# US 2010/0168124 A1 · Novel heterocyclic substituted pyridine compounds with cxcr3 antagonist activity

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- Number: US 2010/0168124 A1
- Document ID: US20100168124A1
- Status: Published application
- Kind: A1
- Application number: 12/642,931
- Filed: 2009-12-21
- Published: 2010-07-01
- Earliest claimed: 2006-03-21
- Assignees: Schering Corporation; Pharmacopeia, Inc.
- Inventors: Stuart B. Rosenblum; Joseph A. Kozlowski; Neng-Yang Shih; Brian F. McGuinness; Douglas W. Hobbs
- Web page: https://patentgrep.com/patent/US20100168124A1

## CPC

- C07D 401/14: containing three or more hetero rings
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/14: Decongestants or antiallergics
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

## Claims

### Claim 1

A compound having the general structure shown in Formula 1
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
Z is N, NO, or NOH
G represents a 5-membered heteroaryl or heterocyclenyl ring containing at least one —C═N— moiety as part of said heteroaryl or heterocyclenyl ring, said heteroaryl or heterocyclenyl ring optionally additionally containing on the ring (i.e., as ring moieties/ring atoms) one or more moieties which can be the same or different, each being independently selected from the group consisting of N,N(→O), O, S, S(O) and S(O)2, further wherein said heteroaryl or heterocyclenyl ring can be either (i) unsubstituted, or (ii) optionally independently substituted on one or more ring carbon atoms with one or more R9 substituents, or on one or more ring nitrogen atoms with one or more R8 substituents, wherein said R8 and R9 substituents can be the same or different;
R3, R5, and R6 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkylaryl, aralkyl, aryl, —CN, CF3, haloalkyl, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl, halogen, hydroxyalkyl, —N═CH—(R31), —C(═O)N(R30)2, —N(R30)2, —OR30, —SO2(R31), —N(R30)C(═O)N(R30)2, —N(R30)C(═O)R31, —(CH2)qOH, —(CH2)qOalkyl, —(CH2)qOalkylaryl, —(CH2)qOaryl, —(CH2)qOaralkyl, —(CH2)qOcycloalkyl, —(CH2)qNH2, —(CH2)qNHalkyl, —(CH2)qN(alkyl)2, —(CH2)qNHalkylaryl, —(CH2)qNHaryl, —(CH2)qNHaralkyl, —(CH2)qNHcycloalkyl, —(CH2)qC(═O)NHalkyl, —(CH2)qC(═O)N(alkyl)2, —(CH2)qC(═O)NHalkylaryl, —(CH2)qC(═O)NHaryl, —(CH2)qC(═O)NHaralkyl, —(CH2)qC(═O)NHcycloalkyl, —(CH2)qSO2alkyl, —(CH2)qSO2alkylaryl, —(CH2)qSO2aryl, —(CH2)qSO2aralkyl, —(CH2)qSO2cycloalkyl, —(CH2)qNSO2alkyl, —(CH2)qNSO2alkylaryl, —(CH2)qNSO2aryl, —(CH2)qNSO2aralkyl, —(CH2)qNSO2cycloalkyl, —(CH2)qSO2NHalkyl, —(CH2)qSO2NHalkylaryl, —(CH2)qSO2NHaryl, —(CH2)qSO2NHaralkyl, —(CH2)qSO2NHcycloalkyl,
the R8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —(CH2)qOH, —(CH2)qOR30, —(CH2)qC(═O)R30, —(CH2)qNH2, —(CH2)qNHR30, —(CH2)q(C(═O)NHR30, —(CH2)qSO2R31, —(CH2)qNSO2R31, —(CH2)qC(═O)OR31, and —(CH2)qSO2NHR30;
the R9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl, —C(═O)N(R30)2, —C(═S)N(R30)2, —C(═O)alkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR30, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2N(R30)2, —N(R30)2, —N(R30)S(O)2R31, —N(R30)C(═O)N(R30)2, —OR30, —SO2(R31), —SO2N(R30)2, ═O and ═S;
the R10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO2H, hydroxyalkyl, —C(═O)N(R30)2, —(CH2)qOH, —(CH2)qOR31, —OR30, halogen, ═O, and —C(═O)R31;
the R11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, hydroxyalkyl, —C(O)N(R30)2, —CO2H, —(CH2)qOH, —(CH2)qOR31, —OR30, halogen, ═O, and —C(═O)R31;
R12 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, haloalkyl, —CN, —C(═O)N(R30)2, —(CH2)qOH, —(CH2)qOR31 and —S(O2)R31;
ring D is a five to nine membered cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independently selected from O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 independently selected R20 moieties;
