# US 6,977,267 B2 · Spiro-hydantoin compounds useful as anti-inflammatory agents

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- Number: US 6,977,267 B2
- Document ID: US6977267B2
- Status: Granted
- Kind: B2
- Application number: 10/262,182
- Filed: 2002-10-01
- Published: 2004-01-15
- Granted: 2005-12-20
- Earliest claimed: 2001-10-01
- Assignees: Bristol-Myers Squibb Company; Cerep SA
- Inventors: T. G. Murali Dhar; Dominique Potin; Magali Jeannine Blandine Maillet; Michele Launay; Eric Antoine Nicolai; Edwin J. Iwanowicz
- Web page: https://patentgrep.com/patent/US6977267B2

## CPC

- C07D 235/02: condensed with carbocyclic rings or ring systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/08: Bronchodilators
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/02: Antidotes
- C07D 233/96: having three double bonds between ring members or between ring members and non-ring members
- C07D 487/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates, enantiomers, and diastereomers, and prodrugs thereof, are useful as inhibitors of LFA-1/ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR4b; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R2,R4a, R4b, and R4c are as defined in the specification.

## Claims

### Claim 1

A compound according to formula (I),
its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof, in which:
L and K, taken independently, are O or S;
Ar is aryl or heteroaryl;
G is selected from a bond, —O—, —N—, —S—, C1-4alkylene, C1-4substituted alkylene, bivalent alkoxy, alkylthio, aminoalkyl, sulfonyl, sulfonamidyl, acyl, and alkoxycarbonyl;
R2 is selected from hydrogen, alkyl, substituted alkyl, OR12, NR12R13, C(═O)R12, CO2R12, C(═O)NR12R13, NR12C(═O)R13, NR12C(═O)OR13, S(O)pR13a, NR12SO2R13a, SO2NR12R13, cycloalkyl, heterocyclo, aryl, and heteroaryl;
R4a, R4b and R4c are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, SR14, OR14, NR14R15, NR14C(═O)R15, CO2R14, C(═O)R14, —C(═O)NR14R15, aryl, heterocyclo, cycloalkyl, and heteroaryl;
R3 is independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C(═O)H, acyl, amide, alkoxycarbonyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocyclo, aryl, and heteroaryl;
R9 is —A1—Q—A2—R16;
A1 is a bond, C1-2alkylene, or C2-3alkenylene;
Q is a bond, —C(═O)—, —C(═O)NR17—, —C(═S)NR17—, —SO2—, —SO2NR17—, —CO2—, or —NR17CO2—;
A2 is a bond, C1-3alkylene, C2-3alkenylene, —C1-4alkylene-NR17—, —C1-4alkylene-NR17C(═O)—, —C1-4alkylene-S—, —C1-4alkylene-SO2—, or —C1-4alkylene-O—, wherein said A2 alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO2H, —CO2(C1-4alkyl), —S(C1-4alkyl), NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2;
R12, R13, R14 and R15 (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R12 is taken together with R13, and/or R14 is taken together with R15 to form a heteroaryl or heterocyclo ring;
R13a is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
R16 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; and
R17 is hydrogen or alkyl; and
p is 1 or 2.

### Claim 2 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein:
G is a bond;
Ar is an aryl or heteroaryl substituted with one to three R1;
R1 is selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR10, NR10R11, C(═O)R10, CO2R10, C(═O)NR10R11, NR10C(═O)R11, NR10C(═O)OR11, SR10, S(O)oR10a, NR10SO2R10a, NHCH(alkyl)CO2R10, SO2NR10R11, cycloalkyl, heterocyclo, aryl, and heteroaryl;
R10 and R11 (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R10 is taken together with R11 to form a heteroaryl or heterocyclo;
R10a is alkyl, substituted alkyl, cycloalkyl, aryl heteroaryl, or heterocyclo; and
o is 1 or 2.

