New uses for corticotropin releasing factor antagonists

Abstract

A method of treating, preventing or inhibiting a disorder selected from the group consisting of cardiovascular or heart related diseases such as stroke, hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, comprising administering to a mammal, including a human, in need of such treatment a therapeutically effective amount of a compound of the formula or pharmaceutically acceptable salt thereof, wherein A, B, D, E, Y, Z, R 3 , R 4 , and R 5 are as defined herein.

What is claimed is:  
     
         1 . A method of treating a disorder selected from the group consisting of cardiovascular or heart related diseases including hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula  
                   
       or a pharmaceutically acceptable salt thereof, wherein 
 the dashed line represents an optional double bond;  
 A is —CR 7  or N;  
 B is —NR 1 R 2 , —CR 1 R 2 R 1 , —C(═CR 1 , R 12 )R 2 , —NHCR 11 R 1 R 2 , —OCR 11 R 1 R 2 , —SCR 11 R 1 R 2 , —CR 11 R 2 OR 1 , —CR 11 R 2 SR 1 , —C(S)R 2 , —NHNR 1 R 2 , —CR 2 R 11 NHR 1  or —C(O)R 2 ;  
 D is: (i) N or —CR 10  when a double bond connects E and D and E is —CR 4 ; (ii) —CR 10  when a double bond connects E and D and E is N; or (iii) —CR 8 R 9 , —CHR 10 , —C═O, —C═S, —C═NH, or —C═NCH 3  when a single bond connects E and D;  
 E is —CR 4 or N when a double bond connects E and D, and E is —CR 4 R 6  or —NR 6  when a single bond connects E and D;  
 Y is N or —CH;  
 Z is NH, O, S, —N(C 1 -C 2  alkyl) or —CR 12 R 13 , wherein R 12  and R 13  are each, independently, hydrogen, trifluoromethyl or methyl, or one of R 12  and R 13  is cyano and the other is hydrogen or methyl;  
 R 1  is hydrogen or C 1 -C 6  alkyl which is optionally substituted with one or two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF 3 , C 1 -C 4  alkoxy, —O—CO—(C 1 -C 4  alkyl), —O—CO—NH(C 1 -C 4  alkyl), —O—CO—N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —NH(C 1 -C 4  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), —N(C 1 -C 4 alkyl)CO(C 1 -C 4  alkyl), —NHCO(C 1 -C 4  alkyl), —CO 2 (C 1 -C 4  alkyl), —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, and (C 1 -C 4  alkyl)sulfanyl, and wherein said C 1 -C 6  alkyl, C 1 -C 4  alkoxy and the C 1 -C 4  alkyl moieties in the foregoing R 1  groups optionally contain one double or triple bond;  
 R 2  is C 1 -C 6  alkyl, heteroaryl, aryl (heteroaryl)C 1 -C 4  alkyl or (aryl)C 1 -C 4  alkyl wherein said aryl and the aryl moiety of said (aryl)C 1 -C 4  alkyl are selected from the group consisting of phenyl and naphthyl, and said heteroaryl and the heteroaryl moiety of said (heteroaryl)C 1 -C 4  alkyl is selected from the group consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R 2  is C 3 -C 8  cycloalkyl or (C 3 -C 8  cycloalkyl)C 1 -C 6  alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C 3 -C 8  cycloalkyl)C 1 -C 6  alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by —NR 14  wherein R 14  is hydrogen or C 1 -C 4  alkyl; and wherein each of the foregoing R 2  groups is optionally substituted by from one to three substituents independently selected from chloro, fluoro and C 1 -C 4  alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C 1 -C 6  alkoxy, —O—CO—(C 1 -C 4 alkyl), —O—CO—N(C 1 -C 4 alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), (C 1 -C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfinyl, and (C 1 -C 4  alkyl)sulfonyl, and wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl and C 1 -C 6  alkyl moieties of the foregoing R 2  groups optionally contain one carbon-carbon double or triple bond;  
