KRAS G12D proteolysis targeting chimeras
Provided herein are KRAS G12D proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS G12D PROTACs, and methods of making and using the KRAS G12D PROTACs, e.g., to promote degradation of KRAS G12D and/or treat KRAS G12D-associated cancers. In an embodiment, the KRAS G12D PROTAC has the following structural formula: [KRAS G12Di]-L′-[Degron], or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., KRAS G12Di, L′, Degron) are as described herein.
1. A compound of the following formula:
[KRAS G12Di]-L′-[Degron],
or a pharmaceutically acceptable salt thereof, wherein:
KRAS G12Di is:
L′ is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1 -C 15 hydrocarbon chain wherein 0-5 methylenes of L′ are replaced by X, each X is independently —O—, —N(R)—, —S—, —OC(O)—, —C(O)—, —C(H)(F)—, —C(F) 2 —, -Cy-, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —N(R)C(O)—, —OC(O)N(R)—, —N(R)C(O)N(R)—,
each -Cy- is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 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 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or (C 1 -C 3 ) alkyl;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
Degron is a cereblon binding moiety.
2. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
X 4 is N or C(R 42 );
R 42 is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —CN, (C 1 -C 6 )alkoxy, —S—(C 1 -C 6 )alkyl or —S—(C 1 -C 6 )haloalkyl;
Y is a bond, O or NR 5 ;
R 1 is hydrogen, hydroxy, halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )cyanoalkyl, (C 1 -C 3 )hydroxyalkyl, —C(O)H, —CO 2 R 5 , —CO 2 N(R 5 ) 2 or (C 5 -C 6 )heteroaryl;
R 2 is hydrogen, —N(R 5 ) 2 , (C 3 -C 12 )heterocyclyl, (C 1 -C 6 )alkyl, -L-(C 3 -C 12 )heterocyclyl, -L-(C 6 -C 14 )aryl, -L-(C 5 -C 14 )heteroaryl, -L-(C 3 -C 12 )cycloalkyl, -L-N(R 5 ) 2 , -L-N(H)C(NH)NH 2 , -L-C(O)N(R 5 ) 2 , -L-(C 1 -C 6 )haloalkyl, -L-OR 5 , -L-NR 5 C(O)—(C 6 -C 14 )aryl, -L-COOH or -L-C(O)O(C 1 -C 6 )alkyl, wherein the (C 3 -C 12 )heterocyclyl, the (C 6 -C 14 )aryl of -L-NR 5 C(O)—(C 6 -C 14 )aryl, the (C 3 -C 12 )heterocyclyl of -L-(C 3 -C 12 )heterocyclyl and the (C 3 -C 12 )cycloalkyl of -L-(C 3 -C 12 )cycloalkyl are optionally substituted with one or more R 6 , and the aryl of -L-(C 6 -C 14 )aryl and (C 5 -C 14 )heteroaryl of -L-(C 5 -C 14 )heteroaryl are optionally substituted with one or more R 7 ;
L is (C 1 -C 4 )alkylene optionally substituted with hydroxy, (C 1 -C 4 )hydroxyalkyl or (C 5 -C 14 )heteroaryl;
R 3 is
R 4 is hydrogen, halogen or (C 1 -C 3 )alkyl;
each R 5 is independently hydrogen or (C 1 -C 3 )alkyl;
each R 6 is independently halogen, hydroxy, (C 1 -C 3 )hydroxyalkyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO 2 F, —N(H)C(O)-phenyl, —N(H)C(O)-phenyl-SO 2 F, (C 1 -C 3 )alkyl-substituted pyrazole, (C 6 -C 14 )aryl (C 1 -C 3 )alkyl, tert-butyldimethylsilyloxy-CH 2 —, —N(R 5 ) 2 , (C 1 -C 3 )alkoxy (C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl-C(O)—, oxo, (C 1 -C 3 )haloalkyl-C(O)—, —SO 2 F, (C 1 -C 3 )alkoxy (C 1 -C 3 )alkoxy, —CH 2 OC(O)N(R 5 ) 2 , —CH 2 N(H)C(O)O—(C 1 -C 6 )alkyl, —CH 2 N(H)C(O)N(R 5 ) 2 , —CH 2 N(H)C(O)(C 1 -C 6 )alkyl, —CH 2 (pyrazolyl), —CH 2 N(H)S(O) 2 (C 1 -C 6 )alkyl, —CH 2 OC(O)(C 3 -C 12 )heterocyclyl, —OC(O)N(R 5 ) 2 , —OC(O)N(H)(C 1 -C 3 )alkyl-O—(C 1 -C 3 )alkyl, —OC(O)N(H)(C 1 -C 3 )alkyl-O—(C 1 -C 3 )alkyl-phenyl-(C 1 -C 3 )alkyl-N(CH 3 ) 2 , —OC(O)N(H)(C 1 -C 3 )alkyl-O—(C 1 -C 3 )alkyl-phenyl, —OC(O)(C 3 -C 12 )heterocyclyl or —CH 2 -(C 3 -C 12 )heterocyclyl, wherein the phenyl of —N(H)C(O)phenyl and —OC(O)N(H)(C 1 -C 3 )alkyl-O—(C 1 -C 3 )alkyl-phenyl is optionally substituted with —C(O)H or —OH, and the (C 3 -C 12 )heterocyclyl of —CH 2 —(C 3 -C 12 )heterocyclyl is optionally substituted with oxo;
