IRAK degraders and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
IRAK is an IRAK binding moiety capable of binding to IRAK4, said compound of formula I is a compound of formula I-vv-2:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is:
(a) C 2-3 hydroxyalkyl substituted with zero to 4 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CN, —CF 3 , —OCH 3 , and cyclopropyl;
(b) C 1-3 alkyl substituted with —O(C 1-3 alkyl) and zero to 4 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CN, —CF 3 , and cyclopropyl;
(c) C 4-8 alkyl substituted with zero to 7 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CF 3 , —CN—OCH 3 , cyclopropyl, and —OP(O)(OH) 2 ;
(d) —(CH 2 ) 2-4 NHC(O)(C 1-6 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1-6 alkyl), (CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 NH(C 1-6 alkyl), or (CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 N(C 1-4 alkyl) 2 ;
(e) cyclohexyl substituted with zero to 2 substituents independently selected from —OH, —OCH 3 , C 1-6 alkyl, C 1-6 hydroxyalkyl, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH(C 1-6 hydroxyalkyl), —C(O)NH(C 3-6 cycloalkyl), —C(O)NH(C 3-6 fluoro cycloalkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)O(C 1-3 alkyl), —NHS(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 (C 1-3 alkyl), —S(C 1-3 alkyl), thiazolyl, methyl pyrazolyl, and C 1-3 alkyl substituted with —OH and cyclopropyl;
(f) —(CH 2 ) 2 (phenyl) wherein said phenyl is substituted with —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), or —S(O) 2 NH 2 ; or
(g) piperidinyl substituted with —C(O)(C 1-3 alkyl);
R 2 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, or triazolyl, each substituted with zero to 2 substituents independently selected from F, Cl, —OH, —CN, C 1-3 alkyl, —CH 2 C(O)OCH 3 , —O(C 1-3 alkyl), —NH 2 , —NH(C 1-3 alkyl), —NH(cyclopropyl), —C(O)NH 2 , —NHC(O)(C 1-3 alkyl), —NH(tetrahydropyranyl), hydroxypyrrolidinyl, ═O, —O(piperidinyl), and pyridinyl; and
R 3 is:
(a) C 1-6 alkyl substituted with zero to 4 substituents independently selected from F, —OH, —CH 3 , —CF 3 , and C 3-6 cycloalkyl;
(b) C 3-6 cycloalkyl substituted with zero to 2 substituents independently selected from F, —OH, C 1-3 hydroxyalkyl, —CH 3 , —CF 2 H, —NH 2 , and —C(O)OCH 2 CH 3 ;
(c) oxetanyl, tetrahydropyranyl, or fluoro tetrahydropyranyl;
(d) phenyl substituted with zero to 2 substituents independently selected from —OH, CN, —O(C 1-3 alkyl), C 1-3 hydroxyalkyl, —C(O)NH 2 , —S(O) 2 NH 2 , —NHS(O) 2 (C 1-3 alkyl), pyrazolyl, imidazolyl, and methyl tetrazolyl; or
(e)
L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,
wherein:
each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
LBM is a ligase binding moiety selected from a cereblon E3 ubiquitin ligase binding moiety and a VHL E3 ubiquitin ligase binding moiety.
2. The compound according to claim 1 , wherein the cereblon E3 ubiquitin ligase binding moiety is selected from:
3. The compound according to claim 1 , wherein the IRAK4 binding moiety is selected from:
4. The compound of claim 1 , wherein L is selected from:
5. The compound of claim 1 , wherein said compound is selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof.
I-#
Structure
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-19
I-20
I-23
I-24
I-25
I-26
I-30
I-31
I-40
I-41
I-43
I-44
I-47
I-48
I-49
I-50
I-51
I-52
I-54
I-55
I-56
I-58
I-61
I-62
I-64
I-65
I-67
I-68
I-69
I-70
I-74
I-77
I-80
I-81
I-84
I-93
I-96
I-97
I-98
I-99
I-100
I-119
I-120
I-174
I-206
I-207
6. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
7. The pharmaceutical composition according to claim 6 , further comprising an additional therapeutic agent.
8. The compound according to claim 1 , wherein the cereblon E3 ubiquitin ligase binding moiety is
wherein:
each of X 1 , X 2 , and X 3 is independently a bivalent moiety selected from a covalent bond, —CH 2 —, —C(O)—, —C(S)—, or
R 1 is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —NR 2 , or an optionally substituted C 1-4 aliphatic;
each R 2 is hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
R 5 is hydrogen or C 1-6 aliphatic;
each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring A is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
m is 0, 1, 2, 3 or 4.
9. The compound according to claim 1 , wherein the VHL E3 ubiquitin ligase binding moiety is
wherein:
each of X 4 and X 5 is independently a bivalent moiety selected from —CH 2 —, —C(O)—, —C(S)—, or
each R 4 is independently hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring C is a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; and
q is 0, 1, 2, 3 or 4.