### Claim 3 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R16 is selected from cycloalkyl, heterocyclo, aryl or heteroaryl optionally substituted with one to three R18;
R18 is selected from C1-6alkyl, substituted C1-6alkyl, halogen, cyano, nitro, OR20, NR20R21, C(═O)R20, CO2R20, C(═O)NR20R21, C(═O)NR20SO2R20a, NR20C(═O)R21, NR20C(═O)OR21, SR20, S(O)uR20a, NR20SO2R20a, NHCH(alkyl)CO2R20, SO2NR20R21, C3-7cycloalky, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl, said C3-7cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl groups in turn being optionally substituted with one to two R22;
R20 and R21 are selected from hydrogen, alkyl, alkenyl, C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl, or when attached to the same nitrogen atom may join to form a heterocyclo or heteroaryl; wherein each of R20 and R21 in turn is optionally substituted with one to two R22;
R20a is selected from hydrogen, alkyl, alkenyl, CO2H, CO2(alkyl), C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocyclo, or a five to six membered heteroaryl; wherein each R20a in turn is optionally substituted with one to two R22; and
R22 is selected from the group consisting of (C1-4)alkyl, (C2-4)alkenyl, hydroxy, cyano, CF3, O(C1-4alkyl), OCF3, C(═O)H, C(═O)(C1-4alkyl), CO2H, CO2(C1-4alkyl), NHCO2(C1-4alkyl), —S(C1-4alkyl), —NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(CH3)3+, SO2(C1-4alkyl), C(═O)(C1-4alkylene)NH2, C(═O)(C1-4alkylene)NH(alkyl), and C(═O)(C1-4alkylene)N(C1-4alkyl)2.

### Claim 4 (depends on 3)

A compound according to claim 3, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
Ar is
R1a and R1b are independently selected from halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, —C(═O)alkyl, —C(═O)NH(CH2)1-4CO2H, —C(═O)NH(CH2)1-4CO2(alkyl), and S(O)2alkyl; or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, and/or —C(═O)alkyl; or alternatively, two R1b groups join together with each other or one R1b joins together with R1a to form a fused benzo ring;
R4a and R4c are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, nitro, aryloxy, and arylthio;
R4b is hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, haloalkoxy, phenyloxy, —CO2H, —C(═O)H, —NH(alkyl), —N(alkyl)2, —CO2alkyl, —C(═O)alkyl, alkylthio, —C(═O)NH(CH2)1-4CO2H, —C(═O)NH(CH2)1-4CO2(alkyl), aryl, heteroaryl, or heterocyclo, wherein each of the aryl, heteroaryl, and heterocyclo groups are optionally substituted with one to two halogen, C1-4alkyl, OMe, CF3, CN, OCF3, CO2H, C(═O)H, CO2alkyl, and/or C(═O)alkyl;
n is 0, 1, or 2; and
y is 0, 1 or 2.

### Claim 5 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, having the formula:

### Claim 6 (depends on 5)

A compound according to claim 5, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which R1a is halogen or cyano, and R4a and R4c are independently selected from halogen, alkyl, cyano, trifluoromethyl, and nitro.

### Claim 7 (depends on 1)

A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R9 is selected from:
A1 is a bond, C1-2alkylene, or C2-3alkenylene;
Q is a bond, —C(—O)—, —C(═O)NR17—, —SO2—, —CO2-, or —NR17CO2—;
A2 is a bond, C1-3alkylene, C2-3alkenylene, -C1-4alkylene-O-, wherein said A2 alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO2H, —CO2(C1-4alkyl), —S(C1-4alkyl), NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2;
R17 is hydrogen or alkyl;
R18 and R19 are selected from hydrogen, (C1-6) alkyl, (C2-6) alkenyl, CO2H, CO2(C1-6alkyl), C(═O)H,
C(═O)(C1-6alkyl), halogen, cyano, hydroxy, (C1-4)haloalkoxy,
NH2, NH(C1-4alkyl), SO2(C1-4alkyl), phenyl, C3-7cycloalkyl, five to six membered
heteroaryl, and four to seven membered heterocyclo, wherein each group R18 and R 19 in turn
is optionally substituted with one to two of (C1-4)alkyl, (C2-4)alkenyl, CO2H, CO2(C1-4alkyl),
C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-4alkyl), and/or SO2(C1-4alkyl);
f is 0,1,2 or 3; and
g is —1,0,1, or 2.

### Claim 8 (depends on 1)

A compound according to claim 1, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R9 is selected from one of:

### Claim 9 (depends on 1)

A compound according to claim 1, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a is halogen, cyano, nitro, trifluoromethyl, OCF3aryl or heteroaryl;
R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, -CO2alkyl, or —C(═O)alkyl;
R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl);
R18 is selected from (C1-4)alkyl, CO2H, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2,—NHCO2(C1-4alkyl), —C(═O)NHSO2(C1-4alkyl), SO2(C1-4alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;
f is 0,1,2 or 3; and
n is 0 or 1.

### Claim 10 (depends on 1)

A compound according to claim 1, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a is halogen, cyano, nitro, trifluoromethyl, OCF3, aryl or heteroaryl;
R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, or —C(═O)alkyl;
R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl);
R18 is selected from (C1-4) alkyl, CO2H, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), —C(═O)NHSO2(C1-4alkyl), SO2(C1-4alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1.

