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US 11,299,488 B2Granted
Five membered-aminoheterocycle and 5,6-or 6,6-membered bicyclic aminoheterocyclic inhibitors of rock for the treatment of heart failure
AssigneeBristol-Myers Squibb Company
InventorsDonald J. P. Pinto, Tarun Kumar Maishal
Life of this patent
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Abstract
The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.
Claims10
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein
- Q, at each occurrence, is independently selected from CR3 and N;
- provided that Q is not all CR3 and that no more than two Q variables are N;
- R1 is a 4-15 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said heterocycle is substituted with 1-6 R7;
- R2, at each occurrence, is independently selected from H and C1-5 alkyl optionally substituted with halogen, C1-4 alkoxy, —OH, CN, —CO2H, —CO2(C1-4 alkyl), —CO(C1-4 alkyl), —CONH2, —CONH(C1-4 alkyl), and —CON(C1-4 alkyl)2;
- R3, at each occurrence, is independently selected from H, halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, —CH2OH, —OCH2F, —OCHF2, —OCF3, CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, —C(═NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
- R4 and R5, at each occurrence, are independently selected from H, OH, —OC1-3 alkyl substituted with 0-4 Rd, C1-3 alkyl with substituted with 0-4 Rd;
- R6 is selected from H and C1-4 alkyl;
- R7, at each occurrence, is independently selected from H, ═O, NO2, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, CF3, —(CH2)n—CO2H, —(CH2)n—CO2(C1-4 alkyl), —(CH2)n—NR8R8, —NHCO(C1-4 alkyl), —NHCOCF3, —NHCO2(C1-4 alkyl), —NHCO2(CH2)2O(C1-4 alkyl), —NHCO2(CH2)3O(C1-4 alkyl), —NHCO2(CH2)2OH, —NHCO2(CH2)2NH2, —NHCO2(CH2)2N(C1-4 alkyl)2, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NR8R8, —NHSO2(C1-4 alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), —SO2N(C1-4 alkyl)2, —SO2NH(CH2)2OH, —SO2NH(CH2)2O(C1-4 alkyl), —(CH2)n—CONR8R8, —O(CH2)n-carbocycle, —O(CH2)n-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle, —(CH2)n-carbocycle, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R9;
- R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, —(CH2)n—C(O)C1-4alkyl, —(CH2)n—C(O)carbocycle, —(CH2)n—C(O)heterocycle, —(CH2)n—C(O)NRaRa, —(CH2)n—C(O)O-alkyl, —(CH2)n—C(O)O-carbocycle, —(CH2)n—C(O)O-heterocycle, —(CH2)n—SO2alkyl, —(CH2)n—SO2carbocycle, (CH2)n—SO2heterocycle, —(CH2)n—SO2NRaRa, —(CH2)n-carbocycle, and —(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
- alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle substituted with 0-4 R9;
- R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, C1-4 alkyl, C1-4 alkoxy, CH2OH, CO(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), —(CH2)nNRaRa, —(CH2)nCONRaRa, —O(CH2)ncarbocycle, —O(CH2)nheterocycle, —O(CH2)nNRaRa, —(CR10R10)n-4-10 membered heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 Rb;
- R10 is selected from H and C1-4 alkyl;
- Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4 alkyl), Rc, CO2Rc, and CONHRc;
- alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
- Rb, at each occurrence, is independently selected from ═O, OH, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, —CONH—C1-4 alkylene-N(C1-4 alkyl)2, —C1-4 alkylene-O—P(O)(OH)2, —NHCO2(C1-4 alkyl), —Rc, CORc, CO2Rc, and CONHRc;
- Rc, at each occurrence, is independently selected from —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of:
- N, NH, N(C1-4 alkyl), O and S(O)p;
- wherein each ring moiety is substituted with 0-2 Rd;
- Rd, at each occurrence, is independently selected from ═O, halogen, —OH, C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl), and heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of:
- N, NH, N(C1-4 alkyl), O, and S(O)p;
- n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
- and
- p, at each occurrence, is independently selected from 0, 1, and 2.
21 more elements
Dependencies are inferred from the claim text.