N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists

Abstract

The present invention provides N-alkyl 2-(disubstituted)alkynyladenosine-5′-uronamides and derivatives thereof and pharmaceutical compositions containing the same that are selective agonists of A2A adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.

What is claimed is: 
     
         1 . A compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from: C 1-8  alkyl and C 3-8  cycloalkyl; 
         R 1  is independently selected from: H, C 1-8  alkyl, and C 3-8  cycloalkyl; 
         q is 1; 
         r is independently selected from 0, 1, 2, 3, 4 and 5; 
         R 2  is selected from: H, C 1-8  alkyl, C 3-8  cycloalkyl-C 0-8  alkylene-,C 1-8  alkoxy-C 1-8  alkylene-, 5-10 membered heterocyclyl-C 0-8  alkylene-, 5-10 membered heteroaryl-C 0-8  alkylene-, and aryl-C 0-8  alkylene-; 
         alternatively, q is 0, r is 1, and R 2  is —C(O)—R 2A ; 
         R 2A  is selected from: C 1-8  alkyl, C 3-8  cycloalkyl-C 0-8  alkylene-,C 1-8  alkoxy-C 1-8  alkylene-, 5-10 membered heterocyclyl-C 0-8  alkylene-, 5-10 membered heteroaryl-C 0-8  alkylene-, and aryl-C 0-8  alkylene-; 
         ring A is a phenyl ring or a 5-6 membered heteroaryl attached via the carbon atom shown and having 1-3 ring heteroatoms selected from O, N, and S(O) p ; 
         ring A is optionally substituted with 1-3 R 3  groups; 
         R 3  is independently selected from: C 1-8  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , OC(O)R a , OCO 2 R a , OC(O)NR a R b , NR b COR a , NR b CO 2 R a , NR b C(O)NR a R b , S(O) p NR a R b , C 3-10 cycloalkyl-C 0-8  alkylene-, 5-10 membered heterocyclyl-C 0-8  alkylene-, aryloxy, aryl-C 0-8  alkylene-, and 5-10 membered heteroaryl-C 0-8  alkylene-; 
         R a  is independently selected from: H, C 1-8  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; 
         R b  is independently selected from: H, C 1-8  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; 
         n is independently selected from: 1, 2, 3, 4, 5, and 6; and, 
         p is independently selected from: 0, 1, and 2. 
       
     
     
         2 . A compound of  claim 1 , wherein the compound is of Formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from: C 1-4  alkyl and C 3-6  cycloalkyl; 
         R 1  is selected from: H and C 1-4  alkyl; 
         R 2  is selected from: H, C 1-4  alkyl, C 3-6  cycloalkyl-C 0-2  alkylene-, and C 1-4  alkoxy-C 1-4  alkylene-; 
         ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, and pyridazinyl; 
         ring A is optionally substituted with 1-2 R 3  groups; 
         R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ; 
         R a  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; 
         R b  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; and, 
         p is independently selected from: 0, 1, and 2. 
       
     
     
         3 . A compound of  claim 2 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: H, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ;   R a  is independently selected from: H and C 1-4  alkyl;   R b  is independently selected from: H and C 1-4  alkyl; and,   p is independently selected from: 0, 1, and 2.   
     
     
         4 . A compound of  claim 3 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, —CN, OR a , CF 3 , and OCF 3 ;   R a  is independently selected from: H and C 1-4  alkyl; and,   R b  is independently selected from: H and C 1-4  alkyl.   
     
     
         5 . A compound of  claim 4 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is phenyl optionally substituted with 1-2 R 3  groups; and,   R 3  is independently selected from: CH 3 , F, Cl, —CN, CF 3 , and OCF 3 .   
     
     
         6 . A compound of  claim 4 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is 3-pyridyl optionally substituted with 1-2 R 3  groups; and,   R 3  is independently selected from: CH 3 , F, Cl, —CN, CF 3 , and OCF 3 .   
     
     
         7 . A compound of  claim 4 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is 4-pyridyl optionally substituted with 1-2 R 3  groups; and,   R 3  is independently selected from: CH 3 , F, Cl, —CN, CF 3 , and OCF 3 .   
     
     
         8 . A compound of  claim 4 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is 2-thienyl optionally substituted with 1-2 R 3  groups; and, R 3  is independently selected from: CH 3 , F, Cl, —CN, CF 3 , and OCF 3 .   
     
     
         9 . A compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein the compound is selected from a compound of Table 1.   
     
     
         10 . A compound of  claim 9 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof. 
       