### Claim 11

A compound having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
L and K, taken independently, are O or S;
R1a and R1b are independently selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR10, NR10R11, C(═O)R10, CO2R10, C(═O)NR10R11, NR10C(═O)R11, NR10C(═O)OR11, SR10, S(O)oR10a, NR10SO2R10a, NHCH(alkyl)CO2R10, SO2NR10R11, cycloalkyl, heterocyclo, aryl, and heteroaryl; or alternatively, two R1b groups join together with each other or one R1b joins together with R1a to form a fused benzo ring;
R2 is selected from hydrogen, alkyl, substituted alkyl, cycloalky, aryl, heterocyclo, and heteraryl;
R4a, R4b, and R4c are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, aryloxy, arylthio, and nitro;
R9 is selected from hydrogen and A1—Q—A2—R16;
A1 is a bond, C1-2alkylene, or C2-3alkenylene;
Q is a bond, —C(═O)—, —C(═O)NR17—, —SO2—, —CO2—, or —NR17CO2—;
A2 is a bond, C1-3alkylene, C2-3alkenylene, —C1-4alkylene-NR17—, —C1-4alkylene-NR17C(═O)—, —C1-4alkylene-S—, —C1-4alkylene-SO2—, or —C1-4alkylene-O—, wherein said A2 alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO2H, —CO2(C1-4alkyl), —S(C1-4alkyl), NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2;
R10 and R11 (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R10 is taken together with R12 to form a heteroaryl or heterocyclo;
R10a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;
R16 is selected from alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo, wherein each R16 is optionally substituted with one to three R18;
R17 is hydrogen or alkyl;
R18 is selected from C1-6alkyl, substituted C1-6alkyl, halogen, cyano, nitro, OR20, NR20R21, C(═O)R20, CO2R20, C(═O)NR20R21, C(═O)NR20SO2R20a, NR20C(═O)R21, NR20C(═O)OR21, SR20, S(O)uR20a, NR20SO2R20a, NHCH(alkyl)CO2R20, NH—(CH2)1-4—CO2R20, SO2NR20R21, C3-7cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl, said C3-7cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl groups in turn being optionally substituted with one to two R22;
R20 and R21 are selected from hydrogen, alkyl, alkenyl, C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl, or when attached to the same nitrogen atom may join to form a heterocyclo or heteroaryl; wherein each of R20 and R21 in turn is optionally substituted with one to two R22;
R20a is selected from alkyl, alkenyl, CO2H, CO2(alkyl), C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl; wherein each R20a in turn is optionally substituted with one to two R22;
R22 is selected from the group consisting of (C1-6)alkyl, (C2-6)alkenyl, hydroxy, cyano, CF3, O(C1-6alkyl), OCF3, C(═O)H, C(═O)(C1-6alkyl), CO2H, CO2(C1-6alkyl), NHCO2(C1-6alkyl), —S(C1-6alkyl), —NH2, NH(C1-6alkyl), N(C1-6alkyl)2, N(CH3)3+, SO2(C1-6alkyl), C(═O)(C1-4alkylene)NH2, C(═O)(C1-4alkylene)NH(alkyl), and C(═O)(C1-4alkylene)N(C1-4alkyl)2;
o and u are independently 1 or 2; and
n is 0, 1 or 2.

### Claim 12 (depends on 11)

A compound according to claim 11, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R4a and R4c are chloro.

### Claim 13 (depends on 11)

A compound according to claim 11, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R1a is cyano or halogen.

### Claim 14 (depends on 11)

A compound according to claim 11, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof.

### Claim 15 (depends on 14)

A compound according to claim 14, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R2 is selected from hydrogen, C1-6alkyl, and C1-6alkyl substituted with amino, NH(C1-4alkyl), N(alkyl)2, C(═O)H, C(═O)C1-4alkyl, CO2H, CO2(C1-4alkyl), SO2C1-4alkyl, SO3H, and/or PO(OH)2;
R4a and R4b are selected from halogen, C1-4alkyl, cyano, halo C1-4alkyl, and halo C1-4alkoxy;
R9 is A1—Q—A2—R16;
R16 is selected from (a) hydrogen and C1-6alkyl or C2-6alkenyl optionally substituted with one to two of OH, O(C1-4alkyl), —CO2H, —CO2(C1-4alkyl), NH2, —NH(C1-4alkyl), and/or N(C1-4alkyl)2, or from (b) furanyl, indolyl, carbazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, piperidyl, pyrrolidinyl, pyridazinyl, C3-7cycloalkyl, piperazinyl, thiazolyl, morpholinyl, 1,2,5,6-tetrahydropyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, benzodioxanyl, benzooxadiazolyl, thienopyrazolyl, tetrahydroquinolinyl, and quinolinyl, wherein each of said cyclic R16 groups in turn is optionally substituted with up to three R18;
R17 is hydrogen or alkyl; and
R18 is selected from hydrogen, (C1-6)alkyl, (C2-6)alkenyl, CO2H, CO2(C1-6alkyl), C(═O)H, C(═O)(C1-6alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), SO2(C1-4alkyl), phenyl, C3-7cycloalkyl, five to six membered heteroaryl, and four to seven membered heterocyclo, wherein each group R18 in turn is optionally substituted with one of two of (C1-4) alkyl, (C2-4) alkenyl, CO2H, CO2(C1-4alkyl),C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-4alkyl, N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), and/or SO2(C1-4alkyl).