 or R 1  and R 2  of said —NR 1 R 2  and said —CR 1 R 2 R 11  are taken together to form a saturated 5 to 8 member ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by a heteroatom selected from O, S and N;  
 R 3  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CH 2 OH, —CH 2 OCH 3 , —O(C 1 -C 4  alkyl), (C 1 - C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfonyl, or (C 1 -C 4  alkyl)sulfinyl, wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl moieties of the foregoing R 3  groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C 1 -C 3  alkoxy, —NH(C 1 -C 2  alkyl), —N(C 1 -C 2 ) 2 , —NHCOCH 3 , fluoro, chloro and C 1 -C 3  thioalkyl;  
 R 4  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, C 1 -C 6  alkoxy, formyl, trifluoromethoxy, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CF 3 , CF 3 , amino, nitro, —NH(C 1 -C 4  alkyl), —N(CH 3 ) 2 , —NHCOCH 3 , —NHCONHCH 3 , (C 1 -C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4 alkyl)sulfonyl, cyano, hydroxy, —CO(C 1 -C 4 alkyl), —CHO, or —CO 2 (C 1 - C 4  alkyl), wherein said C 1 -C 6  alkyl, C 1 -C 6  alkoxy and the C 1 -C 4  alkyl moieties of the foregoing R 4  groups optionally contain one double or triple bond and are optionally substituted with one substituent selected from hydroxy, amino, —NHCOCH 3 , —NH(C 1 -C 2  alkyl), —N(C 1 -C 2  alkyl) 2 , —CO 2 (C 1 -C 4  alkyl), —CO(C 1 -C 4  alkyl), C 1 -C 3  alkoxy, (C 1 -C 3  alkyl)sulfanyl, fluoro, chloro, cyano and nitro;  
 R 5  is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyl optionally contain one or two of O, S or —N—G wherein G is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkanoyl, phenyl or benzyl, wherein each of the above R 5  groups is optionally substituted by from one to three substituents independently selected from fluoro, chloro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and trifluoromethyl, or one substituent selected from bromo, iodo, cyano, nitro, amino, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), —CO(C 1 -C 4  alkyl), —SO 2 NH(C 1 -C 4  alkyl), —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SO 2 NH 2 , —NHSO 2 (C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), and —SO 2 (C 1 -C 4  alkyl), wherein said C 1 -C 4  alkyl and C 1 -C 6  alkyl moieties of the foregoing R 5  groups optionally contain one double or triple bond and are optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, amino, methylamino, dimethylamino and acetyl;  
 R 6  is hydrogen or C 1 -C 6  alkyl, wherein said C 1 -C 6  alkyl is optionally substituted by a single hydroxy, methoxy, ethoxy or fluoro group;  
 R 7  is hydrogen, C 1 -C 4  alkyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, C 1 -C 4  alkoxy, —CO(C 1 -C 4  alkyl), —CO 2 (C 1 -C 4  alkyl), —OCF 3 , CF 3 , —CH 2 OH, —CH 2 OCH 3  or —CH 2 OCH 2 CH 3 ;  
 R 8  and R 9  are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy;  
 or R 8  and R 9  together form an oxo (═O) group;  
 R 10  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, C 1 -C 6  alkoxy, formyl, amino, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SO n (C 1 -C 4  alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido, wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl moieties of the foregoing R 10  groups are optionally substituted by one of hydroxy, trifluoromethyl, amino, carboxy, amido, —NHCO(C 1 -C 4  alkyl), —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), C 1 -C 3  alkoxy, C 1 -C 3  thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; and,  
 R 11  is hydrogen, hydroxy, fluoro, or methoxy.  
 