     
     
         11 . A compound of  claim 1 , wherein the compound is of Formula lb or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from: C 1-4  alkyl and C 3-6  cycloalkyl; 
         R 1  is selected from: H and C 1-4  alkyl; 
         R 2  is selected from: H, C 1-4  alkyl, C 3-6  cycloalkyl-C 0-2  alkylene-, and C 1-4  alkoxy-C 1-4  alkylene-; 
         ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, and pyridazinyl; 
         ring A is optionally substituted with 1-2 R 3  groups; 
         R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ; 
         R a  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; 
         R b  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; and, 
         p is independently selected from: 0, 1, and 2. 
       
     
     
         12 . A compound of  claim 11 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: H, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ;   R a  is independently selected from: H and C 1-4  alkyl;   R b  is independently selected from: H and C 1-4  alkyl; and,   p is independently selected from: 0, 1, and 2.   
     
     
         13 . A compound of  claim 12 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, —CN, OR a , CF 3 , and OCF 3 ;   R a  is independently selected from: H and C 1-4  alkyl; and,   R b  is independently selected from: H and C 1-4  alkyl.   
     
     
         14 . A compound of  claim 1 , wherein the compound is of Formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from: C 1-4  alkyl and C 3-6  cycloalkyl; 
         R 1  is selected from: H and C 1-4  alkyl; 
         R 2A  is selected from: C 1-4  alkyl, C 3-6  cycloalkyl-C 0-2  alkylene-, and C 1-4  alkoxy-C 1-4  alkylene-; 
         ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, and pyridazinyl; 
         ring A is optionally substituted with 1-2 R 3  groups; 
         R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ; 
         R a  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; 
         R b  is independently selected from: H, C 1-4  alkyl and C 3-8  cycloalkyl-C 0-8  alkylene-; and, 
         p is independently selected from: 0, 1, and 2. 
       
     
     
         15 . A compound of  claim 14 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2A  is selected from: methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, Br, I, —CN, OR a , SR a , NR a R b , CF 3 , OCF 3 , COR a , CO 2 R a , C(O)NR a R b , and S(O) p NR a R b ;   R a  is independently selected from: H and C 1-4  alkyl;   R b  is independently selected from: H and C 1-4  alkyl; and,   p is independently selected from: 0, 1, and 2.   
     
     
         16 . A compound of  claim 15 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 R is selected from: methyl, ethyl, and cyclopropyl;   R 1  is H;   R 2A  is selected from: methyl, isobutyl, cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;   ring A is selected from: phenyl, pyridyl, and thienyl;   ring A is optionally substituted with 1-2 R 3  groups;   R 3  is independently selected from: C 1-4  alkyl, F, Cl, —CN, OR a , CF 3 , and OCF 3 ;   R a  is independently selected from: H and C 1-4  alkyl; and,   R b  is independently selected from: H and C 1-4  alkyl.   
     
     
         17 . A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         18 . A method for treating an adenosine A 2A  receptor associated state in a subject, comprising: administering to the subject an effective amount of a compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the adenosine A 2A  receptor associated state is selected from an autoimmune stimulation, inflammation, allergic diseases, skin diseases, infectious diseases, wasting diseases, organ transplantation, tissue or cell transplantation, neuropathic pain, open wounds, adverse effects from drug therapy, a cardiovascular condition, ischemia-reperfusion injury, dialysis, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, founder's disease, glaucoma, and ocular hypertension, spinal injury, myocardial infarction, acute myocardial infarction. 
     
     
         20 . The method of  claim 18 , wherein the adenosine A 2A  receptor associated state is selected from: arthritis, Crohn's disease, chronic obstructive pulmonary disease, sepsis, inflammatory bowel disease, glaucoma, ocular hypertension, diabetic nephropathy, tissue or cell transplantation, 
     
     
         21 . The method of  claim 18 , wherein the adenosine A 2A  receptor associated state is caused by Shiga toxin, Clostridium difficile, or Clostridium difficile toxin A-induced condition. 
     
     
         22 . A method of diagnosing myocardial perfusion abnormalities in a mammal, comprising:
 a. parenterally administering to the mammal a unit dose of a compound of  claim 1 ; and,   b. performing a technique on the mammal to detect the presence of coronary artery stenosis, assess the severity of coronary artery stenosis, or a combination therof.   
     
     
         23 . A method of reducing interocular pressure in a subject, comprising: administering to the subject an effective amount of a compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, such that the intraocular pressure is reduced.