### Claim 16 (depends on 15)

A compound according to claim 15, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a is cyano or halogen;
R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, or —C(═O)alkyl;
R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl);
R18 is selected from (C1-4) alkyl, CO2H, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), —C(═O)NHSO2(C1-4alkyl), SO2(C1-4alkyl), ), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1.

### Claim 17 (depends on 15)

A compound according to claim 15, having the formula,
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereif, in which:
R1a is halogen, cyano, nitro, trifluoromethyl, OCF3, aryl or heteroaryl;
R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, or —C(═O)alkyl;
R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl);
R18 is selected from (C1-4)alkyl, CO2H, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl),—C(═O)NHSO2(C1-4alkyl), SO2(C1-4alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;
f is 0,1,2 or 3; and
n is 0 or 1.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 11)

A pharmaceutical composition comprising at least one compound according to claim 11 and a pharmaceutically acceptable carrier or diluent.

### Claim 20 (depends on 16)

A compound according to claim 16 having the formula,
its enantiomers, disastereomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof.

### Claim 21 (depends on 12)

A compound according to claim 12 having the formula,
its enantiomers, diastereomers, or pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof.

### Claim 22 (depends on 1)

A compound according to claim 1, having the formula (Ie),
or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a R1b are independently selected from halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, -CO2(alkyl), and S(O)2alkyl; or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, -CH2H, -C(═O)H, -CO2alkyl, and/or-C(═O)alkyl; or alternatively , two R1b groups join together with each other or one R1b joins together with R1a to form a fused benzo ring; and
n is 0, 1 or 2.

