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US 12,213,969 B2Granted
2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
AssigneeValo Health, Inc.
InventorsXiaozhang Zheng, Pui Yee Ng, Mary-Margaret Zablocki
Life of this patent
Estimating the term…
Abstract
The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease.
Claims20
A compound of the Formula I:
- 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.
12 more elements
Dependencies are inferred from the claim text.