Substituted pyridines as inhibitors of dnmt1

A method of treating a disease selected from:

• cancer, pre-cancerous syndromes, beta haemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula (Ibr):
• wherein:
• Xlbr and X2br are independently selected from:
• hydrogen,
• —CN,
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• —OC1-6alkyl,
• —ORe,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl,
• heterocycloalkyl substituted from 1 to 4 times by Rd,
• —SH, and
• —SRa;
• Ybr is selected from:
• S, NH, NRz, O, S(O), and S(O)2;
• R1br is selected from:
• —NH2,
• —NHRa,
• —NRbRc,
• —CN,
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• —OC1-6alkyl,
• —ORe,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl,
• heterocycloalkyl substituted from 1 to 4 times by Rd,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rd,
• —SH, and
• —SRa;
• R3br is selected from:
• hydrogen,
• C1-6alkyl,
• Re,
• heterocycloalkyl,
• heterocycloalkyl substituted from 1 to 4 times by Rd,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• heteroaryl, and
• heteroaryl substituted from 1 to 4 times by Rd;
• and
• R5br is selected from:
• —NH2,
• —NHRa,
• —NRbRc,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• —C1-6alkyl,
• —OC1-6alkyl,
• —ORe,
• —Oaryl,
• —Oaryl substituted from 1 to 4 times by Rd,
• —Oheteroaryl,
• —Oheteroaryl substituted from 1 to 4 times by Rd,
• —SH, and
• —SRa;
• where:
• each Ra is independently selected from
• C1-6alkyl,
• Re,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rd,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl, and
• heterocycloalkyl substituted from 1 to 4 times by Rd;
• Rb and Rc are independently selected from:
• C1-6alkyl,
• Re,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rd;
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl, and
• heterocycloalkyl substituted from 1 to 4 times by Rd, or
• Rb and Rc are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• —ORe,
• aryl,
• aryl substituted from 1 to 4 times by Rd,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl, and
• heterocycloalkyl substituted from 1 to 4 times by Rd,
• C1-4alkoxy,
• —CN,
• oxo,
• —OH,
• —COOH,
• —NO2,
• —NH2,
• —N(H)C1-5alkyl,
• —N(H)Re,
• —N(C1-5alkyl)2,
• —NReRe,
• —N(Re)C1-5alkyl,
• —ONHC(NH)NH2,
• —Oheterocycloalkyl,
• —NHcycloalkyl,
• —N(C1-5alkyl)cycloalkyl,
• —NHheterocycloalkyl,
• —N(C1-5alkyl)heterocycloalkyl,
• —S(O)2C1-4alkyl,
• —SO2NH2
• —S(O)2phenyl,
• benzoyl,
• 2-methylcyclopropyl,
• imidazolyl,
• (methoxypyridinylmethyl)amino,
• (methylcyclopropylmethyl)amino,
• (fluorophenylmethyl)amino,
• (methyloxetanylmethyl)amino, and
• (methylcyclobutylmethyl)amino;
• each Rd is independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• C1-6alkyl,
• Re,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• heterocycloalkyl,
• heterocycloalkyl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• aryl,
• aryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• C1-4alkoxy,
• C1-4alkoxy substituted from 1 to 4 times by fluoro,
• —Oaryl,
• —Oaryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —ORe,
• —C(O)H,
• —C(O)Rzz,
• —C(O)aryl,
• —C(O)aryl substituted from 1 to 4 times by Rzz,
• —C(O)heteroaryl,
• —C(O)heteroaryl substituted from 1 to 4 times by Rzz,
• —OC(O)H,
• —CO(O)Rzz,
• —OC(O)aryl,
• —CO(O)aryl substituted from 1 to 4 times by Rzz,
• —OC(O)heteroaryl,
• —OC(O)heteroaryl substituted from 1 to 4 times by Rzz,
• —SH,
• —SRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)H,
• —S(O)Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)2H,
• —S(O)2Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)2NH2,
• —S(O)2NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)2NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —P(O)(CH3)2,
• —NHS(O)2H,
• —NHS(O)2Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NHC(O)H,
• —NHC(O)Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —C(O)NH2,
• —C(O)NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —C(O)NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —C(O)OH,
• —C(O)ORx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• oxo,
• —OH,
• —NH2,
• —NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NH2,
• —CN,
• —NHC(O)NH2,
