Tricyclic CRBN ligands and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of CRBN, and the treatment of CRBN-mediated disorders.
1. A compound of formula I-d:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —CH 2 — or —C(O)—;
X 2 is a carbon atom;
X 3 is —CH 2 —;
R 1 is hydrogen;
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, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
each R 2 is independently hydrogen, deuterium, —R 3 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R;
each L is independently 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 —C(D)(H)—, —C(D) 2 -, -Cy-, —O—, —N(R)—, —Si(R) 2 —, —Si(OH)(R)—, —Si(OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R 3 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 tricyclic ring
wherein
each of Ring B and Ring C is independently a fused ring selected from 6-membered aryl containing 0-1 nitrogen;
is a single or double bond;
L 1 is a covalent bond;
each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
m is 0 or 1.
2. The compound of claim 1 , wherein X 1 is —CH 2 —.
3. The compound of claim 1 , wherein each of Ring B and Ring C is independently a fused ring selected from 6-membered aryl containing 1 nitrogen.
4. A compound selected from:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
6. The compound of claim 1 , wherein X 1 is —C(O)—.
7. The compound of claim 1 , wherein each R 2 is independently hydrogen, R 3 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, or —C(O)N(R) 2 .
8. The compound of claim 1 , wherein each R 2 is independently hydrogen, R 3 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, or —C(O)N(R) 2 .
9. The compound of claim 1 , wherein each L is independently a bivalent, saturated or unsaturated, straight or branched C 1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, or —N(R)C(O)O—.
10. The compound of claim 1 , wherein each L is independently a bivalent, saturated or unsaturated, straight or branched C 1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —S—, or —C(O)—.
11. The compound of claim 1 , wherein each L is independently a covalent bond.
12. The compound of claim 1 , wherein Ring B is benzo and Ring C is benzo.
13. The compound of claim 1 , wherein Ring B is benzo and Ring C is pyridyl.
14. The compound of claim 1 , wherein m is 1.
15. A pharmaceutical composition comprising a compound according to claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.