the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qC(═O)NHR30, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2N(R30)2, -alkynylC(R31)2OR31, —C(═O)R30, C(═O)N(R30)2, —C(═NR30)NHR30, —C(═NOH)N(R30)2, —C(═NOR31)N(R30)2, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)SO2(R31), —N(R30)C(═O)N(R3)2, —N(R30)SO2(R31), —N(R30)S(O)2N(R30)2, —OR30, —OC(═O)N(R30)2, —SO2N(R3)2, —SO2(R31), —OSO2(R31), and —OSi(R30)3; or alternatively two R20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R21 moieties;
the R21 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qC(═O)NHR30, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2N(R30)2, -alkynyl-C(R31)2OR31, —C(═O)R30, —C(═O)N(R30)2, —C(═NR30)NHR30, —C(═NOH)N(R30)2, —C(═NOR31)N(R30)2, —C(═O)OR30, —N(R3)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)SO2(R31), —N(R30)C(═O)N(R30)2, —N(R30)SO2(R31), —N(R30)S(O)2N(R30)2, —OR30, —OC(═O)N(R30)2, —SR30, —SO2N(R30)2, —SO2(R31), —OSO2(R31), and —OSi(R30)3;
Y is selected from the group consisting of —(CR13R13)r—, CHR13C(═O)—, —(CHR13)rO—, (CHR13)rN(R30)—, —C(═O)—, —C(═NR30), —C(═N—OR30)—, —CH(C(═O)NHR30)—, CH-heteroaryl-, —C(R13R13)rC(R13)═C(R13)—, —(CHR13)rC(═O)— and —(CHR13)rN(H)C(═O)—; or alternatively Y is cycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl, or heterocyclyl is fused with ring D;
the R13 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, —CN, —CO2H, —C(═O)R30, —C(═O)N(R30)2, —(CHR30)qOH, —(CHR30)qOR31, —(CHR30)qNH2, —(CHR30)qNHR31, —(CH2)qC(═O)N(R30)2, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2NHR31, —NH2, —N(R30)2, —N(R30)C(═O)N(R30)2, —N(R30)SO2(R31), —OH, OR30, —SO2N(R30)2, and —SO2(R31);
the R30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, —(CH2)qOH, —(CH2)qOalkyl, —(CH2)qOalkylaryl, —(CH2)qOaryl, —(CH2)qOaralkyl, —(CH2)qOcycloalkyl, —(CH2)qNH2, —(CH2)qNHalkyl, —(CH2)qN(alkyl)2, —(CH2)qNHalkylaryl, —(CH2)qNHaryl, —(CH2)qNHaralkyl, —(CH2)qNHcycloalkyl, —(CH2)qC(═O)NHalkyl, —(CH2)qC(═O)N(alkyl)2, —(CH2)qC(═O)NHalkylaryl, —(CH2)qC(═O)NHaryl, —(CH2)qC(═O)NHaralkyl, —(CH2)qC(═O)NHcycloalkyl, —(CH2)qSO2alkyl, —(CH2)qSO2alkylaryl, —(CH2)qSO2aryl, —(CH2)qSO2aralkyl, —(CH2)qSO2cycloalkyl, —(CH2)qNHSO2alkyl, —(CH2)qNHSO2alkylaryl, —(CH2)qNHSO2aryl, —(CH2)qNHSO2aralkyl, —(CH2)qNHSO2cycloalkyl, —(CH2)qSO2NHalkyl, —(CH2)qSO2NHalkylaryl, —(CH2)qSO2NHaryl, —(CH2)qSO2NHaralkyl, —(CH2)qSO2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;
the R31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, —(CH2)qOH, —(CH2)qOalkyl, —(CH2)qOalkylaryl, —(CH2)qOaryl, —(CH2)qOaralkyl, —(CH2)qOcycloalkyl, —(CH2)qNH2, —(CH2)qNHalkyl, —(CH2)qN(alkyl)2, —(CH2)qNHalkylaryl, —(CH2)qNHaryl, —(CH2)qNHaralkyl, —(CH2)qNHcycloalkyl, —(CH2)qC(═O)NHalkyl, —(CH2)qC(═O)N(alkyl)2, —(CH2)qC(═O)NHalkylaryl, —(CH2)qC(═O)NHaryl, —(CH2)qC(═O)NHaralkyl, —(CH2)qC(═O)NHcycloalkyl, —(CH2)qSO2alkyl, —(CH2)qSO2alkylaryl, —(CH2)qSO2aryl, —(CH2)qSO2aralkyl, —(CH2)qSO2cycloalkyl, —(CH2)qNHSO2alkyl, —(CH2)qNHSO2alkylaryl, —(CH2)qNHSO2aryl, —(CH2)qNHSO2aralkyl, —(CH2)qNHSO2cycloalkyl, —(CH2)qSO2NHalkyl, —(CH2)qSO2NHalkylaryl, —(CH2)qSO2NHaryl, —(CH2)qSO2NHaralkyl, —(CH2)qSO2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;
m is 0 to 4;
n is 0 to 4;
each q can be the same or different, each being independently selected from 0 to 5; and
r is 1 to 4;
with the proviso that there are no two adjacent double bonds in any ring, and that when a nitrogen is substituted by two alkyl groups, said two alkyl groups may be optionally joined to each other to form a ring.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein ring G is an unsubstituted or substituted ring selected from the group consisting of dihydroimidazole, pyrrole, dihydropyrrole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, dihydrothiazole, thiazole, dihydrothiadiazole, thiadiazole, triazole and tetrazole.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein Z is N or NO.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein G is selected from the group consisting of:
wherein is a single bond or double bond, R8 and R9 are optional substituents, and two independent R9 substitutents may be substituted on the same ring carbon when the valency so permits.

