Benzopiperazine compositions as BET bromodomain inhibitors
AssigneeFORMA Therapeutics, Inc.
InventorsKenneth W. Bair, Torsten Herbertz, Goss S. Kauffman, Katherine J. Kayser-Bricker, George P. Luke, Matthew W. Martin, David S. Millan, Shawn E. R. Schiller, Adam C. Talbot, Mark J. Tebbe
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Abstract
The present invention relates to inhibitors of bromo and extra terminal (BET) bromodomains that are useful for the treatment of cancer, inflammatory diseases, diabetes, and obesity, having Formula (I): wherein X, Y, Z, R1, R2, R4 and R7 are defined herein.
Claims28
A compound having Formula (VI):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- R10 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —OR1, —NRaR1, CN, —(CRkRl)nS(O)2Ri, —(CRkRl)nNRaS(O)2Ri, —(CRkRl)nS(O)2NRaRi, —(CRkRl)nC(O)ORa, —(CRkRl)nC(O)Ri, —(CRkRl)nC(O)R, —(CRkRl)nC(O)NRaRi, —(CRkRl)nRi, —(CRkRl)nNRaC(O)NRb, and —(CRkRl)nNRaC(O)ORb, wherein each alkyl is substituted with one or more R11;
- or
- each R11 is independently at each occurrence selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, CN, C1-C6 hydroxyalkyl, —(CRkRl)mNH2, C1-C6 alkylamino, C1-C6 dialkylamino, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —S(O)2Ra, —C(O)H, —NRaC(O)ORa, —NRaC(O)C1-C6 alkyl, or oxo;
- or two R11 together can form a heterocycloalkyl ring;
- Ra and Rb are each independently hydrogen, C1-C6 alkyl, —C1-C4 alkyl(aryl), or aryl;
- Rd is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R12;
- Ri is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, —(CH2)qN(H)C1-C6 alkyl, —(CH2)qN(C1-C6 alkyl)2, —(CRkRi)mC3-C7 cycloalkyl, —(CRkR1)maryl, —(CRkRl)mheteroaryl, or —(CRkRl)mheterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R11;
- each R12 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, —CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H)C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, or C1-C6 dialkylamino;
- or
- two R12 together with the carbon to which they are attached form a 4- to 6 membered heterospirocycle;
- or two R12 together when on adjacent carbons form a C4-C6 cycloalkyl optionally substituted with one or more R13;
- or two R12 together when on adjacent carbons form an aryl optionally substituted with one or more R13;
- or two R12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R13;
- or two R12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R13;
- or R12 with the carbon to which it is attached and the adjacent carbon form a C3 cycloalkyl optionally substituted with one or more R13;
- each R13 is independently at each occurrence selected from C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, NO2, —NH2, —CH2NH2, —(CH2)qN(C1-C6 alkyl)2, C1-C6 alkylamino, C1-C6 dialkylamino, —O(CH2)qN(H) C1-C6 alkyl, —O(CH2)qN(C1-C6 alkyl)2, aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O)—C1-C6 alkyl, —S(O)p—N(H)C1-C6 alkyl, —S(O)p—N(C1-C6 alkyl)2, —C(O)C1-C6 alkyl, —NHC(O)(C1-C6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from consisting of C1-C6 alkyl, halogen, CN, C1-C6 alkoxy, hydroxy, NO2, —NH2, C1-C6 alkylamino, and C1-C6 dialkylamino;
- Rk and Rl are each independently at each occurrence selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or halogen;
- each m, n, and p is independently at each occurrence 0, 1, or 2;
- and
- each q is independently at each occurrence 1, 2, 3 or 4.
A compound that is cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate.
A compound that is cyclobutyl (3S)-4-acetyl-7-{1-[(3R)-1,1-dioxo-1λ6-thian-3-yl]-1H-pyrazol-4-yl}-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate.
A compound that is cyclobutyl (3S)-4-acetyl-7-{1-[(3S)-1,1-dioxo-1λ6-thian-3-yl]-1H-pyrazol-4-yl}-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate.
Dependencies are inferred from the claim text.