# US 7,199,125 B2 · Spiro-cyclic compounds useful as anti-inflammatory agents

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- Number: US 7,199,125 B2
- Document ID: US7199125B2
- Status: Granted
- Kind: B2
- Application number: 10/957,255
- Filed: 2004-10-01
- Published: 2005-06-02
- Granted: 2007-04-03
- Earliest claimed: 2003-10-02
- Assignees: Bristol-Myers Squibb Company; Cerep SA
- Inventors: T. G. Murali Dhar; Edwin Iwanowicz; Michele Launay; Dominique Potin; Magali Jeannine Blandine Maillet; Eric Nicolai
- Web page: https://patentgrep.com/patent/US7199125B2

## CPC

- C07D 498/20: Spiro-condensed systems
- C07D 513/20: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to compounds having the formula (I): useful in treating inflammatory and immune diseases, in which K and L are independently, O or S; Q is —C(═O)— or optionally substituted C1-6alkylene; 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; R1 is N or C(R9); and R2, and R3, are as defined in the specification.

## Claims

### Claim 1

A compound of formula (I),
its stereoisomers, or a pharmaceutically-acceptable salt, hydrate, or prodrug 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)—;
J2 is —N(R5)— or —C(R6cR7c)—;
J3 is N(R5) or C(R7dR7d);
provided 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;
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, J2 or J3, R5 may be taken together with one of R6a, R6b R6c or R6d attached to an adjacent atom of ring A to form a fused heterocyclo or heteroaryl ring;
at least one of R6a with R7a, or R6b with R7b, or R6c with R7c are taken together to form a spiro-cycloalkyl or spiro-heterocyclo ring; provided that the spiro-heterocyclo ring is not C2-3 alkylenedioxy;
R6a, R6b, R6c, R6d, R7a, R7b, R7c, and R7d which do not form a spiro-cycloalkyl or spiro-heterocyclo ring 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, R6b, R6c, R6d, R7a, R7b, R7c, and R7d which do not form a spiro-cycloalkyl or spiro-heterocyclo ring and which are attached to the same carbon atom may be taken together to form a keto group;
or R6a, R6b, R6c, R6d, R7a, R7b, R7c, and R7d which do not form a spiro-cycloalkyl or spiro-heterocyclo ring and which are attached to adjacent carbon atoms may be taken together to form a fused benzo, cycloalkyl, heterocyclo, or heteroaryl ring;
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 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 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;
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.

### Claim 2 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, wherein:
K iand L are both O;
Q is a straight chain C1-6alkylene;
Ar is phenyl optionally substituted one to three R20;
R2 and R3 are selected from halogen, (C1-6)alkyl, cyano, halo(C1-6)alkyl, halo(C1-6)alkoxy, nitro, phenyloxy, benzyloxy, and phenylthio;
R20 at each occurrence is 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, —CO2H, —C(═O)H, —CO2(C1-6)alkyl, and/or —C(═O) (C1-6)alkyl; or alternatively, two R20 groups join together with each other to form a fused benzo ring; and
r is 1, 2, 3, or 4.

### Claim 3 (depends on 2)

A compound according to claim 2, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, wherein Q-Ar together form:
wherein
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;
n is 0, 1, or 2; and
r is 1, 2, 3, or 4.

### Claim 4 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, wherein
Y is a bond;
J3 is —CHR6b—;
J2 is is —C(R6cR7c)-wherein R6c with R7, are taken together to form a spiro-cycloalkyl or spiro-heterocyclo ring;
J3 is CH(R6d);
R6b, and R6d are independently selected from
a) hydrogen, halogen, and cyano;
b) —SR16, —OR16, —NR16R17, —C(═O)R16, —CO2R16, —C(═O)NR16R17, —NR16C(═O)R17, —NR16C(═O)OR17, —S(O)qR17a, —NR16SO2R17a, and —SO2NR16R17; and
c) 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 R22;
R16 and R17 are selected independently 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; and
R22 and R23 are at each occurrence selected independently from halogen, cyano, 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.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which
R1 is C(R9); and
R2 and R3 are independently halogen.

### Claim 6

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.

### Claim 7 (depends on 6)

A compound according to claim 6, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which
Y is a bond; and
Q-Ar together form:
wherein
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;
n is 0, 1, or 2; and
r is 1, 2, 3, or 4.

### Claim 8 (depends on 6)

A compound according to claim 6, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which:
R2 and R3 are both halogen; and
R1 is CH.

### Claim 9 (depends on 6)

A compound according to claim 6, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which
Y is a bond;
J1 is —C(R6bR7b)—; and
J3 is —C(R6dR7d)—.

### Claim 10 (depends on 6)

A compound according to claim 6, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which one of Z1 or Z2 is NR25.

### Claim 11

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.

### Claim 12 (depends on 11)

A compound according to claim 11, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which R2 and R3 are independently halogen.

### Claim 13 (depends on 11)

A compound according to claim 11, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which R20a is cyano, halogen, aryl, or heteroaryl.

### Claim 14 (depends on 11)

A compound according to claim 11, or a pharmaceutically-acceptable salt, hydrate, prodrug, or stereoisomer thereof, in which
R1 is CH;
R2 and R3 are independently halogen;
R6 is hydrogen, C1-6alkyl, substituted C1-6alkyl, —C(═O)R26 or CO2R26;
R25 is hydrogen, C1-6alkyl, substituted C1-6alkyl, or —C(═O)R26; and
n is 0.

### Claim 15

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).

### Claim 16 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 17 (depends on 15)

A pharmaceutical composition comprising at least one compound according to claim 15 and a pharmaceutically acceptable carrier or diluent.

### Claim 18 (depends on 1)

A method of inhibiting an LFA-1/ICAM-associated condition in a mammal to treat a disease selected from the group consisting of acute or chronic transplant rejection, rheumatoid arthritis, osteoarthritis, diabetes, asthma, inflammatory bowel disease, psoriasis, and chronic obstructive pulmonary disease comprising administering to the mammal a therapeutically-effective amount of a compound according to claim 1.