### Claim 5 (depends on 4)

The compound of claim 4, wherein
is represented by

### Claim 6 (depends on 4)

The compound of claim 4, wherein
is represented by

### Claim 7 (depends on 4)

The compound of claim 4, wherein
is represented by

### Claim 8 (depends on 4)

The compound of claim 4, wherein
is represented by

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R30)2, —OR30 and —CF3.

### Claim 10 (depends on 9)

The compound according to claim 9, wherein R3 is selected from the group consisting of H, —CH3, —CH2CH3, cyclopropyl, —F, —Cl, —OCH3, —OCF3 and —CF3.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R5 is selected from the group consisting of H, alkyl, halogen, cyano, hydroxy, hydroxyalkyl, and CF3.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R6 is selected from the group consisting of H, alkyl, cycloalkyl, halogen, hydroxyalkyl, —CN, —N(R30)2, —OR30, —N═CH-alkyl, and —NR30C(═O)alkyl.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein R6 is selected from the group consisting of H, —NH2, —CH3, cyclopropyl, —CN and —F.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qN(R30)2, —(CH2)qC(═O)NHR30, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, and —(CH2)qSO2NHR30.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein R9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —C(═O)N(H)R30, —C(═O)alkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qN(R31)2, —N(H)R30, —N(R30)2, —N(H)S(O2)R31, —N(H) C(═O)NH(R30), —OR30, —SO2(R31), —SO2N(H)R30 and —SO2N(R30)2.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein the R9 moieties can be the same or different, each being independently selected from the group consisting of H, cyclopropyl, —CF3, —CH3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH2CH2OCH3, —C(═O)OCH2CH3, —CH2NH2, —CH2CH2NH2, —CH2CH2NHSO2CH3, —CH2CH2SO2CH3, —C(═O)NH2, —C(═O)N(H)CH2CH2OH, —CH2N(H)C(═O)CF3, —C(═O)N(H)-cyclopropyl, —C(═O)N(H)CH2CF3, —NH2, —NHCH3, —N(CH3)2, —N(H)CH2CH3, —N(H)CH(CH3)2, —N(H)CH2CH2CH3, —N(H)cyclopropyl, —N(H)CH2C(═O)OCH3, —N(H)CH2CH2OH, —N(H)CH2CH2NH2, —N(H)CH2CH2NHSO2CH3, —N(H)CH2CH2SO2CH3, —N(H)C(═O)N(H)CH2CH3, —N(H)CH2C(═O)NH2, —OCH3, ═S and ═O.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein R9 moieties can be the same or different, each being independently selected from the group consisting of H, —CF3, —CH3, —CH2CH2OH, —CH2CH2NH2, —NH2, —NHCH3, —N(H)CH2CH3, —N(H)CH(CH3)2, —N(H)CH2CH2CH3, —N(H)CH2C(═O)OCH3, and —N(H)CH2CH2OH.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein R10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyl, and hydroxyalkyl, or wherein two R10 taken together with the carbon atom to which both are attached form >C═O.

