1-C6) alkyl-N (H) heterocycloalkyl, or - (C1-C6) alkyl-heteroaryl； or R11 and R18 are combined to form an optionally substituted heterocycloalkyl ring, and R12 is H；R15, R16, R17, and R18 are each independently H, - (C1-C6) alkyl, - (C3-C6) cycloalkyl, - (C1-C6) alkyl-OR23, - (C1-C6) alkyl-C (O) OR23, or - (C1-C6) alkyl-NR21R22；A is -CN, -CH2CN, -CH＝CHCN, -CH2N (H) C (O) CH2CN, -CH2N (H) C (O) N (H) R24, -C (O) N (H) R34, -C (O) N (H) C (R23) 2C (O) OR29, -C (O) N (H) C (R23) 2C (O) NR32R33, -C (O) N (H) C (R23) 2C＝NR30, -C (O) N (H) SO3H, -C (O) N (H) SO2CH＝CH2, - C (O) N (H) N (R24) C (O) CH＝CH2, -C (O) N (H) N (R24) C (O) CH2Cl,X is optionally substituted - (C1-C6) alkyl-, - (C2-C6) alkenyl-, - (C2-C6) alkynyl, - (C3-C7) cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -O- (C1-C6) alkyl-, -N (R24) (C1-C6) alkyl-, -N (R24) (C6-C10) aryl-, or -SO2 (C1-C6) alkyl-；Y is a bond, optionally substituted - (C1-C6) alkyl-, - (C2-C6) alkenyl-, - (C2-C6) alkynyl, - (C1-C6) alkyl-N (R24) (C1-C6) alkyl-, -O- (C1-C6) alkyl-, -O (C6-C10) aryl-, -N (R24) (C1-C6) alkyl-, -N (R24) SO2 (C1-C6) alkyl-, -N (R24) C (O) (C1-C6) alkyl-, -C (O) (C1-C6) alkyl-, -S (C1-C6) alkyl-, -SO2 (C1-C6) alkyl-, -C (O) NH (C1-C6) alkyl-, - (C3-C7) cycloalkyl-, optionally substituted -C (O) N (R24) aryl-, optionally substituted -N (R24) C (O) aryl-, optionally substituted -N (R24) SO2aryl-, optionally substituted aryl, or optionally substituted heteroaryl；Z is H, halogen, -NH2, -CN, -CF3, -CO2H, - (C1-C12) alkyl, - (C2-C12) alkenyl, - (C2-C12) alkynyl, -C (O) NR25R26, -O- (C1-C12) alkyl, -N (R24) (C1-C12) alkyl, -N (R24) C (O) (C1-C12) alkyl, optionally substituted - (C3-C7) cycloalkyl, - (C1-C6) alkyl-heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl；each R21 and R22 is independently H, - (C1-C6) alkyl, - (C1-C6) heteroalkyl, - (C1-C6) alkyl-CO2H, -C (O) (C1-C6) alkyl, -C (O) N (R31) 2, -SO2N (R31) 2； or R21 and R22 and the nitrogen atom to which they are attached form a heterocycloalkyl ring；each R31 is independently H or - (C1-C6) alkyl； or two R31 and the nitrogen atom to which they are attached form a heterocycloalkyl ring；each R23 is independently H or - (C1-C6) alkyl；each R24 is independently H or - (C1-C6) alkyl；each R25 and R26 is independently H or optionally substituted - (C1-C6) alkyl； or R25 and R26 and the nitrogen atom to which they are attached form a heterocycloalkyl ring；each R27 is independently halogen, - (C1-C6) alkyl, or - (C1-C6) heteroalkyl；each R28 is independently halogen, - (C1-C6) alkyl, or - (C1-C6) heteroalkyl；R29 is -CH2C (O) NH2 or optionally substituted aryl；R30 isR32 is H or - (C1-C6) alkyl；R33 is -CH2CN, -OC (O) (C1-C6) alkyl, or -SO2NH2；R34 is -OH, -NH2, -CN, -CH2CH2CN, -O (C1-C6) alkyl, -C (O) (C1-C6) alkyl, -SO2NH2,p is 0, 1, or 2； andq is 0, 1, or 2；or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
