# US 7,745,460 B2 · Modulators of cellular adhesion

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- Number: US 7,745,460 B2
- Document ID: US7745460B2
- Status: Granted
- Kind: B2
- Application number: 11/978,388
- Filed: 2007-10-29
- Published: 2008-07-24
- Granted: 2010-06-29
- Earliest claimed: 2003-11-05
- Assignees: SARcode Corporation
- Inventors: Wang Shen; Kenneth Barr; Johan D. Oslob; Min Zhong
- Web page: https://patentgrep.com/patent/US7745460B2

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- 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 11/06: Antiasthmatics
- A61P 11/16: Central respiratory analeptics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C04B 35/632: Organic additives
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 217/16: substituted by oxygen atoms
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C04B: LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE {(roofing granules E04D7/005)}; CERAMICS (devitrified glass-ceramics C03C10/00); REFRACTORIES; TREATMENT OF NATURAL STONE
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).

## Claims

### Claim 1

A compound of the structure (I):
or pharmaceutically acceptable salts thereof;
R1 and R2 are each independently hydrogen, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl,
wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q,
wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—;
T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and
Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or
wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety;
wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1CR1D or —SO2R1C;
R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), or —CH2X0;
wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or
R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I;
R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1
wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, C(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
n is an integer from 0-4;
AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety;
A, B, D and E are connected by single bonds; wherein D is N; each occurrence of A, B, and E is CHRi wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety;
p is an integer from 0-4; and,
L is a substituted or unsubstituted C1-6 alkylidene or C2-6 alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O).

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is carboxyl or protected carboxyl, wherein R3 is C(═O)R3A, wherein R3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures:

### Claim 3 (depends on 1)

The compound of claim 1 wherein the compound has the structure:
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB1, RB2 and RE are independently hydrogen or substituted or unsubstituted lower alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure:
wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and RS is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety.

### Claim 5 (depends on 1)

The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure:
wherein R1A is Ar2, SR1B or NR1BR1C; or an alkyl or heteroalkyl moiety; and Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or R1B and R1C, taken together with the nitrogen atom to which they are attached, form a heterocylic or heteroaryl moiety.

### Claim 6 (depends on 1)

The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure:
wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen, C1-6alkyl, C2-6alkenyl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety.

### Claim 7 (depends on 4, 5)

The compound of claim 4, 5, or 6, wherein R3A is independently hydrogen, lower alkyl, phenyl or benzyl.

### Claim 8 (depends on 4, 6)

The compound of claim 4 or 6 wherein Ar2 is one of the following structures:
wherein s is an integer from 0-2; and
each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —ORG1, —SRG1, —NRG1RG2—, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently lower alkyl, or when Y is ORP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group;
RP3 is lower alkyl or —N(RP2)2; and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety.

### Claim 9 (depends on 8)

The compound of claim 8 wherein Ar2 is one of the following structures:

### Claim 10 (depends on 4, 6)

The compound of claim 4 or 6 wherein Ar2 is one of the following structures:
wherein RP3 is lower alkyl and RG1 is hydrogen or lower alkyl.

### Claim 11 (depends on 5)

The compound of claim 5 wherein R1A is —NH2 or a moiety having the structure:
wherein RP1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and each occurrence of RP2 is independently hydrogen or lower alkyl.

### Claim 12 (depends on 11)

The compound of claim 11 wherein R1A is —NH2 or a moiety having the structure:
wherein RP1 is hydrogen or lower alkyl.

### Claim 13 (depends on 5)

The compound of claim 5 wherein R1A is a moiety having one of the structures:
wherein s is an integer between 0 and 2; and
each occurrence of RP1 is independently lower alkyl or is -GRG1 wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower alkyl, aryl or heteroaryl.

### Claim 14 (depends on 13)

The compound of claim 13 wherein R1A is a moiety having one of the structures:
wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen or lower alkyl.

### Claim 15 (depends on 6)

The compound of claim 6, wherein —NH(R2A)Ar2 is one of the following structures:
wherein X1 is N or CRP1;
s is an integer from 0-5; and
each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —RG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and RP3 is alkyl, heteroalkyl, aryl or heteroaryl.