     
     
         2 . The method of    claim 1    wherein B is —NR 1 R 2 , —NHCHR 1 R 2 , —CR 1 R 2 R 11 , —SCHR 1 R 2  or —OCHR 1 R 2 ; R 1  is C 1 -C 6  alkyl which is optionally substituted with a single hydroxy, fluoro or C 1 -C 2  alkoxy group and optionally contains one carbon-carbon double or triple bond; R 2  is benzyl or C 1 -C 6  alkyl which optionally contains one carbon-carbon double or triple bond, wherein said C 1 -C 6  alkyl and the phenyl moiety of said benzyl are optionally substituted with fluoro, C 1 -C 2  alkyl, or C 1 -C 2  alkoxy; and R 11  is hydrogen or fluoro.  
     
     
         3 . The method of    claim 1    wherein R 2  is (aryl)C 1 -C 4  alkyl or (heteroaryl)C 1 -C 4  alkyl in which said aryl or heteroaryl moiety is phenyl, thienyl, benzofuranyl, furanyl, benzothienyl, thiazolyl, pyridyl or benzothiazolyl.  
     
     
         4 . The method of    claim 1    wherein B is NR 1 R 2  or CHR 1 R 2  in which R 1  and R 2  are taken together with N or CH to form a 5- or 6-membered ring optionally having sulfur, oxygen, or, where B is NR 1 R 2 , one more nitrogen in said ring.  
     
     
         5 . The method of    claim 1    wherein B is —NHCHR 1 R 2  or —OCHR 1 R 2 , wherein the CHR 1 R 2  moiety is a 5- or 6-membered ring which optionally contains one oxygen or sulfur.  
     
     
         6 . The method of    claim 5    wherein B is tetrahydrofuranyl, tetrahydrothiafuranyl or cyclopentanyl.  
     
     
         7 . The method of    claim 5    wherein B is tetrahydrofuranyl, tetrahydrothienyl or thiazolidinyl.  
     
     
         8 . The method of    claim 1    wherein R 3  is methyl, chloro, or methoxy; R 4  is methyl, —CH 2 OH, cyano, trifluoromethoxy, methoxy, trifluoromethyl, chloro, —CO 2 CH 3 , —CH 2 OCH 3 , —CH 2 Cl, —CH 2 F, amino or nitro; R 6  is hydrogen, methylsulfinyl, methylsulfanyl, methylsulfonyl, or ethyl; and R 5  is phenyl or pyridyl wherein said phenyl or pyridyl is substituted by one substituent independently selected from fluoro, chloro, bromo, iodo, C 1 -C 4  alkoxy, trifluoromethyl, C 1 -C 3  hydroxyalkyl, —CO 2 (C 1 -C 2  alkyl), (amino)C 1 -C 2  alkyl, —CO(C 1 -C 4  alkyl), and C 1 -C 6  alkyl, wherein said C 1 -C 6  alkyl and said C 1 -C 4  alkyl are optionally substituted by a single hydroxy, or fluoro group and optionally contains one carbon-carbon double or triple bond.  
     
     
         9 . The method of    claim 1    wherein the compound of formula I or II is selected from the group consisting of: 
 4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;  
 2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;  
 2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;  
 3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;  
 2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;  
 4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;  
 2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;  
 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;  
 4-(1-methoxymethyl-propoxy)-3,6-dimethyl-pyridine;  
 [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;  
 [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;  
 [2,5-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine;  
 butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;  
 4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;  
 butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;  
 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester;  
 [3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;  
 [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;  
 [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine;  
 1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;  
 N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;  
 N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;  
 N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine;  
 [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;  
 [3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethyl-propyl)-amine;  
 [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;  
 (1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;  
 (1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;  
 N-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;  
 [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine;  
 4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;  
 butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H -pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;  
 4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;  
 4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;  
 N-butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;  
 (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;  
 [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;  
 N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;  
 N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;  
 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;  
 [4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;  
 6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one, and pharmaceutically acceptable salts of the foregoing compounds.  
 
