# US 2014/0194425 A1 · Novel Pyrrole Inhibitors of S-Nitrosoglutathione Reductase as Therapeutic Agents

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- Number: US 2014/0194425 A1
- Document ID: US20140194425A1
- Status: Published application
- Kind: A1
- Application number: 14/204,849
- Filed: 2014-03-11
- Published: 2014-07-10
- Earliest claimed: 2008-08-15
- Assignees: N30 Pharmaceuticals, Inc.
- Applicants: N30 Pharmaceuticals, Inc.
- Inventors: Jan Wasley; Gary J. Rosenthal; Xicheng Sun; Sarah Strong; Jian Qiu
- Web page: https://patentgrep.com/patent/US20140194425A1

## CPC

- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- 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 3/04: Anorexiants; Antiobesity agents
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 15/10: for impotence
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/327: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/337: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 417/14: 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.

## Claims

### Claim 1

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R2 is selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, CF3, carbamoyl, C1-C6 alkylcarbamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
R3 is selected from the group consisting of hydroxyl, carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, C3-C6 cycloalkyl, cyano, nitro, carboxyl, amino, aminomethyl, acetamido, acetamido-2-methyl, 2-methoxyacetamido, propionamido, tetrahydrofuran-2-ylmethoxy, CF3, carboxyl, ureido, sulfamoylamino, C1-C6 alkylsulfonamido, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl, methylcarbamoyl, dimethycarbamoyl, methoxyethylcarbamoyl, hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl, pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl, 6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, and pyrimidin-5-ylcarbamoyl;
R4 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkyl sulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
n is 0-3;
wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;
with the following provisos:
proviso Ia: when R3 is carboxyl, methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substituted or unsubstituted phenyl-(C1-C3)-alkyl, or phenyl-(C2-C6)-alkenyl; and
proviso Ib: when R2 and R3 are both methoxy, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl.

### Claim 2 (depends on 1)

The method of claim 1 wherein:
Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, pyrimidinyl, substituted pyrimidinyl, furanyl, substituted furanyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl;
R1 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R2 is selected from the group consisting of halogen, C1-C6 alkyl, and CF3;
R3 is selected from the group consisting of hydroxyl, carbamoyl, sulfamoyl, sulfamoylamino, C1-C6 alkoxy, amino, aminomethyl, acetamido, acetamido-2-methyl, 2-methoxyacetamido, propionamido, tetrahydrofuran-2-ylmethoxy, methylsulfamido, carboxyl, C1-C6 alkylamino, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl, methylcarbamoyl, dimethycarbamoyl, methoxyethylcarbamoyl, hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl, pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl, 6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, and pyrimidin-5-ylcarbamoyl;
R4 is selected from the group consisting of hydrogen and C1-C6 alkyl; and
n is 1.

### Claim 3 (depends on 2)

The method of claim 2 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, aryl-phenyl, substituted aryl-phenyl, heteroaryl-phenyl, substituted heteroaryl-phenyl, thiophen-yl, substituted thiophen-yl, aryl-thiophen-yl, substituted aryl-thiophen-yl, heteroaryl-thiophen-yl, substituted heteroaryl-thiophen-yl, pyridinyl, substituted pyridinyl, aryl-pyridinyl, substituted aryl-pyridinyl, heteroaryl-pyridinyl, substituted heteroaryl-pyridinyl, thiazolyl, substituted thiazolyl, aryl-thiazolyl; substituted aryl-thiozolyl; heteroaryl-thiazolyl; substituted heteroaryl-thiazolyl, pyrimidinyl, substituted pyrimidinyl, aryl-pyrimidinyl, substituted aryl-pyrimidinyl, heteroaryl-pyrimidinyl, substituted heteroaryl-pyrimidinyl, furanyl, substituted furanyl, aryl-furanyl, substituted aryl-furanyl, heteroaryl-furanyl, and substituted heteroaryl-furanyl.

### Claim 4 (depends on 2)

The method of claim 2 wherein Ar is selected from the group consisting of phenyl, thiophen-yl, thiazolyl, pyridinyl, pyrimidinyl, or furanyl having 0, 1, 2, or 3 substitutions, wherein such substitutions are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkoxy, amino, cyano, C1-C6 alkyl, imidazolyl, methyl imidazolyl, ethyl imidazolyl, furanyl, methylthio, nitro, triazolyl, tetrazolyl, carbamoyl, pyrazolyl, trifluoromethoxy, trifluoromethyl, 2-amino-2oxoethoxy, ureido, morpholino, pyridinyl, pyrrolyl, methyl sulfonamido, carbamoyl phenyl, 6-oxo-1,6-dihydropyridinyl, 3,5-dimethylisoxazolyl, carboxymethoxy, hydroxyacetamido, methoxyacetamido, sulfamoyl, piperazinyl, oxoimidazolidinyl, methylsulfinyl, methylsulfonyl, pyrrolidinyl, piperidinyl, methylpyrazolyl, phenyl, thiazolyl, hydroxycarbamoyl, cyclopropylimidazolyl, carboxy, methylamino, methoxymethyl, dimethylamino, hydroxymethylimidazolyl, oxooxazolidinyl, formamido, hydroxyphenyl, and thiophen-yl.