10. The compound according to claim 1 , wherein the VHL E3 ubiquitin ligase binding moiety is
11. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
IRAK is an IRAK binding moiety capable of binding to IRAK4, said compound of formula I is a compound of formula I-hhh-1:
or a pharmaceutically acceptable salt thereof, wherein:
HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, wherein said heteroaryl is substituted with R a and R b ;
R a is H, F, Cl, Br, —CN, —OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NH(C 1-4 hydroxyalkyl), —NH(C 1-4 fluoroalkyl), NH(C 1-6 hydroxy-fluoroalkyl), —C(O)NH 2 , —CH 2 NHC(O)(C 1-6 alkyl), —CH 2 NHC(O)(C 1-6 hydroxyalkyl), —CH 2 NHC(O)NH(C 1-6 alkyl), —CH 2 NHC(O)NHCH 2 (phenyl), CH 2 NHC(O)N(C 1-4 alkyl) 2 , —CH 2 NHC(O)O(C 1-4 alkyl), —CH 2 NHC(O)(C 3-6 cycloalkyl), —CH 2 NHC(O)(tetrahydrofuranyl), —CH 2 NHC(O)CH 2 (C 3-6 cycloalkyl), —CH 2 NHC(O)CH 2 (tetrahydropyranyl), —CH 2 NHC(O)CH 2 (phenyl), —NHC(O)(C 1-4 alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl;
R b is H or —NH 2 ;
R 1 is:
(i) C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-8 hydroxy-fluoroalkyl, —(C 1-6 alkylenyl)O(C 1-4 alkyl), —(C 1-6 alkylenyl)O(C 1-4 fluoroalkyl), —(C 1-6 fluoroalkylenyl)O(C 1-4 alkyl), —(C 1-6 fluoroalkylenyl)O(C 1-4 deuteroalkyl), —(C 1-6 fluoroalkylenyl)O(C 1-4 fluoroalkyl), —(C 1-4 fluoroalkylenyl)C(C 3-6 cycloalkyl) 2 (OH), —(C 1-4 alkylenyl)NHC(O)(C 1-4 alkylenyl)OC(O)(C 1-3 alkyl), (C 1-6 alkylenyl)NHS(O) 2 (C 1-4 alkyl), —(C 1-6 alkylenyl)P(O)(C 1-4 alkoxy) 2 , —(C 1-6 fluoroalkylenyl)NH(C 1-4 alkyl), —(C 1-6 alkylenyl)C(O)NH(C 1-4 alkyl), —(C 1-6 fluoroalkylenyl)C(O)NH(C 1-4 alkyl), —(C 1-6 fluoroalkylenyl)C(O)NH(C 1-4 hydroxyalkyl), or —(C 1-6 fluoroalkylenyl)OP(O)(OH) 2 ;
(ii) —(C 1-3 alkylenyl)R x , —(C 1-3 fluoroalkylenyl)R x , —(C 1-3 alkylenyl)C(O)R x , —(C 1-3 alkylenyl)C(O)NHR x , —(C 1-3 fluoroalkylenyl)C(O)R x , or CH 2 CF=(tetrahydropyranyl), wherein R x is a cyclic group selected from C 3 -6 cycloalkyl, tetrazolyl, 1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl, and triazinyl, wherein each cyclic group is substituted with zero to 3 substituents independently selected from F, —OH, —CH 3 , —C(CH 2 ) 2 OH, —OCH 3 , —C(O)CH 2 CN, —S(O) 2 CH 3 , —S(O) 2 NH 2 , —NHC(O)CH 3 , —N(S(O) 2 CH 3 ) 2 , —CH 2 CH 2 (acetamidophenyl), —CH 2 CH 2 (methoxyphenyl), —CH 2 CH 2 (sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl;
(iii) C 3-6 cycloalkyl or C 4-6 cycloalkenyl, each substituted with zero to 3 substituents independently selected from F, —OH, —CN, C 1-3 alkyl, C 1-3 alkoxy, —S(C 1-3 alkyl), NO 2 , —S(O) 2 (C 1-3 alkyl), C 1-4 hydroxyalkyl, —C(C 1-3 alkyl)(OH)(C 3-6 cycloalkyl), —CH 2 C(O)NH(C 1-3 alkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(C 1-4 hydroxyalkyl), —C(O)NH(C 1-3 alkyl), —C(O)NH(C 1-3 deuteroalkyl), —C(O)NH(C 3-6 cycloalkyl), —NHC(O)O(C 1-3 alkyl), —NHS(O) 2 (C 1-3 alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl;
(iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each substituted with zero to 1 substituent selected from —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, —C(O)(C 1-4 alkyl), —S(O) 2 (C 1-4 alkyl), —S(O) 2 NH(C 1-4 alkyl), —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —O(C 1-3 alkylenyl)N(C 1-3 alkyl) 2 , —CH 2 (morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl, methyl sulfonyl azetidinyl, and —C(O)(methylsulfonyl azetidinyl); or
(v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol, tetrahydrobenzo[d]thiazol-2-amine, or 1,3-diazaspiro[4.5]decane-2,4-dione; and
R 2 is:
(i) C 1-7 alkyl or C 2-6 alkenyl, each substituted with zero to three substituents independently selected from F, —OH, and —CN; —(C 1-4 alkylenyl)O(C 1-4 alkyl), (C 1-4 alkylenyl)O(C 1-4 fluoroalkyl), —(C 1-6 alkylenyl)NH 2 , —(C 1-6 alkylenyl)S(O) 2 (C 1-3 alkyl), —(C 1-6 fluoroalkylenyl)NH(C 1-3 alkyl), or —(C 1-6 alkylenyl)NHC(O)(C 1-4 fluoroalkyl);
