Macrocycles that increase p53 activity and the uses thereof

1. A compound of Formula 1:

wherein:

indicates a single or a double bond depending on the identity of X;

X is CR 1 or N when is a single bond; or C when is a double bond;

Y is CR 2 or N;

R is selected from the group consisting of —(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —C(O)NR 8 R 9 , —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-C(O)NR 8 R 9 , —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —C(O)OR a , C(O)OR a , —(CR 8 R 8′ ) n —NH—(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —NH—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n -heteroaryl, —O—(CR 8 R 8′ ) n -heteroaryl —(CR 8 R 8′ ) n —P(O)OR 8 OR 8′ and —(CR 8 R 8′ ) n —OH; wherein: each R 8 and R 8′ is independently selected from the group consisting of H, D, and (C 1 -C 6 )alkyl; or wherein R 8 and R 8′ together with the carbon to which each is attached form (C 3 -C 8 )cycloalkyl;

R 1 is selected from the group consisting of: H, cyano, hydroxy, and alkoxy;

R 2 is H or (C 1 -C 6 )alkyl;

R 3 is (C 1 -C 6 )alkyl;

R 4 is heteroaryl which is optionally substituted with halo, halo-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy;

R 5 is (C 3 -C 7 )alkylene or (C 3 -C 7 )alkenylene, optionally substituted with halo, OH, or —N(R a ) 2 ;

R 6 is independently (C 1 -C 6 )alkyl;

R 7 is haloalkyl or —NR a C(O)R a , C(O)N(R a ) 2 ;

R 9 is independently SO 2 (C 1 -C 6 )alkyl or SO 2 (C 3 -C 8 )cycloalkyl;

R 10 is independently (C 1 -C 6 )alkyl;

R 11 is independently selected from the group consisting of H and halogen;

R a is independently H or (C 1 -C 6 )alkyl;

m is 0, 1, 2, or 3;

n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

p is 0, 1, or 2;

q is 0, 1, 2, or 3; and

t is 0, 1, 2, 3 or 4

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is N and Y is N.

3. The compound of claim 1 , wherein X is CR 1 and Y is N.

4. The compound of claim[s] 1 [-3], wherein R is selected from the group consisting of —(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —C(O)OR a , C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n -heteroaryl, —(CR 8 R 8′ ) n —P(O)OR 8 OR 8′ , and —(CR 8 R 8′ ) n —OH; wherein: each R 8 and R 8′ is independently selected from the group consisting of H, D, and (C 1 -C 6 )alkyl; or wherein R 8 and R 8′ together with the carbon to which each is attached form (C 3 -C 8 )cycloalkyl.

5. The compound of claim 4 , wherein R is selected from the group consisting of —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OR a , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —C(O)OR a ; wherein: each R 8 and R 8′ is independently selected from the group consisting of H, D, and (C 1 -C 6 )alkyl; or wherein R 8 and R 8′ together with the carbon to which each is attached form (C 3 -C 8 )cycloalkyl.

6. The compound of claim 4 , wherein R is —(CR 8 R 8′ ) n —OR a , and n is 1, 2, 3, 4, 5 or 6.

7. The compound of claim 4 , wherein R is —(CR 8 R 8′ ) n —C(O)OR a , and n is 1, 2, 3, 4, 5 or 6.

8. The compound of claim 1 , wherein R 4 is thienyl, optionally substituted with CF 3 , CBr 3 , CCl 3 , CH 3 , Br, Cl, F, or —OCH 3 .

9. The compound of claim[s] 1 [-7], wherein R 4 is

10. The compound of claim 1 , wherein R 5 is —CH═CH—(CH 2 ) y — or —(CH 2 ) x —, x is 2, 3, 4, or 5; y is 1, 2, 3, 4 or 5.