     
     
         10 . The method of    claim 1    wherein said compound is a compound of formula II in which E and D are connected by a double bond, E is —CR 4 , D is —CR 10  or N, Y is N, and A is —CR 7 .  
     
     
         11 . The method of    claim 10    wherein said compound is selected from the group consisting of: 
 butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethylamine;  
 3,6-dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine  
 [3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl]-(1-methoxymethylpropyl)-amine;  
 4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine;  
 (1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-amine;  
 4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;  
 4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;  
 4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl-4-bromophenyl)-7H-pyrrolo[2,3-b]pyridine, and pharmaceutically acceptable salts of the foregoing compounds.  
 
     
     
         12 . The method of    claim 1    wherein said compound is a compound of formula II in which E and D are connected by a double bond, E is —CR 4 , and D, Y and A are N.  
     
     
         13 . The method of    claim 12    wherein said compound is selected from the group consisting of: 
 3-{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;  
 diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 2-{butyl-[6-methyl-3-methylsulfanyl -1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl]-amino}-ethanol;  
 dibutyl-{6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-amine;  
 butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;  
 4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine;  
 2-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine]-butan-1-ol;  
 [3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]-(1-methylpropyl)amine;  
 4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine, and pharmaceutically acceptable salts of the foregoing compounds.  
 
     
     
         14 . The method of    claim 1    wherein said compound is a compound of formula II in which E and D are connected by a double bond, E is —CR 4 , D is —CR 10 , and Y and A are N.  
     
     
         15 . The method of    claim 14    wherein said compound is selected from the group consisting of: 
 n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;  
 4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;  
 n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;  
 2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;  
 2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;  
 2-(S)-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;  
 4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;  
 4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;  
 4-(1-ethyl-butyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo-[2,3-d]pyrimidine;  
 [7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-methoxymethyl-propyl)-amine;  
 2-[7-(2-bromo-4,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;  
 2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;  
 2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;  
 2-[7-(2-fluoromethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol, and pharmaceutically acceptable salts of the foregoing compounds.  
 
     
     
         16 . A method of treating stroke comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula  
                   