(ii) —(C 1-4 alkylenyl)R y wherein R y is C 3-6 cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each substituted with zero to 2 substituents independently selected from F, —OH, and C 1-3 alkyl;
(iii) C 3-6 cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each substituted with zero to 3 substituents independently selected from F, —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, —C(O)(C 1-3 alkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C 1-3 cyanoalkyl), —C(O)O(C 1-3 alkyl), C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)(difluorophenyl), —NH 2 , —NH(C 1-3 alkyl), —NH(C 1-3 fluoroalkyl), —NH(oxetanyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(C 1-3 fluoroalkyl), —NHC(O)(C 3-6 cycloalkyl), —NHC(O)(fluorophenyl), —S(O) 2 (C 1-3 alkyl), imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and methoxypyrimidinyl;
(iv) adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl, bicyclo[1.1.1]pentanyl, or hydroxy-bicyclo[2.2.1]heptanyl; or
(v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or indazolyl, each substituted with 0 to 2 substituents independently selected from F, C 1 , —OH, —CN, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 fluoroalkyl, C 1-4 cyanoalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, —(C 1-3 alkylenyl)O(C 1-3 alkyl), —(C 1-3 alkylenyl)O(C 1-3 fluoroalkyl), —C(O)NH 2 , C(O)NH(C 1-3 alkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)S(O) 2 (C 1-3 alkyl), —S(O) 2 NH 2 , —S(O) 2 (C 1-3 alkyl), pyrazolyl, methyl pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, ethyl tetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and tetrahydropyranyl;
L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,
wherein:
each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
LBM is a ligase ligase binding moiety selected from a cereblon E3 ubiquitin ligase binding moiety and a VHL E3 ubiquitin ligase binding moiety.
12. The compound according to claim 11 , wherein the IRAK4 binding moiety is selected from:
13. The compound according to claim 11 , wherein the cereblon E3 ubiquitin ligase binding moiety is
wherein:
each of X 1 , X 2 , and X 3 is independently a bivalent moiety selected from a covalent bond, —CH 2 —, —C(O)—, —C(S)—, or
R 1 is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —NR 2 , or an optionally substituted C 1-4 aliphatic;
each R 2 is hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring A is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
m is 0, 1, 2, 3 or 4.
14. The compound according to claim 11 , wherein the cereblon E3 ubiquitin ligase binding moiety is selected from:
15. The compound according to claim 11 , wherein the VHL E3 ubiquitin ligase binding moiety is
wherein:
each of X 4 and X 5 is independently a bivalent moiety selected from —CH 2 —, —C(O)—, —C(S)—, or
each R 4 is independently hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, or —N(R)S(O) 2 R;
R 5 is hydrogen or C 1-6 aliphatic;
each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring C is a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; and
q is 0, 1, 2, 3 or 4.
16. The compound according to claim 11 , wherein the VHL E3 ubiquitin ligase binding moiety is
17. The compound according to claim 11 , wherein L is selected from:
18. The compound according to claim 11 , wherein said compound is selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof
I-#
Structure
I-17
I-18
I-21
I-22
I-27
I-29
I-32
I-33
I-34
I-35
I-36
I-37
I-38
I-39
I-42
I-45
I-46
I-57
I-59
I-60
I-63
I-66
I-71
I-72
I-73
I-75
I-76
I-79
I-82
I-83
I-85
I-86
I-88
I-94
I-95
I-101
I-102
I-118
I-121
I-122
I-129
I-131
I-173
19. A pharmaceutical composition comprising a compound according to claim 11 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
20. The pharmaceutical composition according to claim 19 , further comprising an additional therapeutic agent.