### Claim 16 (depends on 15)

The compound of claim 15, wherein —NH(R2A)Ar2 has the following structure:
wherein RP1 is hydrogen, halogen or lower alkyl.

### Claim 17 (depends on 4, 5)

The compound of any one of claims 4, 5, and 6, wherein Ar2 is one of the following structures:
wherein each occurrence of s is an integer from 0-6;
X1, is CHRP1;
X2 and X3 are independently CHRP1, NRP2, CHSO2RP3, or NSO2RP3;
X5 is O, S or NRP2;
each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is ORP5 may also be hydrogen;
each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and
each occurrence of RP3 is independently alkyl, aryl, heteroaryl or —N(RP2)2.

### Claim 18 (depends on 17)

The compound of claim 17 wherein Ar2 is one of the following structures:
wherein X1 is N or CRP1;
s is an integer from 0-6;
each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —RG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and
RP3 is independently lower alkyl or aryl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein L is a moiety having the structure:

### Claim 20 (depends on 1)

The compound of claim 1, wherein AR1 is one of the following structures:
wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 are independently N or CRQ1;
X5 is O, S or NRQ2;
AR3 is a heterocyclic, aryl or heteroaryl moiety;
each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3RQ4—, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and
RQ2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group.

### Claim 21 (depends on 20)

The compound of claim 20, wherein AR1 is one of the following structures:
wherein X0 is F or Cl;
X2 is N or CRQ1;
X5 is CH, O, S or NH; and
RQ1 is hydrogen, methyl, —CF3, —OH, —OCH3, —OCF3 or halogen.

### Claim 22 (depends on 21)

The compound of claim 21, wherein AR1 is one of the following structures:

### Claim 23 (depends on 22)

The compound of claim 22, wherein AR1 is one of the following structures:

### Claim 24 (depends on 1)

The compound of claim 1, wherein AR1-L- is one of the following structures:

### Claim 25 (depends on 8)

The compound of claim 8 wherein Ar2 is:

### Claim 26 (depends on 1)

The compound of claim 1 having the structure:

### Claim 27 (depends on 1)

The compound of claim 1 having the structure:

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent.

### Claim 29 (depends on 28)

The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules and the leukocyte integrin family of receptors.

### Claim 30 (depends on 28)

The pharmaceutical composition of claim 28, wherein the intracellular adhesion molecules are selected from ICAM-1, ICAM-2 and ICAM-3.

### Claim 31 (depends on 28)

The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes.

### Claim 32 (depends on 28)

The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to antagonize Mac-1 and/or LFA-1.

### Claim 33 (depends on 1)

A method of treating an immune or inflammatory disorder in a subject mediated through the CD11/CD18 family of cellular adhesion molecules, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1, wherein the disorder is selected from psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, dermatitis, meningitis, uveitis, eczema, asthma, poison ivy, poison oak, Sjorgen's syndrome, pulmonary fibrosis and rheumatoid arthritis.

### Claim 34 (depends on 33)

The method of claim 33, wherein the CD11/CD18 family of cellular adhesion molecules is LFA-1.

### Claim 35 (depends on 1)

A method of treating an immune or inflammatory disorder in a subject comprising administering to a subject in need thereof a compound of claim 1, wherein the disorder is selected from psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, dermatitis, meningitis, uveitis, eczema, asthma, poison ivy, poison oak, Sjorgen's syndrome, pulmonary fibrosis and rheumatoid arthritis.

### Claim 36 (depends on 1)

The compound of claim 1, wherein AR1 is:
wherein r is an integer from 0-6;
each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3RQ4—, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
L is a moiety having the structure:
—C(═O)NHC(R1)(R2)R3 is a moiety having the following structure:
wherein RS is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—;
RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
R3A is hydrogen, a protecting group, a pharmaceutically acceptable salt or ester;
Ar2 has the following structure:
wherein s is an integer from 0-6;
each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—.

### Claim 37 (depends on 36)

The compound of claim 36, wherein RS is hydrogen.