### Claim 5 (depends on 2)

The method of claim 2 wherein Ar is selected from the group consisting of 4-(1H-imidazol-1-yl)phenyl, 5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl, 4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl, phenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl, 3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl, 3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl, 4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl, 4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl, 4-carbamoylphenyl, 4-(trifluoromethyl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl, 4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl, naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl, 4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl, 4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl, 4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl, 4-ethoxyphenyl, 4-(methylsulfinyl)phenyl, 4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl, 2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl, 4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl, 2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl, 3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl, 4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl, 2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl, 3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl, 2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl, 4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl, 3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl, 5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl, 5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl, 2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl, benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl, 4-chloro-2-(2-methoxyacetamido)phenyl, 4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl, 4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl, 4-chloro-2-(dimethylamino)phenyl, 4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl, 4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl, 4-(1H-imidazol-1-yl)-2-methoxyphenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl, 5-bromothiazol-2-yl, 4-bromothiazol-2-yl, 5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl, 3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl, 3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl, 4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl, 4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl, 5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.

### Claim 6 (depends on 2)

The method of claim 2 wherein Ar is selected from the group consisting of 4-(1H-imidazol-1-yl)phenyl, 5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl, 4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl, 3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl, 3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl, 4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl, 4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl, 4-carbamoylphenyl, 4-(trifluoromethyl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl, 4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl, naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl, 4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl, 4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl, 4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl, 4-ethoxyphenyl, 4-(methylsulfinyl)phenyl, 4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl, 2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl, 4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl, 2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl, 3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl, 4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl, 2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl, 3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl, 2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl, 4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl, 3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl, 5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl, 5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl, 2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl, benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl, 4-chloro-2-(2-methoxyacetamido)phenyl, 4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl, 4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl, 4-chloro-2-(dimethylamino)phenyl, 4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl, 4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl, 4-(1H-imidazol-1-yl)-2-methoxyphenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl, 5-bromothiazol-2-yl, 4-bromothiazol-2-yl, 5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl, 3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl, 3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl, 4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl, 4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl, 5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.

### Claim 7 (depends on 4)

The method of claim 4 wherein the compound of formula I is selected from the group consisting of:
3-(1-(4-carbamoyl-2-methylphenyl)-5-(thiazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2,6-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-hydroxy-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyanophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-ethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-iodophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(6-methoxypyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(benzo[d]thiazol-6-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-nitrophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(4H-1,2,4-triazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-methoxy-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-hydroxy-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(6-(1H-imidazol-1-yl)pyridin-3-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-carbamoylthiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-carbamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-amino-2-oxoethoxy)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-tetrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(2-(benzo[d][1,3]dioxol-5-yl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid; 3-(1-(4-amino-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-morpholinophenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrrol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2,5-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(naphthalen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3′-carbamoylbiphenyl-4-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyridin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(carboxymethoxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-hydroxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methoxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(piperazin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-ethoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(dimethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-methoxyethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-hydroxyethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(oxazol-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-chloro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2,3-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(piperidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyanophenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-2-yl)phenyl)-1H-pyrrol-2-yl)propanoate; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-methoxypyrimidin-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-acetamido-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-((tetrahydrofuran-2-yl)methoxy)-2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2-methoxyacetamido)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(biphenyl-4-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-(1H-imidazol-1-yl)pyrimidin-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-cyano-4-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(thiazol-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyano-3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-(dimethylamino)ethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3,5-dimethyl-4-nitrophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-amino-3,5-dimethylphenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-(1H-imidazol-1-yl)thiazol-4-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(pyridin-3-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-(6-methoxypyridin-3-ylcarbamoyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(6-methoxypyridin-3-ylcarbamoyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiazol-5-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(hydroxycarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(pyridin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridazin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridin-3-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyrimidin-5-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-(2-methoxyacetamido)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-acetamido-4-chlorophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(1-(4-carbamoyl-2-methylphenyl)-5-(2-carboxyethyl)-1H-pyrrol-2-yl)benzoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(2-methoxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methoxymethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiazol-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiazol-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(4-hydroxyphenyl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 2-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiophen-3-yl)phenyl)-1H-pyrrol-2-yl)acetic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(1H-imidazol-1-yl)furan-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)furan-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromofuran-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; and 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)butanoic acid.

### Claim 8 (depends on 1)

The method of claim 1 comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.

