COMPOUNDS AND METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINSThe present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.A bifunctional compound comprising a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (ULM), and a protein targeting moiety (PTM) connected directly or through a chemical linker (L);wherein ULM is a group according to the chemical structure:wherein, each R5 and R6 is independently -OH, -SH, or optionally substituted alkyl or R5, R6, and the carbon atom to which they are attached form a carbonyl;R7 is H or optionally substituted alkyl;E is a bond, C=O, or C=S;G is a bond, optionally substituted alkyl, -COOH or C=J;J is O or N-R8;R8 is H, CN, optionally substituted alkyl or optionally substituted alkoxy;M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic or each R9 and R10 is independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulphide linked ULM, optionally substituted heteroaryl, or haloalkyl; or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;R11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionallysubstituted heteroaryl, optionally substituted aryl, or R12 is H or optionally substituted alkyl;R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, each R14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocycloalkyl;R15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;each R16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;each R25 is independently H or optionally substituted alkyl; or both R25 groups can be taken together to form an oxo or optionally substituted cycloalkyl group;R23 is H or OH;Z1, Z2, Z3, and Z4 are independently C or N; ando is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 2. The compound of claim 1, wherein R15 is selected from the group consisting of:wherein R30 is H or an optionally substituted alkyl. 3. The compound of claim 1 or 2, wherein E is C=O; M is R11 is R18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; andp is 0, 1, 2, 3, or 4. 4. The compound of any of claims 1-3, wherein R11 is selected from the group consisting of: 5. The compound of claim 1 or 2, whereinE is C=O; M is ;R11 is optionally substituted heteroaryl or optionally substituted heterocyclic or ;q is 1 or 2;R20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, or R21 is H or optionally substituted alkyl; andR22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl. 6. The compound of claim 1 or 2, whereinE is C=O; M is R11 is an optionally substituted heterocycle, an optionally substituted heteroaryl, anoptionally substituted aryl or .R12 is H or optionally substituted alkyl;R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, 7. The compound of claim 5 or 6, wherein R11 is selected from the group consisting of: 8. The compound of claim 1, wherein wherein ULM is a group according to the chemical structure:;wherein X is O or SY is H, methyl or ethylR17 is H, methyl, ethyl, hydoxymethyl or cyclopropyl;M is optionally substituted heteroaryl, optionally substituted aryl,R9 is H; R10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;R11 is optionally substituted heteroaromatic, optionally substituted heterocyclic,optionally substituted aryl or R12 is H or optionally substituted alkyl; andR13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 9. The compound of claim 1, according to the chemical structure:wherein Y is H, methyl or ethyl;R9 is H;R10 is isopropyl, te...
타겟화된 단백질들의 향상된 분해를 위한 화합물들 및 방법들본 발명은 타겟화된 유비퀴틴화의 조절제들, 특히, 본 발명에 따른 이작용성 화합물들에 의해 분해되고/거나 그밖에 억제되는 다양한 폴리펩티드들 및 다른 단백질들의 억제제들로서 유용성이 발견된, 이작용성 화합물들에 관한 것이다. 특히, 본 발명은 한편으로 유비퀴틴 리가아제에 결합하는 VHL 리간드를 함유하고, 다른 한편으로 타겟 단백질이 그러한 단백질의 분해(및 억제)를 달성하기 위해 유비퀴틴 리가아제의 근위에 배치되도록 타겟 단백질을 결합하는 모이어티를 함유하는, 화합물들에 관한 것이다. 본 발명은 타겟화된 폴리펩티드들의 분해/억제와 일치하는, 본 발명에 따른 화합물들과 관련된 광범위한 약리학적 활성들을 나타낸다.폰 히펠-린다우(VHL; Von Hippel-Lindau) E3 유비퀴틴 리가아제 결합 모이어티(ULM; ubiquitin ligase binding moiety), 및 직접적으로 또는 화학적 링커(L)를 통해 연결된 단백질 타겟팅 모이어티(PTM; protein targeting moiety)를 포함하는 이작용성 화합물, 또는 이의 약제학적으로 허용되는 염, 입체이성질체, 용매화물 또는 다형체로서,ULM이 하기 화학 구조에 따른 기인 화합물:상기 식에서, 각 R5 및 R6은 독립적으로, -OH, -SH, 또는 임의적으로 치환된 알킬이거나, R5, R6, 및 여기에 결합된 탄소 원자는 카보닐을 형성하며;R7은 H 또는 임의적으로 치환된 알킬이며;E는 결합, C=O, 또는 C=S이며;G는 결합, 임의적으로 치환된 알킬, -COOH 또는 C=J이며;J는 O 또는 N-R8이며;R8은 H, CN, 임의적으로 치환된 알킬 또는 임의적으로 치환된 알콕시이며;M은 임의적으로 치환된 아릴, 임의적으로 치환된 헤테로아릴, 임의적으로 치환된 헤테로시클릭 또는 이며;각 R9 및 R10은 독립적으로, H; 임의적으로 치환된 알킬, 임의적으로 치환된 시클로알킬, 임의적으로 치환된 하이드록시알킬, 임의적으로 치환된 티오알킬, 디설파이드 연결된 ULM, 임의적으로 치환된 헤테로아릴, 또는 할로알킬이거나; R9, R10, 및 여기에 결합된 탄소 원자는 임의적으로 치환된 시클로알킬을 형성하며;R11은 임의적으로 치환된 헤테로시클릭, 임의적으로 치환된 알콕시, 임의적으로 치환된 헤테로아릴, 임의적으로 치환된 아릴 또는 이며;R12는 H 또는 임의적으로 치환된 알킬이며;R13은 H, 임의적으로 치환된 알킬, 임의적으로 치환된 알킬카보닐, 임의적으로 치환된 (시클로알킬)알킬카보닐, 임의적으로 치환된 아르알킬카보닐, 임의적으로 치환된 아릴카보닐, 임의적으로 치환된 (헤테로시클릴)카보닐, 또는 임의적으로 치환된 아르알킬; 임의적으로 치환된 (옥소알킬)카바메이트이며;각 R14는 독립적으로, H, 할로알킬, 임의적으로 치환된 시클로알킬, 임의적으로 치환된 알킬 또는 임의적으로 치환된 헤테로시클로알킬이며;R15는 H, 임의적으로 치환된 헤테로아릴, 할로알킬, 임의적으로 치환된 아릴, 임의적으로 치환된 알콕시, 또는 임의적으로 치환된 헤테로시클릴이며;각 R16은 독립적으로, 할로, 임의적으로 치환된 알킬, 임의적으로 치환된 할로알킬, CN, 또는 임의적으로 치환된 할로알콕시이며;각 R25는 독립적으로, H 또는 임의적으로 치환된 알킬이거나; 두 개의 R25 기 모두는 함께 결합되어 옥소 또는 임의적으로 치환된 시클로알킬 기를 형성할 수 있으며;R23은 H 또는 OH이며; Z1, Z2, Z3, 및 Z4는 독립적으로, C 또는 N이며;o는 0, 1, 2, 3, 또는 4이다.