US 12,304,904 B2
Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
Xiaozhang Zheng, Lexington, MA (US); Pui Yee Ng, Lexington, MA (US); Aleksandra Rudnitskaya, Roslindale, MA (US); and David R. Lancia, Jr., Boston, MA (US)
Assigned to VALO HEALTH, INC., Boston, MA (US)
Filed by Valo Health, Inc., Boston, MA (US)
Filed on May 12, 2023, as Appl. No. 18/196,459.
Application 18/196,459 is a division of application No. 17/124,778, filed on Dec. 17, 2020, granted, now 11,702,412.
Application 17/124,778 is a division of application No. 16/522,082, filed on Jul. 25, 2019, granted, now 10,870,645, issued on Dec. 22, 2020.
Application 16/522,082 is a division of application No. 16/199,489, filed on Nov. 26, 2018, granted, now 10,407,418, issued on Sep. 10, 2019.
Application 16/199,489 is a division of application No. 15/013,811, filed on Feb. 2, 2016, granted, now 10,183,934, issued on Jan. 22, 2019.
Claims priority of provisional application 62/110,719, filed on Feb. 2, 2015.
Prior Publication US 2023/0357216 A1, Nov. 9, 2023
Int. Cl. C07D 225/04 (2006.01); A61P 19/02 (2006.01); A61P 25/28 (2006.01); A61P 35/00 (2006.01); C07D 225/06 (2006.01); C07D 225/08 (2006.01); C07D 245/04 (2006.01); C07D 245/06 (2006.01); C07D 267/22 (2006.01); C07D 281/18 (2006.01); C07D 291/08 (2006.01); C07D 413/06 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 513/04 (2006.01); C07D 515/04 (2006.01)
CPC C07D 413/06 (2013.01) [C07D 267/22 (2013.01)] 20 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X1 is CR1R2, NR3, C═O, SO2, S(O) or S;
X2 is CR1R2, O, C═O, SO2, S(O) or S;
X3, X4 and X5 are each independently CR1R2, C═O, S(O) or SO2;
Y1 and Y4 are each independently N or CR1;
Y2 and Y3 are each independently N or CR1 when not bonded to —C(O)NHOH and Y2 and Y3 are C when bonded to —C(O)NHOH;
L is a bond, —(CR1R2)n—, —C(O)—, —C(O)O—, —C(O)NR3—, —S(O)2—, —S(O)2NR3—, —S(O)—, —S(O)NR3—, —C(O)(CR1R2)nO—, or —C(O)(CR1R2)n—;
R is independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —C5-C12spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more-OH, halogen, oxo, —NO2, —CN, —R1, —R2, —OR3, —NHR3, —NR3R4, —S(O)2NR3R4, —S(O)2R1, —C(O)R1, —CO2R1, —NR3S(O)2R1, —S(O)R1, —S(O)NR3R4, —NR3S(O)R1, heterocyclyl, aryl, or heteroaryl, with the proviso that when L is —C(O)— the spiroheterocyclyl is not bound to L via a nitrogen atom;
R1 and R2 are independently, and at each occurrence, —H, R3, R4, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —OH, halogen, —NO2, —CN, —NHC1-C6alkyl, —N(C1-C6alkyl)2, —S(O)2N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)2R5, —S(O)2(C1-C6alkyl), —(C1-C6alkyl)S(O)2R5, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2C1-C6alkyl, or (CHR5)nNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO2, oxo, —CN, —R5, —OR3, —NHR3, NR3R4, —S(O)2N(R3)2—, —S(O)2R5, —C(O)R5, —CO2R5, —NR3S(O)2R5, —S(O)R5, —S(O)NR3R4, —NR3S(O)R5, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;
or R1 and R2 may combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;
or R1 and R2, when on adjacent atoms, can combine to form a heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, or cycloalkenyl;
or R1 and R2, when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocycloalkyl wherein the bridge between X1 and X4 cannot contain exactly one carbon;
R3 and R4 are independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —S(O)2N(C1-C6alkyl)2, —S(O)2(C1-C6alkyl), —(C1-C6alkyl)S(O)2R5, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, or —(CHR5)nN(C1-C6alkyl)2, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO2, oxo, —CN, —R5, —O(C1-C6)alkyl, —NH(C1-C6)alkyl, N(C1-C6alkly)2, —S(O)2N(C1-C6alkyl)2, —S(O)2NHC1-C6alkyl, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2C1-C6alkyl, —S(O)R5, —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)R5, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;
R5 is independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C3-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, halogen, —NO2, —CN, —NHC1-C6alkyl, —N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —S(O)2N(C1-C6alkyl)2, —S(O)2C1-C6alkyl, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)SO2C1-C6alkyl, —S(O)(C1-C6alkyl), —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)(C1-C6alkyl) or (CH2)nN(C1-C6alkyl)2; and
n is independently, and at each occurrence, an integer from 0 to 6;
provided that X1, X2, X3, X4 and X5 are not all CR1R2 at the same time.