### Claim 9

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof:
wherein
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
X1-X4 is independently selected from the group consisting of C and N;
R5 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, carboxyl, C1-C6 alkylhydroxy, sulfamoyl, C1-C6 alkylsulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
R6 is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, amino, CF3, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, 1H-imidazol-1-yl, and 2-methyl-1H-imidazol-1-yl;
or alternatively R5 and R6 together form a substituted or unsubstituted 5 or 6 membered heterocyclic ring containing up to 2 heteroatoms chosen from O, N or S;
R7 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
n is 0-3;
wherein R5 can be hydrogen only when at least one of X1-X4 is N;
and further wherein, X1 and X3 must be CH or N unless R5 and R6 together form a 5 or 6 membered heterocyclic ring or at least one of X1-X4 is N;
and wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;
with the following provisos:
proviso IIa: when all X are C and one of R5, R6, or R7 are carboxyl, methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substituted or unsubstituted phenyl-(C1-C3)-alkyl, or phenyl-(C2-C6)-alkenyl; and
proviso IIb: when all X are C and one of R5, R6, or R7 are independently selected from the group consisting of halogen or methyl, then Ar cannot be 4-hydroxyphenyl or 4-C1-C6 acyl-oxy-phenyl; and
proviso IIc: when all X are C and R5 is methyl, Cl, hydroxyl, trifluoromethyl and R6 is methyl, methyoxy, carboxyethyl, Cl, or carboxypropyl, and n is 1, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl; and
proviso IId: when all X are C and R5 and R6 together form a heterocyclic ring and the resulting bicyclic ring system is benzo[d]thiazol substituted at the 2 position with C1-C3 alkyl, then Ar cannot be phenyl, 4-F-phenyl, 4-methoxy-phenyl, or thiophen-yl.

### Claim 10 (depends on 9)

The method of claim 9 wherein:
Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, and substituted thiazolyl.

### Claim 11 (depends on 9)

The method of claim 9 wherein the compound of formula II is selected from the group consisting of:
3-(5-(4-methoxyphenyl)-1-(1-oxoisoindolin-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-methoxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-benzo[d]imidazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(5-carbamoylpyridin-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-chloro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(6-carbamoylpyridin-3-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-benzo[d]imidazol-6-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1,3-dioxoisoindolin-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indazol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-aminobenzo[d]thiazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(quinolin-6-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3,5-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-chloro-4-cyanophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(isoquinolin-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(isoquinolin-7-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-oxoindolin-5-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-cyano-4-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-fluoro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-aminobenzo[d]isoxazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 5-(2-(2-carboxyethyl)-5-phenyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid; 3-(1-(3-aminobenzo[d]isoxazol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; and 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrol-2-yl)propanoic acid.

### Claim 12 (depends on 9)

The method of claim 9 comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 9 together with a pharmaceutically accepted carrier or excipient.

### Claim 13

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof:
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
X5-X8 are independently selected from the group consisting of N, C and S, wherein at least one X must be N or S;
R8 and R9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, amino, CF3, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, aryl, aryloxyl, substituted aryl, heteroaryl, substituted heteroaryl, and null if X5-X8 are all N;
n is 0-3;
wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl.

### Claim 14 (depends on 13)

The method of claim 13 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl.

### Claim 15 (depends on 13)

The method of claim 13 wherein the compound of formula III is selected from the group consisting of:
3-(1-(5-carbamoylthiophen-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(5-carbamoylthiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbamoylthiophen-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(5-carbamoylthiophen-3-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-(2-amino-2-oxoethyl)thiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
and 3-(1-(4-carbamoylthiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid.

### Claim 16

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula IV or a pharmaceutically acceptable salt thereof:
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R10 is hydroxyl, carbamoyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, hydroxyethyl, pyridin-3-ylamino, piridin-4-ylamino, 1-methylpyrrolidin-3-yloxy, trifluoroacetyl, imidazol-1-yl, acetamido, methylsulfamido, 2-oxooxazolidin-3-yl, 2-hydroxyethylamino, and methylcarbamoyl;
n is 0-3;
wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;
with the following proviso:
proviso IVa: when R10 is hydroxyl or carbamoyl, Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl when n is 0 or 1.

### Claim 17 (depends on 16)

The method of claim 16 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, and substituted thiazolyl.

### Claim 18 (depends on 16)

The method of claim 16 wherein Ar is selected from phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 1H-imidazol-1-yl-phenyl, 2-methyl-1H-imidazol-1-yl-phenyl, 1H-imidazol-1-yl-thiophen-2-yl, and 2-methyl-1H-imidazol-1-yl-thiopheny-2-yl.

### Claim 19 (depends on 16)

The method of claim 16 wherein the compound of formula IV is selected from the group consisting of: 3-(1-(4-carbamoylphenyl)-5-(3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-ureidophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-amino-2-oxoethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-amino-2-oxoethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxyphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 2-(1-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)acetic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(1H-imidazol-1-yl)thiophen-2-yl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1-hydroxyethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxyphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(pyridin-3-ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(1-methylpyrrolidin-3-yloxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(pyridin-4-ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-(2,2,2-trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(2,2,2-trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1H-imidazol-1-yl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-hydroxyethylamino)phenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; and 3-(1-(4-hydroxyphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid.

### Claim 20 (depends on 16)

The method of claim 16 wherein the pulmonary wherein the pulmonary disorder is selected from the group consisting of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD).