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US 2004/0116467 A1Published application
Hexahydro-benzimidazolone compounds useful as anti-inflammatory agents
AssigneesBristol-Myers Squibb Company, Cerep SA
InventorsT.G. Murali Dhar, Dominique Potin, Magali Jeannine Blandine Maillet, Michele Launay, Eric Antoine Nicolai, Edwin J. Iwanowicz
Life of this patent
Estimating the term…
Abstract
The present invention is directed to compounds having the formula (I): 1 useful in treating inflammatory and immune diseases, in which K is O or S; Q is —C(═O)— or optionally substituted C1-4alkylene; Ar is optionally-substituted aryl or heteroaryl; J1, J2, J3, and Y are selected so that ring A is a five-to-six membered optionally-substituted cycloalkenyl or heterocyclo ring having 0 to 2 nitrogen heteroatoms; Z is N or C(R9); and R1, R2, R3 and R9 are as defined in the specification.
Claims20
A compound of formula (I),
- 47
- its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof, in which:
- K is O or S;
- Q is a bond, —C(═O)— or branched or straight chain C1-4alkylene optionally substituted with one to two R4;
- Ar is optionally-substituted aryl or heteroaryl;
- J1 is a bond, —N(R5)—, or —CR6aR7a)—;
- J2 is —N(R5)— or —C(R6bR7b)—;
- J3 is —N(R5)— or —C(R6cR7c)—;
- provided, however, that only one of J1, J2 and J3 may be —N(R5)—, so that ring A is a five-to-six membered cycloalkyl or heterocyclo ring having from 0 to 2 heteroatoms;
- Y is N or C(R8);
- Z is N or C(R9);
- R1 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —OR10, —NR10R11, —C(═O)R10, —CO2R10, —C(═O)NR10R11, —S(O)pR11a, SO2NR10R11, cycloalkyl, heterocyclo, aryl, and heteroaryl;
- R2 and R3 are independently selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —SR12, —OR12, —NR12R13, —CO2R12, —C(═O)R12, —C(═O)NR12R13, aryl, heterocyclo, cycloalkyl, and heteroaryl;
- R4 is selected from OH, O(C1-4alkyl), halogen, cyano, CF3, OCF3, NH2, NH(C1-4alkyl), and N(C1-4alkyl)2;
- R5 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cyano, —OR14, —NR14R15, —C(═O)R14, —CO2R14, —C(═O)NR14R15, —S(O)pR15a, —SO2NR14R15, aryl, heterocyclo, cycloalkyl, and heteroaryl;
- or when R5 is joined to atom J1, J2 or J3, R5 may be taken together with one of R6a, R6b or R6c attached to an adjacent atom of ring A to form a fused heterocyclo or heteroaryl ring;
- or when R5 is joined to atom J3, R5 may be taken together with R8 to form a fused heterocyclo ring;
- R6a, R6b, R6c, R7a, R7b, R7c and R8 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, —SR16, —OR16, —NR16R17, —C(═O)R16, —CO2R16, —C(═O)NR16R17, —NR16C(═O)R17, —NR16C(═O)OR17, S(O)qR17a, —NR16SO2R17a, —SO2NR16R17, aryl, heterocyclo, cycloalkyl, and heteroaryl;
- or R6a with R7a, or R6b with R7b, or R6c with R7c are taken together to form a keto group (═O) or a spiro cycloalkyl or heterocyclo ring;
- or R6b taken together with either R6a or R6c may form a fused benzo, cycloalkyl, heterocyclo, or heteroaryl ring;
- or R6c taken together with R8 may form a fused cycloalkyl or heterocyclo;
- R9 is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —SR18, —OR18, —NR18R19, —CO2R18, —C(═O)R18, —C(═O)NR18R19, aryl, heterocyclo, cycloalkyl, and heteroaryl;
- R10, R11, R12, R13, R14, R15, R16, R17, R18, and R19 (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
- or (ii) any two of R10, R1, R12, R13, R14, R15, R16, R17, R18, and R19 when attached to the same nitrogen atom may be taken together to form a heteroaryl or heterocyclo ring, with the remainder of R10, R11, R12, R13, R14, R15, R16, R17, R18, and R19 being selected independently from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
- R11a, R15a, and R17a are independently selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
- p is 1, 2, or 3;
- and
- q is 1, 2, or 3.
