Organic compounds

Abstract

Optionally substituted 4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or 4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine compounds or Compounds of Formula (I), processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising the same.

1 . An optionally substituted 4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or 4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, in free or salt form. 
     
     
         2 . The compound according to  claim 1 , wherein said compound is a Compound of Formula II-A or II-B 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is C(═O), C(═S), C(═N(R 20 )) or CH 2 ; 
 (ii) L is a single bond, —N(H)—, —CH 2 —, —S—, —S(O)— or —S(O 2 )—; 
 (iii) R 1  is H or C 1-4  alkyl (e.g., methyl); 
 (iv) R 4  is H or C 1-6  alkyl (e.g., methyl or isopropyl) and R 2  and R 3  are, independently,
 H 
 C 1-6 alkyl (e.g., methyl, isopropyl) optionally substituted with halo or hydroxy (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is methyl, ethyl, isopropyl or hydroxyethyl), 
 aryl, 
 heteroaryl, 
 (optionally hetero)arylalkoxy, 
 (optionally hetero)arylC 1-6 alkyl, 
 R 2  and R 3  together form a 3- to 6-membered ring; 
 
 or 
 R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively); 
 (v) R 5  is
 a) -D-E-F, wherein:
 D is C 1-4 alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene); 
 E is a single bond, C 2-4 alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); 
 F is
 H, 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), 
 halo (e.g., F, Br, Cl), 
 haloC 1-4 alkyl (e.g., trifluoromethyl), 
 —C(O)—R 15 , 
 —N(R 16 )(R 17 ), or 
 C 3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); 
 
 wherein D, E and F are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C 1-4 alkyl (e.g., methyl), haloC 1-4 alkyl (e.g., trifluoromethyl), C 1-4 alkoxy (e.g., methoxy), hydroxy, C 1-4 carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), 
 for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-4 alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or F is a C 3-7 heterocycloalkyl (e.g., pyrrolidinyl) optionally substituted with a C 1-6 alkyl (e.g., 1-methylpyrrolidin-3-yl); or 
 
 b) a substituted heteroarylalkyl, e.g., substituted with haloC 1-4 alkyl; 
 c) attached to the nitrogen on the pyrrolo portion of Formula II-A or II-B 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, 
 C 1-4 alkyl, 
 haloC 1-4 alkyl (e.g., triflouromethyl) 
 C 1-4 alkoxy (e.g. methoxy), 
 C 3-7 cycloalkyl, 
 heteroC 3-7 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), 
 C 1-4 haloalkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl, 
 arylcarbonyl (e.g., benzoyl), 
 alkylsulfonyl (e.g., methylsulfonyl), 
 heteroarylcarbonyl, or 
 alkoxycarbonyl; 
 
             wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently, optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), 
             provided that when X, Y, or Z is nitrogen, R 7 , R 9 , or R 10 , respectively, is not present; 
           
         
         (vi) R 6  is
 H, 
 C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isobutyl), 
 C 3-7 cycloalkyl (e.g., cyclopentyl or cyclohexyl), 
 heteroC 3-7 cycloalkyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyrid-4-yl), 
 arylC 1-4  alkyl (e.g., benzyl), 
 when L is a single bond, —CH 2 —, —N(H)—, —S—, —S(O)— or S(O 2 )—, 
 wherein the aryl and heteroaryl are optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, or an additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or C 3-8 cycloalkyl; 
 
         or R 6  is
 H, 
 arylamino (e.g., phenylamino), 
 heteroarylamino, 
 N,N-diC 1-4 alkylamino, 
 N,N-diarylamino, 
 N-aryl-N-(arylC 1-4 alkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or 
 —N(R 18 )(R 19 ), 
 when L is a single bond or —CH 2 —, 
 
         (vii) wherein the aryl and heteroaryl are optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, or an additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or C 3-8 cycloalkyl; 
         (viii) R 7  is H, C 1-6 alkyl (e.g., methyl or ethyl), halogen (e.g., Cl), —N(R 18 )(R 19 ), hydroxy or C 1-6 alkoxy; 
         (ix) n=0 or 1; 
         (x) when n=1, A is —C(R 13 R 14 )—, wherein R 13  and R 14 , are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-4 alkoxy, (optionally hetero)arylC 1-4 alkyl or R 13  or R 14  can form a bridge with R 2  or R 4 ; 
         (xi) R 15  is C 1-4 alkyl, haloC 1-4 alkyl, —OH or —OC 1-4 alkyl (e.g., —OCH 3 ) 
         (xii) R 16  and R 17  are independently H or C 1-4 alkyl; 
         (xiii) R 18  and R 19  are independently H, C 1-4 alky (e.g., methyl, ethyl, n-propyl, isobutyl), C 3-8 cycloalky (e.g., cyclohexyl or cyclopenyl), heteroC 3-8 cycloalky (e.g., pyrrolidinyl, piperidinyl, morpholinyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl), wherein said aryl and heteroaryl are optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) C 1-4 alkyl (e.g., methyl), haloC 1-4 alkyl (e.g., trifluoromethyl), C 1-4 carboxy, or an additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or C 3-8 cycloalkyl, 
         (xiv) R 20  is H, C 1-4 alkyl or C 3-7 cycloalkyl; 
       
       in free or salt form. 
     