11. The compound of claim 1 selected from the group consisting of:

1-[2-(2-METHOXYETHOXY)PHENYL]-4-[[(10aR)-6,7,10,10a,11,12,13,14-OCTAHYDRO-16-OXO-1-(TRIFLUOROMETHYL)-11(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-16H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLOUNDECIN-11-YL]CARBONYL]PIPERAZINE;

1-[2-(2-HYDROXYETHOXY)PHENYL]-4-[[(10aR)-6,7,10,10a,11,12,13,14-OCTAHYDRO-16-OXO-1-(TRIFLUOROMETHYL)-11(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-16H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLOUNDECIN-11-YL]CARBONYL]PIPERAZINE;

1-[[(12aR)-6,7,8,9,12,12a,13,14,15,16-DECAHYDRO-18-OXO-1-(TRIFLUOROMETHYL)-13(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-18H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLOTRIDECIN-13-YL]CARBONYL]-4-[2-(2-METHOXYETHOXY)PHENYL]PIPERAZINE;

1-[2-(2-HYDROXYETHOXY)PHENYL]-4-[[(11aR)-7,8,11,11a,12,13,14,15-OCTAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12-YL]CARBONYL]PIPERAZINE;

1-[[(11aR)-7,8,9,10,11,11a,12,13,14,15-DECAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12(S)-YL]CARBONYL]-4-[2-(2-HYDROXYETHOXY)PHENYL]PIPERAZINE;

1-[[(12aR)-6,7,8,9,12,12a,13,14,15,16-DECAHYDRO-18-OXO-1-(TRIFLUOROMETHYL)-13-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-18H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLOTRIDECIN-13(S)-YL]CARBONYL]-4-[2-(2-HYDROXYETHOXY)PHENYL]PIPERAZINE;

1-[[(12aR)-6,7,8,9,10,11,12,12a,13,14,15,16-DODECAHYDRO-18-OXO-1-(TRIFLUOROMETHYL)-13(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-18H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLOTRIDECIN-13-YL]CARBONYL]-4-[2-(2-HYDROXYETHOXY)PHENYL]PIPERAZINE;

4-[2-[4-[[(11aR)-7,8,11,11a,12,13,14,15-OCTAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12-YL]CARBONYL]-1-PIPERAZINYL]PHENOXY]BUTANOIC ACID;

1-[2-(2-HYDROXYETHOXY)PHENYL]-4-[[(9aR)-7,8,9,9a,10,11,12,13-OCTAHYDRO-15-OXO-1-(TRIFLUOROMETHYL)-10S-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,15H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAZECIN-10-YL]CARBONYL]PIPERAZINE;

ETHYL 1-[3-[2-[1-CYANO-4-[[(9Z,11aR)-7,8,11,11a,12,13,14,15-OCTAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12-YL]CARBONYL]CYCLOHEXYL]PHENOXY]PROPYL]CYCLOBUTANE CARBOXYLATE;

ETHYL 4-[2-[4-HYDROXY-1-[[(9Z,11aR)-7,8,11,11a,12,13,14,15-OCTAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12-YL]CARBONYL]-4-PIPERIDINYL]PHENOXY]-2,2-DIMETHYL]BUTANOATE;

ETHYL 2,2-DIMETHYL-4-[2-[1,2,3,6-TETRAHYDRO-1-[[(9Z,11aR)-7,8,11,11a,12,13,14,15-OCTAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′-b][1,5]OXAAZACYCLODODECIN-12-YL]CARBONYL]-4-PYRIDINYL]PHENOXY]BUTANOATE; and

1-[3-[2-[4-CYANO-1-[[(11aR)-7,8,9,10,11,11a,12,13,14,15-DECAHYDRO-17-OXO-1-(TRIFLUOROMETHYL)-12(S)-[[5-(TRIFLUOROMETHYL)-3-THIENYL]OXY]-6H,17H-DIPYRIDO[1,2-e:2′,3′b][1,5]OXAAZACYCLODODECIN-12YL]CARBONYL]-4-PIPERIDINYL]PHENOXY]PROPYL]CYCLOBUTANECARBOXYLIC ACID;

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.