25 more elements
A compound having the formula (Ia),
- 49
- its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof, in which:
- Q is —C(═O)— or —(CHR4a)t—
- Ar is aryl or heteroaryl optionally substituted with one to three R20;
- Y is N or C(R8);
- Z is N or C(R9);
- R1 is selected from hydrogen, C1-6alkyl, —C(═O)H, —C(═O)(C1-6alkyl), —CO2H, —CO2(C1-6alkyl), or C1-6alkyl substituted with one to two of hydroxy, —O(C1-6alkyl), —C(═O)H, —C(═O)(C1-6alkyl), —CO2H, —CO2(C1-6alkyl), —C(═O)NH2, —C(═O)NH2, —C(═O)NH(C1-4alkyl), —C(═O)N(C1-4alkyl)2, —NH2, —NH(C1-4alkyl), and —N(C1-4alkyl)2;
- R2 and R3 are independently selected from halogen, (C1-4)alkyl, cyano, halo(C1-4)alkyl, halo(C1-4)alkoxy, nitro, phenyloxy, benzyloxy, and phenylthio;
- R4a is selected from hydrogen, OH, O(CH3), O(CH2CH3), halogen, cyano, CF3, OCF3, NH2, NH(CH3), and N(CH3)2;
- R6 and R8 at each occurrence are independently selected from (a) halogen, nitro, and cyano;
- or from (b) —SR16, —OR16, —NR16R17, —C(═O)R16, —CO2R16, —C(═O)NR16R17, —NR16C(═O)R17, —NR16C(═O)OR17, —S(O)qR17a, NR16SO2R17a) and —SO2NR16R17;
- or from (c) alkyl, alkenyl, aryl, heterocyclo, cycloalkyl, and heteroaryl, in turn optionally substituted with one to two groups selected from R22;
- and/or (d) two R6 groups taken together form keto (═O), with the remainder of the R6 groups selected from (a), (b), and (c);
- R9 is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —SR18, —OR18, —NR18R19, —CO2R18, —C(═O)R18, —C(═O)NR18R19, aryl, heterocyclo, cycloalkyl, and heteroaryl;
- R16 and R17 are selected independently of each other from hydrogen, C1-6alkyl, phenyl, four to seven membered heterocyclo, C3-7cycloalkyl, and five to six membered heteroaryl, each of which in turn is optionally substituted with one to two groups selected from R23;
- R17a is C1-6alkyl, phenyl, four to seven membered heterocyclo, C3-7cycloalkyl, five to six membered heteroaryl each of which is optionally substituted with one to two groups selected from R23;
- R20 at each occurrence is selected from halogen, C1-6alkyl, hydroxy, (C1-4)alkoxy, (C1-4)alkylthio, cyano, nitro, —CO2H, —C(═O)H, —CO2(C1-4)alkyl, —C(═O)(C1-4)alkyl, —C(═O)NH(CH2)rCO2H, —C(═O)NH(CH2)rCO2(C4alkyl), S(O)2(C1-4alkyl), phenyl, benzyl, phenyloxy, benzyloxy, five to six membered heteroaryl, C3-7cycloalkyl, and four to seven membered heterocyclo, wherein each of the alkyl, alkoxy, and cyclic groups in turn are optionally substituted with one to three of R24;
- R22, R23 and R24 are at each occurrence selected independently from halogen, cyano, nitro, C1-6alkyl, hydroxy, trifluoromethyl, trifluoromethoxy, —O(C1-6alkyl), —C(═O)H, —C(═O)(C1-6alkyl), —CO2H, —CO2(C1-6alkyl), —C(═O)NH2, —C(═O)NH2, —C(═O)NH(C1-4alkyl), —C(═O)N(C1-4alkyl)2, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, hydroxy(C1-4)alkyl, methoxy(C1-4)alkyl, ethoxy(C1-4)alkyl, amino(C1-4)alkyl, and halo(C1-4)alkyl;
- m is 0 or 1;
- p and q are independently 1, 2, or 3;
- r and s are 0, 1, 2, 3 or 4;
- and
- t is 0, 1 or 2.
20 more elements
Dependencies are inferred from the claim text.