• —NHC(O)NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NHC(O)NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• each Re is independently selected from:
• C1-6alkyl substituted with from 1 to 9 substituents independently selected from:
• fluoro,
• chloro,
• bromo,
• iodo,
• —OC1-6alkyl,
• —OC1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —OC(O)C1-6alkyl,
• —OC(O)C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —ONHC(NH)NH2,
• —OP(O)(OH)2,
• —SH,
• —SRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)H,
• —S(O)Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)2H,
• —S(O)2Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• oxo,
• —OH,
• —NH2,
• —NHRxx,
• where Rxx is selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with C1-4alkoxy, C1-4alkoxy substituted with from 1 to 6 substituents independently selected from:
• fluoro, triazolyl, cyclopropyl,oxo, —ORxy, —COOH, CN, and —NRxyRxz, where Rxy and Rxz are Independently selected from:
• hydrogen, aryl, C1-5alkyl heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —ORxy, —COOH, —CN, and —NRxyRxz, where Rxy and Rxz are Independently selected from:
• hydrogen, aryl, C1-5alkyl and C1-5alkyl substituted with from 1 to 4 substituents independently selected from:
• fluoro, triazolyl, cyclopropyl,oxo, —OH, —OC1-5alkyl, —OC1-5alkyl substituted from 1 to 6 times by fluoro and —COOH,
• —NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-4alkoxy, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, C1-4alkoxy, triazolyl, cyclopropyl, oxo, —OH, —COOH,
• —NH2, and —CN,
• guanidino,
• —C(O)OH,
• —C(O)ORx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —C(O)NH2,
• —C(O)NHRx,
• where Rx is selected from aryl, heteroaryl, —OH, C1-4alkoxy, cycloalkyl, cycloalkyl substituted with HO—(C1-4alkyl)-, heterocyloalkyl, heterocyloalkyl substituted with HO—(C1-4alkyl)-, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, heteroaryl, —NH2, and —CN,
• —C(O)NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with HO—(C1-4alkyl)-, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• or Rx1 and Rx2 taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from fluoro, oxo, —OH, HO—(C1-4alkyl)-, —COOH, —NH2, and —CN,
• aryl,
• aryl substituted from 1 to 4 times by Rx,
• where Rx is selected from fluoro, chloro, bromo, iodo, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —N(CH3)2, —NHC(O)C1-4alkyl, and —CN,
• —Oaryl,
• —Oaryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —N(CH3)2, and —CN,
• heteroaryl,
• heteroaryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-4alkoxy, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —Oheteroaryl,
• —Oheteroaryl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —N(CH3)2, and —CN,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —N(CH3)2, and —CN,
• heterocycloalkyl,
• heterocycloalkyl substituted from 1 to 4 times by Rx,
• where Rx is selected from oxo, —OH, —N(C1-4alkyl)2, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, —N(CH3)2, and —CN,
• —S(O)2NH2,
• —S(O)2NHRx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —S(O)2NRx1Rx2,
• where Rx1 and Rx2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 Substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NHS(O)2H,
• —NHS(O)2Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —OC(O)NH2,
• —NHC(O)Rx,
• where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from:
• fluoro, oxo, —OH, —COOH, —NH2, and —CN,
• —NHC(O)NHRxp,
• where Rxp is selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C1-6alkyl substituted with from 1 to 4 substituents independently selected from:
• —COOH, —NH2, and —CN,
• —NHC(O)NRx3Rx4,
• where Rx3 and Rx4 are each independently selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C1-6alkyl substituted with from 1 to 6 Substituents independently selected from:
• —COOH, —NH2, and —CN,
• —NHC(O)C(O)NH2,
• —NO2, and
• —CN;
• and
• R2 is selected from
• C1-6alkyl,
• Re,
• cycloalkyl,
• cycloalkyl substituted from 1 to 4 times by Rd,
• heterocycloalkyl, and
• heterocycloalkyl substituted from 1 to 4 times by Rd;
• Rzz is selected from
• C1-6alkyl, and
• Re;
• provided that:
• X1br and X2br are not both hydrogen;
• or a pharmaceutically acceptable salt or prodrug thereof.