### Claim 19 (depends on 18)

The compound according to claim 18, wherein R10 is selected from the group consisting of —CH3, —CH2CH3 and —CH2CH2CH3, or wherein two R10 taken together with the carbon atom to which both are attached form >C═O, and m is 0-2.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein R11 is selected from the group consisting of H, alkyl, and hydroxyalkyl, wherein two R11 taken together with the carbon atom to which both are attached form >C═O.

### Claim 21 (depends on 20)

The compound according to claim 20, wherein R11 is H or —CH3.

### Claim 22 (depends on 1)

The compound according to claim 1, wherein R12 is selected from the group consisting of H, CN, —C(═O)N(R30)2 and alkyl.

### Claim 23 (depends on 22)

The compound according to claim 22, wherein R12 is selected from the group consisting of H, —CH3, CN and —CH2CH3.

### Claim 24 (depends on 1)

The compound according to claim 1, wherein the ring atoms of ring D are independently C or N and wherein ring D is substituted by 0-4 R20 moieties.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R20 moieties.

### Claim 26 (depends on 1)

The compound according to claim 1, wherein the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, —(CH2)qOR31, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)SO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)N(R30)2, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R3)2, —N(R30)SO2(R31), —N(R30)SO2N(R30)2, —OR30, —OC(═O)N(R30)2, —SR30, —SO2N(R30)2, —SO2(R31), —OSO2(R31), and —OSi(R30)3.

### Claim 27 (depends on 1)

The compound according to claim 1, wherein the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3, CF3, OCF3, —(CH2)qOR31, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R3)2, —N(R30)C(═O)N(R30)2, —OR30, —OC(═O)N(R30)2, and —OSO2(R31).

### Claim 28 (depends on 1)

The compound according to claim 1, wherein two R20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R21 moieties.

### Claim 29 (depends on 1)

The compound according to claim 1, wherein the R20 moieties can be the same or different, each being independently selected from the group consisting of H, —CN, —CH3, —CF3, —CH2OH, —CO2CH3, —NH2, —NHCH3, —OCF3, —OH, F, Cl, Br, —C(═NOH)NH2, —OCH2CH2S(O2)CH3, —C(═O)NH2,

### Claim 30 (depends on 1)

The compound according to claim 1, wherein Y is selected from the group consisting of: —(CHR13)r—, —(CR13R13)r—, —C(═O)— and —CHR13C(═O)—.

### Claim 31 (depends on 1)

The compound according to claim 1, wherein Y is selected from the group consisting of: —CH2—, —CH(CH3)—, —CH(CH2OH)—, —C(═O)— and —CH(CO2alkyl)-.

### Claim 32 (depends on 1)

The compound according to claim 1, wherein m is 0-2.

### Claim 33 (depends on 1)

The compound according to claim 1, wherein n is 0-2.

### Claim 34 (depends on 1)

The compound according to claim 1, wherein q is 1 or 2.

### Claim 35 (depends on 1)

The compound according to claim 1, wherein r is 1 or 2.

### Claim 36 (depends on 1)

The compound according to claim 1, wherein m is 0-2; n is 0-2; q is 1 or 2; and r is 1 or 2.

### Claim 37 (depends on 1)

The compound according to claim 1, wherein Z is N, ring G is selected from the group consisting of:
wherein is a single bond or a double bond, R8 and R9 are optional substituents, and two independent R9 substitutents may be substituted on the same ring carbon when the valency so permits;
R3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R30)2, —OR30 and —CF3;
R5 is selected from the group consisting of H, alkyl, halogen, cyano, hydroxy, hydroxyalkyl, and CF3;
R6 is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, —CN, —N(R30)2, —OR30, —N═CH-alkyl, and —NR30C(═O)alkyl;
R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qN(R30)2, —(CH2)qC(═O)NHR30, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, and —(CH2)qSO2NHR30;
R9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —C(═O)N(H)R30, —C(═O)alkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —N(H)R30, —N(H)S(O2)R31, —N(H) C(═O)NH(R30), —OR30, —SO2(R31), and —SO2N(H)R30;
R10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl;
R11 is selected from the group consisting of: H, alkyl, hydroxyalkyl, and carbonyl;
R12 is selected from the group consisting of H, CN, —C(═O)N(R30)2 and alkyl;
ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R20 moieties;
the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3, CF3, OCF3, —(CH2)qOR31, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)2, —OR30, —OC(═O)N(R30)2,
and —OSO2(R31);
Y is selected from the group consisting of: —CH2—, —CH(CH3)—, —CH(CH2OH)—, —C(═O)— and —CH(CO2alkyl)-;
m is 0-2;
n is 0-2;
q is 1 or 2; and
r is 1 or 2.

