Organic compounds

Abstract

The present invention relates to optionally substituted 3-amino-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino or 4-thioxo derivatives, e.g., 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

1 . A 3-amino-(optionally 4-imino or 4-thioxo)-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6-ones in free or salt form. 
     
     
         2 . The compound according to  claim 1 , which is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; 
 (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
 (iii) R 2  is
 H, 
 C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl), 
 N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl or 2-aminopropyl), 
 arylC 0-6 alkyl (e.g., phenyl or benzyl), wherein said aryl is optionally substituted with one or more C 1-6 alkoxy, for example, C 1-6 alkoxyarylC 0-6 alkyl (e.g., 4-methoxybenzyl), 
 heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkoxy (e.g., C 1-6 alkoxyheteroarylC 1-6 alkyl); 
 -G-J wherein G is a single bond or C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino, for example,
 —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 alkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), 
 —C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl); 
 
 
 (iv) R 3  is
 1) -D-E-F wherein:
 D is a single bond, C 1-6 alkylene (e.g., methylene), or arylC 1-6 alkylene (e.g., benzylene or —CH 2 C 6 H 4 —); 
 E is
 a single bond, 
 C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), 
 C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), 
 heteroarylene (e.g., pyridinylene or pyrimidinylene), 
 aminoC 1-6 alkylene (e.g., —CH 2 —N(H)—), 
 amino (e.g., —N(H)—); 
 C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene), 
 
 F is
 H, 
 halo (e.g., F, Br, Cl), 
 C 1-6 alkyl (e.g., isopropyl or isobutyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 C 3-8 cycloalkyl optionally containing one or more atom selected from a group consisting of N, S or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with one or more C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, 
 heteroaryl (e.g., pyridyl (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl)), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkyl, halo (e.g., fluoro) or haloC 1-6 alkyl; 
 C 1-6 alkoxy, 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), 
 —C(O)—R 13 , wherein R 13  is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; 
 —N(R 14 )(R 15 ); 
 
 or 
 
 2) a substituted heteroarylC 1-6 alkyl, e.g., substituted with haloC 1-6 alkyl; or 
 3) attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of Formula A 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein:
 X, Y and Z are, independently, N or C, 
 R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and 
 R 10  is 
  halogen (e.g., fluoro or chloro), 
  C 1-6 alkyl, 
  C 3-8 cycloalkyl, 
  heteroC 3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), 
  haloC 1-6 alkyl (e.g., trifluoromethyl), 
  aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), 
  C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), 
  arylcarbonyl (e.g., benzoyl), 
  heteroarylcarbonyl, 
  C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), 
  Aminocarbonyl, 
  —N(R 14 )(R 15 ); 
  wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl) 
  preferably R 10  is phenyl, pyridyl, e.g., 2-pyridyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); 
 provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
           
         
         (v) R 4  and R 5  are independently:
 H, 
 C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), 
 C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), 
 C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), 
 —C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); 
 
         (vi) R 6  is H, C 1-6 alkyl (e.g., methyl or ethyl) or C 3-8 cycloalkyl; 
         (vii) R 14  and R 15  are independently H or C 1-6 alkyl, 
       
       in free or salt form. 
     
     
         3 . The compound according to  claim 2 , which compound is a Compound of Formula II, wherein:
 (i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—;   (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl);   (iii) R 2  is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl),   (iv) R 3  is attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of Formula A   
       
         
           
           
               
               
           
         
         
           wherein:
 X, Y and Z are, independently, N or C, 
 R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and 
 R 10  is phenyl or pyridyl, e.g., 2-pyridyl, optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); 
 provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
         
         (i) R 4  is H and R 5  phenyl optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); 
         (ii) R 6  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
         (iii) R 14  and R 15  are independently H or C 1-6 alkyl, 
       
       in free or salt form. 
     
     
         4 . The compound according to  claim 1 , which compound is a Compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; 
 (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
 (iii) R 2  is
 H, 
 C 1-6 alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), 
 —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally substituted with one or more amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl (e.g., 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl), 
 C 3-8 heterocycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 
 C 3-8 cycloalkyl-C 1-6 alkyl (e.g., cyclopropylmethyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), 
 —N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl,2-aminopropyl), 
 hydroxyC 1-6 alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl), 
 arylC 1-6 alkyl (e.g., benzyl), 
 heteroarylC 1-6 alkyl (e.g., pyridinylmethyl), 
 C 1-6  alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl); 
 -G-J wherein:
 G is a single bond or, alkylene (e.g., methylene); 
 J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C 1-6 alkyl (e.g., (1-methylpyrrolidin-2-yl)); 
 