Q is a bond or O;
each R 7 is independently halogen, hydroxy, —C(O)H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )hydroxyalkyl or —N(R 5 ) 2 ;
L′ is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1 -C 15 hydrocarbon chain wherein 0-5 methylenes of L′ are replaced by X;
each X is independently —O—, —N(R)—, —S—, —OC(O)—, —C(O)—, —C(H)(F)—, —C(F) 2 —, -Cy-, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —N(R)C(O)—, —OC(O)N(R)—, —N(R)C(O)N(R)—,
each -Cy- is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 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 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or (C 1 -C 3 )alkyl;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
Degron is a cereblon binding moiety.
3. The compound of claim 2 , wherein Y is O.
4. The compound of claim 2 , wherein R 1 is hydrogen.
5. The compound of claim 3 , wherein R 2 is -L-(C 3 -C 12 )heterocyclyl, wherein the (C 3 -C 12 )heterocyclyl of -L-(C 3 -C 12 )heterocyclyl is optionally substituted with one or more R 6 .
6. The compound of claim 5 , wherein L is methylene.
7. The compound of claim 2 , wherein R 3 is
8. The compound of claim 2 , wherein R 3 is
9. The compound of claim 2 , wherein R 4 is halogen.
10. The compound of claim 9 , wherein R 4 is fluoro.
11. The compound of claim 2 , wherein each R 6 is independently halogen, hydroxy, (C 1 -C 3 )hydroxyalkyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy or cyano.
12. The compound of claim 1 , wherein L′ is a bivalent, saturated or unsaturated, straight or branched C 1 -C 15 hydrocarbon chain wherein 1 or 2 methylenes of L′ are replaced by Cy and 1-3 methylenes of L′ are replaced by X, wherein:
each X is independently —O—, —C(O)—, —N(R)— or —N(R)C(O)—.
13. The compound of claim 12 , wherein each -Cy- is independently a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
14. The compound of 13 , wherein each -Cy- is a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen, and sulfur, and is linked via a nitrogen atom.
15. The compound of claim 12 , wherein each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecanylene.
16. The compound of claim 1 , wherein L′ comprises -Cy 1 -(CH 2 ) 0-1 —X—(CH 2 ) 0-1 -Cy 2 -, wherein Cy 1 and Cy 2 are each independently -Cy-.
17. The compound of claim 16 , wherein Cy 1 is a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen, and sulfur, and is linked via a nitrogen atom.
18. The compound of claim 17 , wherein Cy 1 is piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecanylene.
19. The compound of claim 16 , wherein Cy 2 is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecanylene.
20. The compound of claim 16 , wherein X is O or N(R).
21. The compound of claim 20 , wherein R is H.
22. The compound of claim 1 , wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.
23. The compound of claim 22 , wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.
24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
25. A pharmaceutical combination comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
26. A compound, or a pharmaceutically acceptable salt thereof, selected from:
27. A pharmaceutical composition comprising a compound of claim 26 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
28. A method of reducing a level or activity of KRAS G12D in a cell expressing KRAS G12D, comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
29. A method of reducing a level or activity of KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
30. A method for treating a KRAS G12D-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.