### Claim 38 (depends on 34)

The compound according to claim 34, wherein
is represented by
is represented by

### Claim 39 (depends on 1)

The compound according to claim 1, wherein said compound is represented by any one of structural Formulae 2-7:
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
the R8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, or —(CH2)qSO2NHR31;
the R9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, arylalkyl, alkylaryl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, —C(═O)N(H)R30, —C(═O)alkyl, —N(H)R30, —N(H)S(O2)R31, —N(H)C(═O)NH(R30), —OR30, —SO2(R31), ═O, ═S, and —SO2N(H)R30;
L is CH or N;
in Formula 4 is a single bond or a double bond; and
m, p, R10, R11, R20 and Y are as defined in claim 1.

### Claim 40 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, R3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R30)2, —OR30 and —CF3.

### Claim 41 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, R6 is selected from the group consisting of H, alkyl, halogen, —N(R30)2, —OR30 and —NR1C(═O)alkyl.

### Claim 42 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, R9 moieties are the same or different, each being independently selected from the group consisting of H, cyclopropyl, —CF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH2CH2OCH3, —C(═O)OCH2CH3, —CH2NH2, —CH2CH2NH2, —CH2CH2NHSO2CH3, —CH2CH2SO2CH3, —C(═O)NH2, —C(═O)N(H)CH2CH2OH, —CH2N(H)C(═O)CF3, —C(═O)N(H)-cyclopropyl, —C(═O)N(H)CH2CF3, —NH2, —NHCH3, —N(CH3)2, —N(H)CH2CH3, —N(H)CH(CH3)2, —N(H)CH2CH2CH3, —N(H)CH2C(═O)OCH3, —N(H)CH2CH2OH, —N(H)CH2CH2NH2, —N(H)CH2CH2NHSO2CH3, —N(H)CH2CH2SO2CH3, —N(H)C(═O)N(H)CH2CH3, —N(H)CH2C(═O)NH2, and —OCH3.

### Claim 43 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, R10 is selected from the group consisting of H, alkyl, aralkyl, and hydroxyalkyl, or wherein two R10 taken together with the carbon atom to which both are attached is >C═O.

### Claim 44 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3, CF3, OCF3, —(CH2)qOR31, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)2, —OR30, —OC(═O)N(R30)2, —OSO2(R31),

### Claim 45 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, the R20 moieties can be the same or different, each being independently selected from the group consisting of H, —CN, —CH3, —CF3, —CH2OH, —CO2H, —CO2CH3, —NH2, —NHCH3, —OCF3, —OH, F, Cl, Br, —C(═NOH)NH2, —OCH2CH2S(O2)CH3, —C(═O)NH2,

### Claim 46 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, L is CH.

### Claim 47 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, L is N.

### Claim 48 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7, Y is selected from the group consisting of: —CH2—, —C(═O)—, —CH(CH2OH)— and —CH(CO2alkyl)-.

### Claim 49 (depends on 39)

The compound according to claim 39, wherein in Formulae 2-7:
R3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R30)2, —OR30 and —CF3;
R6 is selected from the group consisting of H, alkyl, halogen, —N(R30)2, —OR30, and —NR1C(═O)alkyl;
the R9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —C(═O)N(H)R30, —C(═O)alkyl, —N(H)R30, —N(H)S(O2)R31, —N(H)C(═O)NH(R30), —OR30, —SO2(R31), and —SO2N(H)R30;
R10 is selected from the group consisting of H, alkyl, aralkyl, and hydroxyalkyl, or wherein two R10 taken together with the carbon atoms to which both are attached is >C═O;
the R20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3, CF3, OCF3, —(CH2)qOR31, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNR30SO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)2, —OR30, —OC(═O)N(R30)2, and —OSO2(R31),
Y is selected from the group consisting of: —CH2—, —C(═O)—, —CH(CH2OH)— and —CH(CO2alkyl)-;
m is 0-2;
q is 1 or 2; and
r is 1 or 2.

### Claim 50 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt, or solvate thereof.

### Claim 51

A compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 52

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 53 (depends on 1)

A compound according to claim 1, in purified form.

