Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

1. A compound having a chemical structure:

ARB-Link-E3LB

wherein ARB is an AR binding moiety that does not bind to a ligand binding domain, E3LB is an E3 ligase binding moiety, and Link is a linker coupling the AR binding moiety to the E3 ligase binding moiety; and

wherein the E3LB moiety is a structure selected from the group consisting of:

wherein:

R 110 are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 111 are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 112 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH 2 ) v COR 115 , -CH 2 CHR 116 COR 117 or CH 2 R 118 , where v=1-3, R 115 and R 117 are independently selected from OH, or NR 118 R 119 , R 116 is NR 118 R 119 , R 118 is optionally substituted aryl or optionally substituted heterocyclyl where the optional substituents include alkyl and halogen, and R 119 is hydrogen or optionally substituted alkyl;

R 114 is selected from the group consisting of:

wherein A is a C 4-8 aliphatic ring, B is an aryl or N-containing heteroaryl and optionally substituted by alkyl or haloalkyl;

Y is N, O, C═O, or S, and

X is S or O.

2. The compound of claim 1 , wherein the AR binding moiety is a structure selected from the group consisting of:

wherein:

Ring1 is 3-7 membered alicyclic with 0-4 heteroatoms and substituted by 1 or more halo, CN, C≡CH, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, or C 2-6 alkynyl, bridged or spiro, bicyclic rings with 0-4 heteroatoms and substituted by 1 or more halo, CN, C≡CH, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or

Ring2 is aryl, 2-benzyloxy-3,4difluoro, heteroaryl independently substituted by 1 or more halo, hydroxyl, CN, C≡CH, NR 102 R 103 , OCH3, OC 1-3 alkyl (optionally substituted by 1 or more halo), C 1-6 alkyl (linear branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and substituted with 1 or more halo, hydroxyl, CN, C ≡CH, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, or C 2-6 alkynyl, wherein R 102 and R 103 are independently H, halo, C 1-6 alkyl (optionally substituted by 1 or more F) or, taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms,

and

R 101 is independently H, OH, CONH 2 , CONR 102 R 103 , SONH 2 , SONR 102 R 103 , SO 2 NH 2 , SO 2 NR 102 R 103 , NHCO C 1-3 alkyl (optionally substituted by 1 or more halo), NR 102 COC 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 SO 2 C 1-3 alkyl (optionally substituted by 1 or more halo), NR 102 SOC 1-3 alkyl (optionally substituted by 1 or more halo), CN, C≡CH, NH 2 , NR 102 R 103 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CHF 2 , CH 2 F, CF 3 , halo, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl) or, taken together with an R 101 on an adjacent bonded atom, together with the atoms they are attached to, form a 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2 heteroatoms,

wherein R 102 and R 103 are independently H, halo, C 1-6 alkyl (optionally substituted by 1 or more F) or, taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms.

3. The compound of claim 1 , wherein the linker moiety is a structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C (═CNO 2 )NR L4 , C 3-11 cycloaklyl (optionally substituted with 0-6 R L1 and/or R L2 groups), and heteroaryl (optionally substituted with 0-6 R L1 and/or R L2 groups), wherein R L1 , R L2 , R L3 , R L4 , and R L5 are each independently selected from the group consisting of H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC-C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , SiC(1_8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 and NHSO 2 NH 2 , and wherein R L1 and R L2 each, independently may be linked to another A group to form a cycloalkyl and or heterocyclyl moiety that can be further substituted with 0-4 R L5 groups.

4. The compound of claim 1 , wherein the linker moiety is a structure selected from the group consisting of:

5. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide, and

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide.

6. A pharmaceutical composition, comprising:

an effective amount of the compound of claim 1 , and

a pharmaceutically acceptable carrier, additive and/or excipient.

7. The pharmaceutical composition of claim 6 , further comprising at least one additional anticancer agent.

8. The compound according to claim 1 , wherein the E3LB moiety is the structure:

wherein:

R 110 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 111 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 112 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heterocyclyl; and

R 114 is selected from the group consisting of:

wherein A is a C 4-8 aliphatic ring, B is an aryl or N-containing heteroaryl and optionally substituted by alkyl or haloalkyl.

