US 12,213,969 B2
2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
Xiaozhang Zheng, Lexington, MA (US); Pui Yee Ng, Lexington, MA (US); and Mary-Margaret Zablocki, Revere, MA (US)
Assigned to VALO HEALTH, INC., Boston, MA (US)
Filed by Valo Health, Inc., Boston, MA (US)
Filed on Jun. 29, 2023, as Appl. No. 18/215,887.
Application 18/215,887 is a division of application No. 17/130,704, filed on Dec. 22, 2020, granted, now 11,730,721.
Application 17/130,704 is a division of application No. 16/719,332, filed on Dec. 18, 2019, granted, now 10,874,649, issued on Dec. 29, 2020.
Application 16/719,332 is a division of application No. 16/309,980, granted, now 10,555,935, issued on Feb. 11, 2020, previously published as PCT/US2017/037970, filed on Jun. 16, 2017.
Claims priority of provisional application 62/351,399, filed on Jun. 17, 2016.
Prior Publication US 2023/0414585 A1, Dec. 28, 2023
Int. Cl. A61K 31/438 (2006.01); C07D 209/54 (2006.01); C07D 221/20 (2006.01); C07D 401/04 (2006.01); C07D 401/06 (2006.01); A61K 31/407 (2006.01); A61P 25/14 (2006.01); A61P 25/28 (2006.01); A61P 35/00 (2006.01)
CPC A61K 31/438 (2013.01) [C07D 209/54 (2013.01); C07D 221/20 (2013.01); C07D 401/04 (2013.01); C07D 401/06 (2013.01); A61K 31/407 (2013.01); A61P 25/14 (2018.01); A61P 25/28 (2018.01); A61P 35/00 (2018.01)] 20 Claims
 
1. A compound of the Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X1, X2, X3, X4, X5, and X6 are each independently, at each occurrence, —CR1R2—, —NR3—, —O—, —C(O)—, —S(O)2—, —S(O)—, or —S—;
Y1, Y2, Y3 and Y4 are each independently, at each occurrence, N or CR1, wherein —C(O)NHOH is attached at Y2 or Y3, and Y2 or Y3 is a carbon atom when attached to —C(O)NHOH;
L is a bond, —(CR1R2)p—, —C(O)NR3—, —S(O)2—, —S(O)2NR3—, —S(O)—, —S(O)NR3—, —C(O)(CR1R2)pO—, or —C(O)(CR1R2)p—;
R is —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —C5-C12spirocycloalkyl, 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, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO2, —CN, —R1, —R2, —SR3, —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;
R1 and R2 are independently, 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 and O, —OH, halogen, —NO2, —CN, —NH(C1-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)2(C1-C6alkyl), or —(CHR5)pNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —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;
or R1 and R2, when on the same atom, can combine with the carbon atom to which they are both attached to form a cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, or spirocycloalkenyl;
or R1 and R2, when on adjacent or non-adjacent atoms, can combine to form a heterocyclyl, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or cycloalkenyl;
R3 and R4 are independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and 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)pN(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-C6alkyl), —N(C1-C6alkyl)2, —S(O)2N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2(C1-C6alkyl), —S(O)R5, —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)R5, heterocyclyl, aryl, or heteroaryl;
R5 is independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO2, —CN, —NHC1-C6(alkyl), —N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —S(O)2N(C1-C6alkyl)2, —S(O)2(C1-C6alkyl), —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2(C1-C6alkyl), —S(O)(C1-C6alkyl), —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)(C1-C6alkyl) or —(CH2)pN(C1-C6alkyl)2;
p is 0, 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, or 4;
m is 0, 1, or 2; and
wherein the sum m+n is 4.