### Claim 54 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with at least one pharmaceutically acceptable carrier.

### Claim 55 (depends on 54)

The pharmaceutical composition of claim 54, further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.

### Claim 56 (depends on 1)

A method of treating a CXCR3 chemokine receptor mediated disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 57 (depends on 56)

A method according to claim 56, further comprising administering concurrently or sequentially at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease, in combination with a pharmaceutically acceptable carrier.

### Claim 58 (depends on 56)

The method according to claim 56, wherein the compound binds to a CXCR3 receptor.

### Claim 59 (depends on 56)

The method according to claim 56, further comprising administering concurrently or sequentially at least one medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal anti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-α compounds, TNF-alpha-convertase inhibitors, cytokine inhibitors, MMP inhibitors, glucocorticoids, corticosteroids, chemokine inhibitors, CB2-selective inhibitors, p38 inhibitors, biological response modifiers; anti-inflammatory agents and therapeutics.

### Claim 60 (depends on 56)

The method according to claim 56, wherein the disease is an inflammatory or immune disease.

### Claim 61 (depends on 60)

The method according to claim 60, wherein said inflammatory or immune disease is selected from the group consisting of neurodegenerative disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, juvenile rheumatoid arthritis, atherosclerosis, vasculitis, chronic heart failure, cerebrovascular ischemia, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis, eczema, urticaria, type I diabetes, asthma, conjunctivitis, ophthalmic inflammation, otitis, allergic rhinitis, chronic obstructive pulmonary disease, sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Behcet's syndrome, pulmonary fibrosis, endometriosis, gout, cancer, cachexia, a viral infection, a bacterial infection, an organ transplant condition, a skin transplant condition, and a graft versus host disease.

### Claim 62 (depends on 1)

A method of inhibiting or blocking T-cell mediated chemotaxis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 63 (depends on 1)

A method of treating inflammatory bowel disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 64 (depends on 63)

The method according to claim 63, further comprising administering concurrently or sequentially at least one compound selected from the group consisting of: sulfasalazine, 5-aminosalicylic acid, sulfapyridine, anti-TNF compounds, anti-IL-12 compounds, corticosteroids, glucocorticoids, T-cell receptor directed therapies, immunosuppressives, methotrexate, azathioprine, and 6-mercaptopurines.

### Claim 65 (depends on 1)

A method of treating or preventing graft rejection in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 66 (depends on 65)

The method according to claim 65, further comprising administering concurrently or sequentially at least one compound selected from the group consisting of: cyclosporine A, FK-506, FTY720, beta-interferon, rapamycin, mycophenolate, prednisolone, azathioprine, cyclophosphamide and an antilymphocyte globulin.

### Claim 67 (depends on 1)

A method of treating multiple sclerosis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: beta-interferon, glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA-4 inhibitors, FTY720, anti-IL-12 compounds, fumarates and CB2-selective inhibitors.

### Claim 68 (depends on 1)

A method of treating multiple sclerosis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunomide, sulfasalazine, corticosteroids, β-methasone, β-interferon, glatiramer acetate, prednisone, etanercept, and infliximab.

### Claim 69 (depends on 1)

A method of treating rheumatoid arthritis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: non-steroidal anti-inflammatory agents, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, cyclosporine, methotrexate, steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, caspase (ICE) inhibitors and other classes of compounds indicated for the treatment of rheumatoid arthritis.

### Claim 70 (depends on 1)

A method of treating rheumatoid arthritis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one B cell targeted therapy selected from the group consisting of rituximab, CLTA4-Ig, and anti-IL-6R antibodies.

### Claim 71 (depends on 1)

A method of treating psoriasis in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressives, cyclosporins, methotrexate, steroids, corticosteroids, anti-TNF-α compounds, anti-IL compounds, anti-IL-23 compounds, vitamin A and D compounds and fumarates.

### Claim 72 (depends on 1)

A method of treating ophthalmic inflammation or dry eye in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressives, cyclosporins, methotrexate, FK506, steroids, corticosteroids, and anti-TNF-α compounds.

### Claim 73 (depends on 61)

A method according to claim 61, further comprising administering to the patient concurrently or sequentially at least one medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal antiinflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-α compounds, TNF-alpha-convertase inhibitors, cytokine inhibitors. MMP inhibitors, corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, p38 inhibitors, biological response modifiers; anti-inflammatory agents and therapeutics.