Spiro-cyclic compounds useful as anti-inflammatory agents

A compound having the formula (Ia)

• or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which
• K and L are independently O or S;
• Q is a bond, —C(═O)— or branched or straight chain C1-6alkylene optionally substituted with one to two R4;
• Ar is aryl or heteroaryl;
• Y is a bond or —C(R6aR7a)—;
• J1 is —N(R5)— or —C(R6bR7b)—;
• J3 is —N(R5)— or —C(R6dR7d)—;
• provided, that only one of J1 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;
• Z1 and Z2 are independently NR25, S or O;
• so that Z forms a spiro heterocyclic ring provided that Z is not a C2-3 alkylenedioxy ring and that only one of Z1 and Z2 may be NR25;
• R1 is N or C(R9);
• 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(C1-6alkyl), halogen, cyano, CF3, OCF3, NH2, NH(C1-6alkyl), and N(C1-6alkyl)2;
• R5 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —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, J3 or Y, R5 may be taken together with one of R6a, R6b or R6d attached to an adjacent atom of ring A to form a fused heterocyclo or heteroaryl ring;
• R6a, R6b, R6d, R7a, R7b, R7b and R7d 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;
• 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;
• 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 R12, R13, R14, R15, R16, R17, R18, and R19 when attached to the same nitrogen atom (as in NR12R13, NR14R15, NR16R17, or NR18R19) may be taken together to form a heteroaryl or heterocyclo ring, with the remainder of 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;
• R25 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —NR26R27, —C(═O)R26, —CO2R26, —C(═O)NR26R27, —S(O)pR27, —SO2NR26R27, aryl, heterocyclo, cycloalkyl, and heteroaryl;
• R26, and R27 are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
• p is 0, 1, 2, or 3;
• and
• q is 1, 2, or 3.

A compound of formula (Ib),

• its stereoisomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof, in which:
• one of Z1 or Z2 is NR25 and the other of Z1 or Z2 is O or S;
• R1 is N or C(R9);
• R2 and R3 are independently selected from halogen, (C1-6)alkyl, cyano, halo(C1-6)alkyl, halo(C1-6)alkoxy, nitro, phenyloxy, benzyloxy, and phenylthio;
• R6 is 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);
• 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;
• R20a and R20b are independently selected from halogen, C1-6alkyl, hydroxy, (C1-6)alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, cyano, nitro, —CO2H, —C(═O)H, —CO2(C1-6)alkyl, —C(═O) (C1-6)alkyl, —C(═O)NH(CH2)rCO2H, —C(═O)NH(CH2)rCO2(C1-6alkyl), and —S(O)2(C1-6alkyl);
• or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with one to two of halogen, C1-6alkyl, hydroxy, (C1-6)alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, cyano, nitro, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —CO2H, —C(═O)H, —CO2(C1-6)alkyl, and/or —C(═O) (C1-6)alkyl;
• or alternatively, two R20b groups join together with each other or one R20b joins together with R20a to form a fused benzo ring;
• 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(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, hydroxy(C1-6)alkyl, methoxy(C1-6)alkyl, ethoxy(C1-6)alkyl, amino(C1-6)alkyl, and halo(C1-6)alkyl;
• R25 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —NR26R27, —C(═O)R26, —CO2R26, —C(═O)NR26R27, —S(O)pR27, —SO2NR26R27, aryl, heterocyclo, cycloalkyl, and heteroaryl;
• R26 and R27 are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo
• n, s and and p are independently 0, 1, or 2;
• q is 1, 2, or 3;
• and
• r is 0, 1, 2, 3 or 4.

A compound selected from the group consisting of,

• (i) (2R,5S,7a′S)-7a′-[(4-bromophenyl)-methyl]-2′-(3,5-dichlorophenyl)-5-methyldihydro-1′H,4H-spiro[1,3-oxazolidine-2,6′-pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• (2R,5R,7a′S)-7a′-[(4-bromophenyl)-methyl]-2′-(3,5-dichlorophenyl)-5-methyldihydro-1′H,4H-spiro[1,3-oxazolidine-2,6′-pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• (2R,5R,7a′S)-7′a-[(4-Bromophenyl)methyl]-2′-(3,5-dichlorophenyl)dihydro-5-methylspiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• (2S,5R,7a′S)-7′a-[(4-Bromophenyl)methyl]-2′-(3,5-dichlorophenyl)dihydro-5-methylspiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo [1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• (2R,7a′S)-7′a-[(4-Bromophenyl)methyl]-2′-(3,5-dichlorophenyl)dihydrospiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• (2S,7a′S)-7′a-[(4-Bromophenyl)methyl]-2′-(3,5-dichlorophenyl)dihydrospiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• 4-[[(2R,5R,7a′S)-2′-(3,5-Dichlorophenyl)dihydro-5-methyl-1′,3′,4-trioxospiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo[1,2-c]imidazol]-7′a(7′H)-yl]methyl]benzonitrile;
• 4-[[(2S,5R,7a′S)-2′-(3,5-Dichlorophenyl)dihydro-5-methyl-1′,3′,4-trioxospiro[oxazolidine-2,6′(5′H)-[1H]pyrrolo[1,2-c]imidazol]-7′a(7′H)-yl]methyl]-benzonitrile;
• (2R,5R,7a′S)-2′-(3,5-dichlorophenyl)-7a′-[[4-(pyrimidin-4-yl)-phenyl)-methyl]-5-methyldihydro-1′H,4H-spiro[1,3-oxazolidine-2,6′-pyrrolo[1,2-c]imidazole]-1′,3′,4(2′H)-trione;
• ethyl (4′S,6R,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• ethyl (4′S,6R,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• ethyl (4′R,6R,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• ethyl (4′R,6S,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• (±) ethyl (4′S,7aS)-3′-acetyl-7a-ethyl-2-methyl-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• or
• (±) ethyl (4′S,7aS)-7a-(4-bromophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate;
• or
• (ii) a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer of (i).