 
 (iv) R 3  is
 1) -D-E-F wherein:
 D is a single bond, C 1-6 alkylene (e.g., methylene), or arylalkylene (e.g., pbenzylene or —CH 2 C 6 H 4 —); 
 E is
 a single bond, 
 C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), 
 —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), 
 heteroarylene (e.g., pyridinylene or pyrimidinylene), 
 aminoC 1-6 alkylene (e.g., —CH 2 —N(H)—), 
 amino (e.g., —N(H)—); 
 C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene), 
 
 F is
 H, 
 halo (e.g., F, Br, Cl), 
 C 1-6 alkyl (e.g., isopropyl or isobutyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, 
 heteroaryl optionally substituted with C 1-6 alkyl, (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said heteroaryl is optionally substituted with halo (e.g., fluoro) or haloC 1-6 alkyl; 
 amino (e.g., —NH 2 ), 
 C 1-6 alkoxy, 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), 
 —C(O)—R 13 , 
 —N(R 14 )(R 15 ); or 
 
 
 2) a substituted heteroarylaklyl, e.g., substituted with haloalkyl; or 
 3) attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and R 10  is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
           
         
         (v) R 4  and R 5  are independently
 H, 
 C 1-6 alkyl (e.g., methyl, isopropyl), 
 C 3-8 cycloalkyl (e.g., cyclopentyl), 
 C 3-8 heterocycloalkyl (e.g., pyrrolidin-3-yl), 
 aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkoxy, C 1-6 alkyl, or another aryl group (e.g., biphenyl-4-ylmethyl); 
 
         (vi) R 6  is H, C 1-6 alkyl (e.g., methyl) or C 3-8 cycloalkyl; 
         (vii) R 13  is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and 
         (viii) R 14  and R 15  are independently H or C 1-6 alkyl, 
       
       in free or salt form. 
     
     
         5 . The compound according to  claim 2  wherein R 3  is attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of 
       
         
           
           
               
               
           
         
         wherein: 
         X, Y and Z are, independently, N or C, 
         R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and 
         R 10  is phenyl or pyridyl, e.g., 2-pyridyl, or pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); 
         provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present in free or salt form. 
       
     
     
         6 . The compound according to  claim 2  wherein R 1  is C 1-6 alkyl, in free or salt form. 
     
     
         7 . The compound according to  claim 6  wherein R 2  is C 1-6 alkyl, in free or salt form. 
     
     
         8 . The compound according to  claim 7  wherein R 4  is H and R 5  is optionally substituted with halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or another aryl group, in free or salt form. 
     
     
         9 . The compound according to  claim 1  selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         10 . The compound according to  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         11 . The compound according to  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         12 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         13 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 2 , in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         15 . A method for the treatment or prophylaxis of any of the following conditions: Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling; comprising administering a therapeutically effective amount of a compound according to  claim 2 , in free or pharmaceutically acceptable salt form. 
     
     
         16 . The method of  claim 15 , wherein the condition is Parkinson's disease. 
     
     
         17 . The method of  claim 15 , wherein the condition is cognitive impairment. 
     
     
         18 . The method of  claim 15 , wherein the condition is narcolepsy. 
     
     
         19 . The method of  claim 18  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         20 . The method of  claim 15 , wherein said condition is female sexual dysfunction. 
     
     
         21 . The method of  claim 20 , further comprising administering a compound or compounds selected from a group consisting of estradiol, estriol, estradiol esters, progesterone and progestins to a patient in need thereof. 
     
     
         22 . A method for the treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a compound according to  claim 2 , in free or pharmaceutically acceptable salt form, to a patient in need of such treatment. 
     
     
         23 . A pharmaceutical composition comprising a compound according to  claim 2 , in free or opthamologically acceptable salt form, in combination or association with an opthamologically acceptable diluents or carrier. 
     
     
         24 . A method for the treatment or prophylaxis of psychosis including schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering an effective amount of a compound according to  claim 2 , in free or pharmaceutically acceptable salt form. 
     
     
         25 - 28 . (canceled) 
     
     
         29 . The compound according to  claim 2 , wherein
 (i) Q is —C(═S)— or —C(═N(R 6 ))—;   (ii) R 1  is C 1-6 alkyl (e.g., methyl or ethyl);   (iii) R 2  is 2,2-dimethylpropyl;   (iv) R 3  is attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of Formula A   
       
         
           
           
               
               
           
         
         
           wherein:
 X, Y and Z are, independently, N or C, 
 R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and 
 R 10  is heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl) 
 provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
         
         (v) R 4  is H and R 5  is phenyl optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); 
         (vi) R 6  is H, 
       
       in free or salt form. 
     
     
         30 . The compound according to  claim 29 , wherein:
 (i) Q is —C(═S)—;   (ii) R 1  is methyl;   (iii) X, Y and Z are C;   (iv) R 8 , R 9 , R 11  and R 12  are H; and   (v) R 10  is triazolyl (e.g., 1,2,4-triazol-1-yl),   
       in free or salt form.