     
         3 . The compound according to  claim 1 , wherein said compound is a Compound of Formula I-A or I-B 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is C(═O), C(═S), C(═N(R 20 )) or CH 2 ; 
 (ii) L is a single bond, —N(H)—, —CH 2 —, —S—, —S(O)— or —S(O 2 )—; 
 (iii) R 1  is H or C 1-4  alkyl (e.g., methyl); 
 (iv) R 4  is H or C 1-6  alkyl and R 2  and R 3  are, independently, H or C 1-6 alkyl optionally substituted with halo or hydroxy (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylC 1-6 alkyl; or
 R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively); 
 
 (v) R 5  is
 a) -D-E-F, wherein:
 D is C 1-4 alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene); 
 E is a single bond, C 2-4 alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); 
 F is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl), haloC 1-4 alkyl (e.g., trifluoromethyl), —C(O)—R 15 , —N(R 16 )(R 17 ), or C 3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); 
 wherein D, E and F are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C 1-4 alkyl (e.g., methyl), haloC 1-4 alkyl (e.g., trifluoromethyl), for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-4 alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl), or F is a C 3-7 heterocycloalkyl (e.g., pyrrolidinyl) optionally substituted with a C 1-6 alkyl (e.g., 1-methylpyrrolidin-3-yl); or 
 
 b) a substituted heteroarylalkyl, e.g., substituted with haloalkyl; 
 c) attached to the nitrogen on the pyrrolo portion of Formula I-A or I-B 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, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present; 
           
         
         (vi) R 6  is
 H, 
 C 1-4 alkyl, 
 C 3-7 cycloalkyl (e.g., cyclopentyl), 
 aryl, 
 heteroaryl, 
 arylC 1-4 alkyl (e.g., benzyl), 
 arylamino (e.g., phenylamino), 
 heteroarylamino, 
 N,N-diC 1-4 alkylamino, 
 N,N-diarylamino, 
 N-aryl-N-(arylC 1-4 alkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or 
 —N(R 18 )(R 19 ); 
 wherein the aryl or heteroaryl is optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6 alkoxy; 
 
         (vii) R 7  is H, C 1-6 alkyl, halogen (e.g., Cl), —N(R 18 )(R 19 ); 
         (viii) n=0 or 1; 
         (ix) when n=1, A is —C(R 13 R 14 )—, wherein R 13  and R 14 , are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-4 alkoxy or (optionally hetero)arylC 1-4 alkyl; 
         (x) R 15  is C 1-4 alkyl, haloC 1-4 alkyl, —OH or —OC 1-4 alkyl (e.g., —OCH 3 ) 
         (xi) R 16  and R 17  are independently H or C 1-4 alkyl; 
         (xii) R 18  and R 19  are independently H, C 1-4 alky or aryl (e.g., phenyl) wherein said aryl is optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) 
         (xiii) R 20  is H, C 1-4 alkyl or C 3-7 cycloalkyl, 
       
       in free or salt form. 
     
     
         4 . The compound according to  claim 2 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         5 . The compound according to  claim 2 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         6 . 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. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein salt and the diluents or carrier are opthalmically acceptable. 
     
     
         8 . A method of treating 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 an effective amount of a compound according to  claim 2 . 
     
     
         9 . The method of  claim 8 , wherein the condition is Parkinson's disease. 
     
     
         10 . The method of  claim 8 , wherein the condition is cognitive impairment. 
     
     
         11 . The method of  claim 8 , wherein the condition is narcolepsy. 
     
     
         12 . The method of  claim 11  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         13 . The method of  claim 8 , wherein said condition is female sexual dysfunction. 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . A method for the treatment of 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, in an opthalmically compatible carrier to the eye of a patient in need thereof. 
     
     
         16 . A method for the treatment of psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering a therapeutically effective amount of a compound according to  claim 2 , in free or pharmaceutically acceptable salt form, to a patient in need thereof. 
     
     
         17 . A method for the treatment of traumatic brain injury comprising administering to a patient in need thereof, a compound according to  claim 2 , in free or pharmaceutically acceptable salt form. 
     