9. The compound according to claim 8 , wherein the E3LB moiety is the structure:

wherein:

R 110 is hydrogen or optionally substituted alkyl;

R 111 is hydrogen or optionally substituted alkyl;

R 112 is optionally substituted alkyl or optionally substituted cycloalkyl; and

R 114 is:

wherein B is an aryl or N-containing heteroaryl and optionally substituted by alkyl or haloalkyl.

10. The compound according to claim 9 , wherein the E3LB moiety is the structure:

wherein:

R 110 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 111 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 112 is selected from propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, and cyclohexylethyl; and

R 114 is:

wherein each B is independently selected from phenyl, napthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, and oxazolyl.

11. The compound according to claim 1 , wherein the AR binding moiety is the structure:

wherein Ring1 is:

Ring2 is:

and

R 101 is H.

12. The compound according to claim 1 , wherein the linker moiety is a structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, NR L3 , CONR L3 , and CO, wherein R L1 , R L2 , and R L3 , are each independently selected from the group consisting of H, halo, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, OC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, CONHC 1-8 alkyl, N(C 1-8 alkyl)CONH(C 1-8 alkyl), and NHCONH(C 1-8 alkyl).

13. The compound according to claim 12 , wherein the linker moiety is a structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, NR L3 and CONR L3 , wherein R L1 and R L2 , are each independently selected from the group consisting of H and C 1-8 alkyl, and wherein R L3 is H.

14. The compound according to claim 1 , wherein the compound is (S)-1-((S)-2-cyclohexyl-2((S)-2-(methylamino)propanamido)acetyl)-N-((S)-((6 -(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide.

15. The compound according to claim 4 , wherein the AR binding moiety is the structure:

and wherein:

Ring1 is 3-7 membered alicyclic with 0-4 heteroatoms and substituted by 1 or more halo, CN, C≡CH, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), or C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), or

Ring2 is aryl or heteroaryl independently substituted by 1 or more halo, hydroxyl, CN, C≡CH, OC 1-3 alkyl (optionally substituted by 1 or more halo), C 1-6 alkyl (linear branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo),

and

R 101 is independently H, OH, CONH 2 , SONH 2 , NHCO-C 1-3 alkyl (optionally substituted by 1 or more halo), CN, NH 2 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CHF 2 , CH 2 F, CF 3 , halo, or C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl).

16. The compound according to claim 4 , wherein the AR binding moiety is the structure:

wherein Ring1 is:

Ring2 is:

and

R 101 is H.

17. The compound according to claim 16 , wherein the E3LB moiety is the structure:

wherein:

R 110 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 111 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R 112 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heterocyclyl; and

R 114 is selected from the group consisting of:

wherein A is a C 4-8 aliphatic ring, B is an aryl or N-containing heteroaryl and optionally substituted by alkyl or haloalkyl.

18. The compound according to claim 17 , wherein the E3LB moiety is the structure:

wherein:

R 110 is hydrogen or optionally substituted alkyl;

R 111 is hydrogen or optionally substituted alkyl;

R 112 is optionally substituted alkyl or optionally substituted cycloalkyl; and

R 114 is:

wherein B is an aryl or N-containing heteroaryl and optionally substituted by alkyl or haloalkyl.

19. The compound according to claim 18 , wherein the E3LB moiety is the structure:

wherein:

R 110 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 111 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 112 is selected from propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, and cyclohexylethyl; and

R 114 is:

wherein each B is independently selected from phenyl, napthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, and oxazolyl.

20. The compound according to claim 13 , wherein the AR binding moiety is the structure:

wherein Ringl is:

Ring 2 is:

and

R 101 is H; and

wherein the E3LB moiety is the structure:

wherein:

R 110 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 111 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, and cyclopropylmethyl;

R 112 is selected from propyl, isopropyl, cyclopropyl, 2-methylpropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, and cyclohexylethyl; and

R 114 is:

wherein each B is independently selected from phenyl, napthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, and oxazolyl.