Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators

Patent metadata

Field	Value
Publication number	US-10793529-B2
Application number	US-201816159971-A
Country	US
Kind code	B2
Filing date	Oct 15, 2018
Priority date	Dec 8, 2008
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

Cyclohexane derivatives of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the PGI2 receptor.

Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pulmonary arterial hypertension (PAH) and related disorders; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clot formation in an angioplasty or coronary bypass surgery individual or in an individual suffering from atrial fibrillation; atherosclerosis; atherothrombosis; asthma or a symptom thereof; a diabetic-related disorder such as diabetic peripheral neuropathy, diabetic nephropathy or diabetic retinopathy; glaucoma or other disease of the eye with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn's disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; ischemia-reperfusion injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructive pulmonary disorder (COPD).

First claim

What is claimed is:

1. A method for modulating the activity of the prostacyclin receptor in an individual, comprising administering to the individual a compound having the structure of Formula Ia:

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof
wherein:
R 1 is H or C 1 -C 8 alkyl;
R 2 is H, C 1 -C 8 alkyl, aryl or heteroaryl, wherein the C 1 -C 8 alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio and aryl;
R 3 is H, C 1 -C 8 alkyl, aryl or heteroaryl, wherein the C 1 -C 8 alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, and aryl; and
X is N or CH.

2. The method of claim 1 , wherein the individual is a human that has a disorder selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, a symptom of asthma, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or other disease of the eye with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disorder.

3. The method of claim 1 , wherein the individual is a human that has pulmonary arterial hypertension.

4. The method of claim 3 , wherein the pulmonary arterial hypertension is selected from the group consisting of:
(a) idiopathic pulmonary arterial hypertension;
(b) familial pulmonary arterial hypertension;
(c) pulmonary arterial hypertension associated with a collagen vascular disease selected from the group consisting of scleroderma, calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasias syndrome, systemic lupus erythematosus, rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis;
(d) pulmonary arterial hypertension associated with a congenital heart disease selected from the group consisting of atrial septic defect, ventricular septic defect and patent ductus arteriosus;
(e) pulmonary arterial hypertension associated with portal hypertension;
(f) pulmonary arterial hypertension associated with human immunodeficiency virus infection;
(g) pulmonary arterial hypertension associated with ingestion of a drug or toxin;
(h) pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia;
(i) pulmonary arterial hypertension associated with splenectomy;
(j) pulmonary arterial hypertension associated with significant venous or capillary involvement;
(k) pulmonary arterial hypertension associated with pulmonary veno-occlusive disease; and
(l) pulmonary arterial hypertension associated with pulmonary capillary hemangiomatosis.

5. The method of claim 1 , wherein R 1 is H.

6. The method of claim 1 , wherein R is C 1 -C 6 alkyl.

7. The method of claim 1 , wherein:
R 2 is H, C 1 -C 8 alkyl, aryl or heteroaryl, wherein the C 1 -C 8 alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylthio, and phenyl; and
R 3 is H, C 1 -C 8 alkyl, aryl or heteroaryl, wherein the C 1 -C 8 alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylthio, and phenyl.

8. The method of claim 1 , wherein:
R 2 is C 1 -C 8 alkyl, aryl or heteroaryl, each optionally substituted; and
R 3 is C 1 -C 8 alkyl, aryl or heteroaryl, each optionally substituted.

9. The method of claim 1 , wherein:
R 2 is H, methyl, phenyl, 1H-pyrazol-4-yl, pyridinyl, thiophen-2-yl or thiophen-3-yl, wherein the methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylthio and phenyl; and
R 3 is H, methyl, phenyl, 1H-pyrazol-4-yl, pyridinyl, thiophen-2-yl or thiophen-3-yl, wherein the methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylthio, and phenyl.

10. The method of claim 1 , wherein
R 2 is H, benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-4-yl, thiophen-2-yl, thiophen-3-yl, 4-methylthiophen-2-yl, or 5-methylthiophen-2-yl; and
R 3 is H, benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-4-yl, thiophen-2-yl, thiophen-3-yl, 4-methylthiophen-2-yl, or 5-methylthiophen-2-yl.

11. The method of claim 1 , wherein:
R 2 is benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl, 2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl, 6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl or thiophen-3-yl; and
R 3 is H, phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-

Assignees

• Arena Pharm Inc

Inventors

• Tran Thuy-Anh
• Hayashi Rena
• Ibarra Jason B
• Ullman Brett
• Zou Ning

Classifications

• A61P11/08

  Bronchodilators · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D237/14 Primary

  Oxygen atoms · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title