     
         18 . A method for lengthening or enhancing growth of the eyelashes by administering an effective amount of a prostaglandin analogue, e.g., bimatoprost, concomitantly, simultaneously or sequentially with an effective amount of a compound according to  claim 2 , in free or salt form. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . The compound according to  claim 2 , wherein
 (i) Q is C(═O), C(═S), C(═N(R 20 )) or CH 2 ;   (ii) L is —N(H)—, —S—, —S(O)— or —S(O 2 )—;   (iii) R 1  is H or C 1-4  alkyl (e.g., methyl);   (iv) R 4  is H or C 1-6 alkyl (e.g., methyl or isopropyl) and R 2  and R 3  are, independently,
 H 
 C 1-6 alkyl (e.g., methyl, isopropyl) optionally substituted with halo or hydroxy (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is methyl, ethyl, isopropyl or hydroxyethyl), 
 aryl, 
 heteroaryl, 
 (optionally hetero)arylalkoxy, 
 (optionally hetero)arylC 1-6 alkyl, or 
 R 2  and R 3  together form a 3- to 6-membered ring; 
   or   R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively);   (v) R 5  is attached to the nitrogen on the pyrrolo portion of Formula II-A or II-B 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
 C 1-4 alkoxy (e.g. methoxy), 
 C 3-7 cycloalkyl, 
 heteroC 3-7 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl, 
 
           wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently, optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), 
           provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present; 
         
         (vi) R 6  is
 H, 
 C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isobutyl), 
 C 3-7 cycloalkyl (e.g., cyclopentyl or cyclohexyl), 
 heteroC 3-7 cycloalkyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyrid-4-yl), 
 arylC 1-4 alkyl (e.g., benzyl), 
 wherein the aryl and heteroaryl are optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, or an additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or C 3-8 cycloalkyl; 
 
         (vii) R 7  is H, C 1-6 alkyl (e.g., methyl or ethyl), halogen (e.g., Cl), —N(R 18 )(R 19 ), hydroxy or C 1-6 alkoxy; 
         (viii) n=0 or 1; 
         (ix) when n=1, A is —C(R 13 R 14 )—, wherein R 13  and R 14 , are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-4 alkoxy, (optionally hetero)arylC 1-4 alkyl or R 14  can form a bridge with R 2  or R 4 ; 
         (x) R 18  and R 19  are independently H, C 1-4 alky (e.g., methyl, ethyl, n-propyl, isobutyl), C 3-8 cycloalky (e.g., cyclohexyl or cyclopenyl), heteroC 3-8 cycloalky (e.g., pyrrolidinyl, piperidinyl, morpholinyl), aryl (e.g., phenyl) or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) C 1-4 alkyl (e.g., methyl), haloC 1-4 alkyl (e.g., trifluoromethyl), C 1-4 carboxy, or an additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or C 3-8 cycloalkyl; 
         (xi) R 20  is H, C 1-4 alkyl or C 3-7 cycloalkyl; 
       
       in free or salt form. 
     
     
         23 . The compound according to  claim 2 , wherein
 (i) Q is C(═O);   (ii) L is a —N(H)— or a single bond;   (iii) R 1  is H or C 1-4  alkyl (e.g., methyl);   (iv) R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively);   (v) R 5  is attached to the nitrogen on the pyrrolo portion of Formula II-A or II-B 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
 C 3-7 cycloalkyl, 
 heteroC 3-7 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), 
 aryl (e.g., phenyl), or 
 heteroaryl (e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl, 
 wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently, optionally substituted with one or more C 1-4 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-4 alkyl (e.g., trifluoromethyl), hydroxy, C 1-4 carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), 
 provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present; 
 
         
         (vi) R 6  is H or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6 alkoxy; 
         (vii) R 7  is H; and 
         (viii) n=0, 
       
       in free or salt form. 
     
     
         24 . The compound according to  claim 3 , wherein:
 (i) Q is C(═O);   (ii) L is a —N(H)—;   (iii) R 1  is H or C 1-4  alkyl (e.g., methyl);   (iv) R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively);   (v) R 5  is -D-E-F, wherein:
 D is methylene; 
 E is phenylene; 
 F is heteroaryl (e.g., pyridyl e.g., pyrid-2-yl), 
   (vi) R 6  is H or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6 alkoxy;   (vii) R 7  is H; and   (viii) n=0,   
       in free or salt form. 
     
     
         25 . The compound according to  claim 3 , wherein:
 (i) Q is C(═O);   (ii) L is a —N(H)—;   (iii) R 1  is H or C 1-4  alkyl (e.g., methyl);   (iv) R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively);   (v) R 5  is -D-E-F, wherein:
 D is methylene; 
 E is phenylene; 
 F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-4 alkyl (e.g., 5-methylpyrid-2-yl), 
   (vi) R 6  is H or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6 alkoxy;   (vii) R 7  is H; and   (viii) n=0,   
       in free or salt form. 
     
     
         26 . The compound according to  claim 3 , wherein
 (i) Q is C(═O);   (ii) L is a —N(H)—;   (iii) R 1  is H or C 1-4  alkyl (e.g., methyl);   (iv) R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively);   (v) R 5  is -D-E-F, wherein:
 D is methylene; 
 E is phenylene; 
 F is pyridyl; 
   (vi) R 6  is H or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6 alkoxy;   (vii) R 7  is H; and   (viii) n=0,   
       in free or salt form. 
     
     
         27 . The compound according to  claim 2  selected from any of the following: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         28 . The compound according to  claim 2  selected from any of the following: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         29 . The compound according to  claim 2  wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         30 . The compound according to  claim 2  wherein the compound is: 
       
         
           
           
               
               
           
         
         in free or salt form.