       or a pharmaceutically acceptable salt thereof, wherein 
 B is —NR 1 R 2 , —CR 1 R 2 R 11 , —C(═CR 1 R 12 )R 2 , —NHCR 11 R 1 R 2 , —OCR 11 R 1 R 2 , —SCR 11 R 1 R 2 , —CR 11 R 2 OR 1 , —CR 11 R 2 SR 1 , —C(S)R 2 , —NHNR 1 R 2 , —CR 2 R 11 NHR, or —C(O)R 2 ;  
 D is N or —CR 10 ;  
 R 1  is hydrogen or C 1 -C 6  alkyl which is optionally substituted with one or two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF 3 , C 1 -C 4  alkoxy, —O—CO—(C 1 -C 4  alkyl), —O—CO—NH(C 1 -C 4  alkyl), —O—CO—N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —NH(C 1 -C 4  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), —N(C 1 -C 4 alkyl)CO(C 1 -C 4  alkyl), —NHCO(C 1 -C 4  alkyl), —CO 2 (C 1 -C 4  alkyl), —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, and (C 1 -C 4  alkyl)sulfanyl, and wherein said C 1 -C 6  alkyl, C 1 -C 4  alkoxy and the C 1 -C 4  alkyl moieties in the foregoing R 1  groups optionally contain one double or triple bond;  
 R 2  is C 1 -C 6  alkyl, heteroaryl, aryl, (heteroaryl)C 1 -C 4  alkyl or (aryl)C 1 -C 4  alkyl wherein said aryl and the aryl moiety of said (aryl)C 1 -C 4  alkyl are selected from the group consisting of phenyl and naphthyl, and said heteroaryl and the heteroaryl moiety of said (heteroaryl)C 1 -C 4  alkyl is selected from thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R 2  is C 3 - C 8  cycloalkyl or (C 3 -C 8  cycloalkyl)C 1 -C 6  alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C 3 - C 8  cycloalkyl)C 1 -C 6  alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by —NR 14  wherein R 14  is hydrogen or C 1 -C 4  alkyl; and wherein each of the foregoing R 2  groups is optionally substituted by from one to three substituents independently selected from chloro, fluoro and C 1 -C 4  alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C 1 -C 6  alkoxy, —O—CO—(C 1 -C 4 alkyl), —O—CO—N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), (C 1 -C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfinyl, and (C 1 -C 4  alkyl)sulfonyl, and wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl and C 1 -C 6  alkyl moieties of the foregoing R 2  groups optionally contain one carbon-carbon double or triple bond;  
 or R 1  and R 2  of said —NR 1 R 2  and said —CR 1 R 2 R 11  are taken together to form a saturated 5 to 8 member ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by a heteroatom selected from O, S and N;  
 R 3  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CH 2 OH, —CH 2 OCH 3 , —O(C 1 -C 4  alkyl), (C 1 - C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfonyl, or (C 1 -C 4  alkyl)sulfinyl, wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl moieties of the foregoing R 3  groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C 1 -C 3  alkoxy, —NH(C 1 -C 2  alkyl), —N(C 1 -C 2 ) 2 , —NHCOCH 3 , fluoro, chloro and C 1 -C 3  thioalkyl;  
 R 4  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, C 1 -C 6  alkoxy, formyl, trifluoromethoxy, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CF 3 , CF 3 , amino, nitro, —NH(C 1 -C 4  alkyl), —N(CH 3 ) 2 , —NHCOCH 3 , —NHCONHCH 3 , (C 1 -C 4  alkyl)sulfanyl, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4 alkyl)sulfonyl, cyano, hydroxy, —CO(C 1 -C 4 alkyl), —CHO, or —CO 2 (C 1 -C 4  alkyl), wherein said C 1 -C 6  alkyl, C 1 -C 6  alkoxy and the C 1 -C 4  alkyl moieties of the foregoing R 4  groups optionally contain one double or triple bond and are optionally substituted with one substituent selected from hydroxy, amino, —NHCOCH 3 , —NH(C 1 -C 2  alkyl), —N(C 1 -C 2  alkyl) 2 , —CO 2 (C 1 -C 4  alkyl), —CO(C 1 -C 4  alkyl), C 1 -C 3  alkoxy, (C 1 -C 3  alkyl)sulfanyl, fluoro, chloro, cyano and nitro;  
 R 5  is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyl optionally contain one or two of O, S or —N—G wherein G is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkanoyl, phenyl or benzyl, wherein each of the above R 5  groups is optionally substituted by from one to three substituents independently selected from fluoro, chloro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and trifluoromethyl, or one substituent selected from bromo, iodo, cyano, nitro, amino, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), —CO(C 1 -C 4  alkyl), —SO 2 NH(C 1 -C 4  alkyl), —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SO 2 NH 2 , —NHSO 2 (C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), and —SO 2 (C 1 -C 4 alkyl), wherein said C 1 -C 4  alkyl and C 1 -C 6  alkyl moieties of the foregoing R 5  groups optionally contain one double or triple bond and are optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, amino, methylamino, dimethylamino and acetyl;  
 R 10  is hydrogen, C 1 -C 6  alkyl, fluoro, chloro, bromo, iodo, C 1 -C 6  alkoxy, formyl, amino, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SO (C 1 -C 4  alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido, wherein said C 1 -C 6  alkyl and the C 1 -C 4  alkyl moieties of the foregoing R 10  groups are optionally substituted by one of hydroxy, trifluoromethyl, amino, carboxy, amido, —NHCO(C 1 -C 4  alkyl), —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —CO 2 (C 1 -C 4  alkyl), C 1 -C 3  alkoxy, C 1 -C 3  thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; and,  
 R 11  is hydrogen, hydroxy, fluoro, or methoxy.