마크로시클릭 광범위 항생제본원에는 몇몇 실시양태에서 광범위 생활성을 갖는 항균 화합물이 제공된다. 다양한 실시양태에서, 화합물은 박테리아에서 필수 단백질인 박테리아 1형 신호 펩티다제(SpsB)의 억제에 의하여 작용한다. 본원에 기재된 화합물을 사용한 약학 조성물 및 치료 방법도 또한 제공된다.하기 화학식 (I)의 화합물 또는 그의 약학적 허용 가능한 염, 용매화물 또는 프로드러그:상기 식에서,R1 및 R2는 각각 독립적으로 H, -(C1-C6)알킬, -(C1-C6)알킬-OR23, -CH2CH(OH)CH2NH2, -CH2CH(헤테로시클로알킬)CH2NH2, -CH2C(O)NH2, -CH2C(O)N(H)CH2CN, -(C1-C6)알킬-C(O)OR23, -(C1-C6)알킬-NR21R22, -(C1-C6)알킬-C(O)NR25R26, -(C1-C6)알킬-N(R23)C(O)(C1-C6)알킬NR21R22, -(C1-C6)알킬-C(O)N(R23)(C1-C6)알킬 또는 임의로 치환된 헤테로시클로알킬이며;R6, R7 및 R8은 각각 독립적으로 H 또는 -(C1-C6)알킬이며;R9는 H, -(C1-C6)알킬, -(C1-C6)할로알킬 또는 -(C3-C6)시클로알킬이며;R10은 H 또는 -(C1-C6)알킬이며;R11 및 R12는 각각 독립적으로 H, -NH2, -(C1-C6)알킬, -(C1-C6)알킬-OR23, -(C1-C6)알킬-SR23, -(C1-C6)알킬-C(O)OR23, -(C1-C6)알킬-NR21R22, -(C1-C6)알킬-CN, -(C1-C6)알킬-C(O)NR25R26, -(C1-C6)알킬-S(O)-(C1-C6)알킬, -(C1-C6)알킬-N(H)CH=NH, -(C1-C6)알킬-N(H)C(NH)NH2, -(C1-C6)알킬-헤테로시클로알킬, 임의로 치환된 -(C1-C6)알킬-N(H)헤테로시클로알킬 또는 -(C1-C6)알킬-헤테로아릴이거나; 또는 R11 및 R18은 합하여 임의로 치환된 헤테로시클로알킬 고리를 형성하며, R12는 H이며;R15, R16, R17 및 R18은 각각 독립적으로 H, -(C1-C6)알킬, -(C3-C6)시클로알킬, -(C1-C6)알킬-OR23, -(C1-C6)알킬-C(O)OR23 또는 -(C1-C6)알킬-NR21R22이며;A는 -CN, -CH2CN, -CH=CHCN, -CH2N(H)C(O)CH2CN, -CH2N(H)C(O)N(H)R24, -C(O)N(H)R34, -C(O)N(H)C(R23)2C(O)OR29, -C(O)N(H)C(R23)2C(O)NR32R33, -C(O)N(H)C(R23)2C=NR30, -C(O)N(H)SO3H, -C(O)N(H)SO2CH=CH2, -C(O)N(H)N(R24)C(O)CH=CH2, -C(O)N(H)N(R24)C(O)CH2Cl, , , , , , , ,  또는 이며;X는 임의로 치환된 -(C1-C6)알킬-, -(C2-C6)알케닐-, -(C2-C6)알키닐, -(C3-C7)시클로알킬-, 임의로 치환된 헤테로시클로알킬, 임의로 치환된 아릴, 임의로 치환된 헤테로아릴, -O-(C1-C6)알킬-, -N(R24)(C1-C6)알킬-, -N(R24)(C6-C10)아릴- 또는 -SO2(C1-C6)알킬-이며;Y는 결합, 임의로 치환된 -(C1-C6)알킬-, -(C2-C6)알케닐-, -(C2-C6)알키닐, -(C1-C6)알킬-N(R24)(C1-C6)알킬-, -O-(C1-C6)알킬-, -O(C6-C10)아릴-, -N(R24)(C1-C6)알킬-, -N(R24)SO2(C1-C6)알킬-, -N(R24)C(O)(C1-C6)알킬-, -C(O)(C1-C6)알킬-, -S(C1-C6)알킬-, -SO2(C1-C6)알킬-, -C(O)NH(C1-C6)알킬-, -(C3-C7)시클로알킬-, 임의로 치환된 -C(O)N(R24)아릴-, 임의로 치환된 -N(R24)C(O)아릴-, 임의로 치환된 -N(R24)SO2아릴-, 임의로 치환된 아릴 또는 임의로 치환된 헤테로아릴이며;Z는 H, 할로겐, -NH2, -CN, -CF3, -CO2H, -(C1-C12)알킬, -(C2-C12)알케닐, -(C2-C12)알키닐, -C(O)NR25R26, -O-(C1-C12)알킬, -N(R24)(C1-C12)알킬, -N(R24)C(O)(C1-C12)알킬, 임의로 치환된 -(C3-C7)시클로알킬, -(C1-C6)알킬-헤테로시클로알킬, 임의로 치환된 아릴 또는 임의로 치환된 헤테로아릴이며;각각의 R21 및 R22는 독립적으로 H, -(C1-C6)알킬, -(C1-C6)헤테로알킬, -(C1-C6)알킬-CO2H, -C(O)(C1-C6)알킬, -C(O)N(R31)2, -SO2N(R31)2이거나; 또는 R21 및 R22 및 이들이 연결되어 있는 질소 원자는 헤테로시클로알킬 고리를 형성하며;각각의 R31은 독립적으로 H 또는 -(C1-C6)알킬이거나; 또는 2개의 R31 및 이들이 연결되어 있는 질소 원자는 헤테로시클로알킬 고리를 형성하며;각각의 R23은 독립적으로 H 또는 -(C1-C6)알킬이며;각각의 R24는 독립적으로 H 또는 -(C1-C6)알킬이며;각각의 R25 및 R26은 독립적으로 H 또는 임의로 치환된 -(C1-C6)알킬이거나; 또는 R25 및 R26 및 이들이 연결되어 있는 질소 원자는 헤테로시클로알킬 고리를 형성하며;각각의 R27은 독립적으로 할로겐, -(C1-C6)알킬 또는 -(C1-C6)헤테로알킬이며;각각의 R28은 독립적으로 할로겐, -(C1-C6)알킬 또는 -(C1-C6)헤테로알킬이며;R29는 -CH2C(O)NH2 또는 임의로 치환된 아릴이며;R30은 이며;R32는 H 또는 -(C1-C6)알킬이며;R33은 -CH2CN, -OC(O)(C1-C6)알킬 또는 -SO2NH2이며;R34는 -OH, -NH2, -CN, -CH2CH2CN, -O(C1-C6)알킬, -C(O)(C1-C6)알킬, -SO2NH2, ,  또는 이며;p는 0, 1 또는 2이며;q는 0, 1 또는 2이다.