### Claim 23 (depends on 22)

A compound according to claim 22, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a halogen, cyano, nitro, trifluoromethyl, OCF3aryl or heteroaryl;
R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, or —C(═O)alkyl;
R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl);
R9 is selected from C1-10alkyl, substituted C1-10alkyl, C2-10alkenyl, substituted C2-10alkenyl, C3-6cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, —(CH2),phenyl,—(CH2), tetrazolyl,—(CH2),pyridyl,—(CH2),thienyl,—(CH2), thiazolyl,—(CH2),pyrrolyl,—(CH2)imidazolyl,—(CH2), isoxazolyl,—(CH2), benzofuryl,—(CH2),pyrazolyl,—C(═O)H, —C(═O)(alkyl), —C(═O)C1-10alkyl, —C(═O)phenyl, —C(═O)piperidyl,—C(═O)morpholinyl,—C(═O)C3-6cycloalkyl, —C(═O) pyrrolidinyl, —C(═O)quinolyl, —C(═O)quinolyl,—C(═O)imidazolyl,—C(═O)pyrazolyl,—C(═O)thiazolyl,—C(═O)quinoxalinyl,—C(═O)pyridyl, —C(═O)-1,2,5,6—tetrahydropyridyl,—C(═O)benzothiazolyl,—C(═O)benzotriazolyl,—C(═O)-1,2,5,6- tetrahydropyridyl, —tetrahydropyridyl,—C(═O)benzothiazolyl,—C(═O)benzotriazolyl,—C(═O)benzodioxanyl,—C(═O)(CH2)spyrrolidinyl, —C(═O)(CH2)spiperidyl, —C(═O)CH═CH(phenyl), —C(═O)CH═CH(pyridyl), —C(═O)CH2O(alkyl), —C(═O)CH2S(alkyl), —C(═O)CH2S(pyridyl), —C(═O)CH2SO2(alkyl), —C(═O)CH2SO2(phenyl), —C(═O)CH2NH(phenyl), —C(═O)CH2NH(benzyl), —C(═O)CH2NH(thiazolyl), —C(═O)CH2NHC(═O)pyridyl, —C(═O)CH2NHC(═O)phenyl, —(CH2)tSO2(alkyl), —(CH2)tSO2(phenyl), —(CH2)tSO2(thienyl), —(CH2)tSO2(imidazolyl), —(CH2)tSO2(furyl), (CH2)tSO2(pyrrolyl), SO2NH(phenyl), —C(═S)NH2, —C(═S)NH(alkyl), —C(═S)NH(phenyl), —(CH2)C(═O)pyrrolidinyl, —(CH2)C(═O)piperidyl, —(CH2)C(═O)piperazinyl, —CO2(alkyl), —CO2(phenyl), —CO2(benzyl), NHCO2(alkyl), —(CH2)tC(═O)NH(phenyl), —(CH2)tC(═O)NH(piperidyl), —(CH2)tC(═O)NH(thienyl), —(CH2)tC(═O)NH(thiazolyl), —(CH2)tC(═O)NH(cyclopentyl), —(CH2)tC(═O)NH(cyclopentenyl), —(CH2)tC(═O)NH(benzyl), —CH2)tC(═O)NH(pyrrolidinyl), —(CH2)tC(═O)NH(piperazinyl), —(CH2)tC(═O)NH2, —(CH2)tC(═O)NH(alkyl), —(CH2)tC(═O)N(alkyl)2, —(CH2)tC(═O)N(C1-4alkyl)(phenyl), —(CH2)tC(═O)N(C1-4alkyl)(thienyl), —(CH2)tC(═O)N(C1-4alkyl)(thiazolyl), —(CH2)tC(═O)N(C1-4alkyl)(benzyl), —(CH2)tC(═O)N(C1-4alkyl)CO2(alkyl), wherein each R9 is optionally substituted with one to two R18;
R18 is selected from —(CH2)qhalogen, —(CH2)qnitro, —(CH2)qcyano, —(CH2)qhaloalkyl, —(CH2)qhaloalkoxy, —(CH2)qSR24, C3-7cycloalkyl, —SO2R24, —OR24, —(CH2)qCO2R24, —(CH2)qNR24R25, —(CH2)qNHCO2R24, —C(═O)NH—SO2R24, —C(═O)(CH2)qNR24R25, —O(CH2)rNR24R25, —C(═O)R24, —(CH2)qR24 and —C1-4alkyl or —C2-4alkenyl optionally substituted with CO2R24;
R24 is selected from hydrogen, alkyl, phenyl, benzyl, C3-7cycloalkyl, five or six membered heteroaryl, and four to seven membered heterocyclo, in turn optionally substituted with one to two C1-4alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —CO2H, CO2C1-4alkyl, C1-4alkoxy, —S(C1-4alkyl), amino, and/or aminoC1-4alkyl, provided that when R24 is attached to a sulfonyl group as in —SO2R24, then R24 is not hydrogen;
R25 is selected from hydrogen and alkyl; and
n is 0, 1, or 2;
p is 1 or 2;
q is 0,1, 2, 3, or 4;
r is 1, 2, 3, or 4;
s is 0,1, 2, 3, or 4; and
t is 1, 2, 3, or 4.

### Claim 24 (depends on 22)

A compound according to claim 22, or a pharmaceutically-acceptable salt, hydrate, salt, hydrate, prodrug, or enantiomer thereof, wherein R9 is selected from:
A1 is a bond, C1-2alkylene, or C2-3alkenylene;
Q is a bond, —C(═O)—, —C(=O)NR17—, —SO2—, —CO2—, or —NR17CO2—;
A2 is a bond, C1-3alkylene, C2-3alkylene, —C1-4alkylene-NR17—, —C1-4alkylene-NR17C(═C)-,—C1-4alkylene-S-, —C1-4alkylene-SO2-, or —C1-4alkylene-O-, wherein said A2 alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO2H, —CO2(C1-4alkyl), —S(C1-4alkyl), NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2;
R17 is hydrogen or alkyl;
R18 and R19 are selected from hydrogen, (C1-6)alkyl, (C2-6)alkenyl, CO2H, CO2(C1-6alkyl), C(═O)H,
C(═O)(C1-6alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)2, N(C1-4alkyl)2+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl),—C(═O)NHSO2(C1-4alkyl), SO2(C1-4)alkyl), phenyl, C3-7cycloalkyl, five to six membered heteroaryl, and four to seven membered hetereocyclo, wherein each group R18 and R19 in turn is optionally substituted with one or two of (C1-4) alkyl, (C2-4) alkenyl, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4) alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2, C1-4alkyl), and/or SO2(C1-4alkyl);
f is 0,1,2 or 3; and
g is —1,0,1, or 2.