2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one derivatives and related compounds as c5a receptor modulators for treating vasculitis and inflammatory diseases

Abstract

The present invention relates to derivatives of formula (I)wherein Ring A, X, Y, Z, RA, R1, R2, R3 and R4 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as C5a receptor modulators.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 Y represents CR 6 ; one of X and Z represents NR 7 , O or S, and the other of X and Z represents N; or 
 Y represents N; one of X and Z represents NR 8 , and the other of X and Z represents N or CH; 
 
         ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclic ring containing the ring nitrogen atom to which R 1  is attached, wherein said ring A is optionally mono-substituted with R A ; wherein R A  represents (C 1-4 )alkyl; 
         R 1  represents phenyl; 5-membered heteroaryl, or 6-membered heteroaryl wherein said phenyl, 5-membered heteroaryl or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; cyano; or (C 3-6 )cycloalkyl; 
         R 2  represents phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl independently is mono-, or di-, or tri-substituted, wherein the substituents are independently selected from
 (C 1-4 )alkyl; 
 (C 1-4 )alkoxy; 
 (C 1-3 )fluoroalkyl; 
 (C 1-3 )fluoroalkoxy; 
 halogen; 
 (C 3-6 )cycloalkyl-X 21 —, wherein X 21  represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; or 
 R 21a R 21b N—, wherein R 21a  and R 21b  independently represent hydrogen or (C 1-4 )alkyl; 
 
         R 3  represents hydrogen or (C 1-3 )alkyl; 
         R 4  represents hydrogen, or (C 1-4 )alkyl; 
         wherein said ring B  is optionally substituted by one or two substituents independently selected from oxo, hydroxy, fluoro, (C 1-4 )alkyl or (C 1-4 )alkoxy; and wherein 
         R B  independently represents
 hydrogen; 
 (C 1-4 )alkyl; 
 (C 2-4 )fluoroalkyl; 
 (C 1-4 )alkyl-C(O)—; 
 (C 1-4 )alkoxy-C(O)—; 
 (C 1-4 )alkyl-SO 2 —; 
 R N7 R N8 N—SO 2 — wherein R N7  and R N8  are independently hydrogen or (C 1-4 )alkyl; 
 
         R N9 R N10 N—C(O)— wherein R N9  and R N10  are independently hydrogen or (C 1-4 )alkyl; 
         Ring C -O—C(O)—, and wherein ring C  is (C 3-6 )cycloalkyl optionally containing one ring oxygen atom, wherein ring C  is optionally substituted with one R C , wherein R C  is (C 1-4 )alkyl or (C 1-4 )fluoroalkyl; or 
         Ring D , wherein ring D  is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N or S, wherein ring D  is unsubstituted or mono-substituted with R D , wherein R D  is (C 1-4 )alkyl or (C 1-4 )fluoroalkyl; 
         R 6  represents
 hydrogen; 
 (C 1-4 )alkyl; 
 (C 1-4 )fluoroalkyl; or 
 (C 3-6 )cycloalkyl-(C 0-4 )alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C 1-4 )alkyl; 
 
         R 7  represents
 hydrogen; 
 (C 1-4 )alkyl; or 
 (CH 3 ) 3 Si—(CH 2 ) 2 —O—(C 1-4 )alkylene-; and 
 
         R 8  represents
 hydrogen; 
 (C 1-4 )alkyl; 
 (C 2-4 )fluoroalkyl; 
 (C 3-6 )cycloalkyl-(C 0-4 )alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C 1-4 )alkyl; 
 (C 1-4 )alkoxy-C(O)—(C 1-4 )alkylene-; or 
 (CH 3 ) 3 Si—(CH 2 ) 2 —O—(C 1-4 )alkylene-; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 ; wherein ring A represents a fragment 
       
         
           
           
               
               
           
         
         wherein said ring A is selected from azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,4-diyl, piperidin-1,3-yl, and azepan-1,4-diyl; and wherein said ring A is substituted with R 1  on the ring nitrogen atom, and optionally substituted, on the ring carbon atom linked to the rest of the molecule, with R A , wherein R A  is (C 1-4 )alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . (canceled) 
     
     
         4 . The compound according to  claim 1 , wherein R 1  represents
 phenyl which is mono- or di-substituted, wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; halogen; cyano; and (C 1-3 )fluoroalkyl; or   pyridinyl which is di-substituted, wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; halogen; and (C 1-3 )fluoroalkyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  represents phenyl which is mono-, or di-substituted; wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule;
 wherein said ortho-substituent is (C 1-4 )alkyl); (C 1-4 )alkoxy; halogen; or (C 1-3 )fluoroalkyl;   and, if present, the remaining substituent independently is methyl; methoxy; halogen; or cyano;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound according to  claim 1 , wherein R 1  is 2-chloro-6-methyl-phenyl, 2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl, 2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl, 2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl, 4-chloro-2,5-dimethyl-2H-pyrazol-3-yl, 2,5-dimethyl-4-cyano-pyrazol-3-yl, 3-fluoro-pyridin-2-yl, 3-methoxy-pyridin-2-yl, 2-methoxy-4-methyl-pyridin-3-yl, 2-fluoro-4-methyl-pyridin-3-yl, 2-methyl-4-fluoro-, 2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethoxy-pyridin-3-yl, 4-methoxy-6-methyl-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl, 2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl, 2-bromo-6-fluoro-phenyl, 2-fluoro-6-difluoromethyl-phenyl, 2-fluoro-6-cyclopropyl-phenyl, 2-methoxy-4-chloro-pyridin-3-yl, 2-methoxy-4-difluoromethyl-pyridin-3-yl, or 2-methoxy-4-trifluoromethyl-pyridin-3-yl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The compound according to  claim 1 , wherein R 2  represents phenyl, 5-membered heteroaryl; or 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is mono-, or di-, or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 ) alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; (C 3-6 )cycloalkyl-X 21 —, wherein X 21  represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl contains one optional ring oxygen atom; and R 21a R 21b N—, wherein R 21a  and R 21b  independently represent hydrogen or (C 1-4 )alkyl;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The compound according to  claim 5 , wherein R 2  represents
 phenyl; wherein said phenyl is mono-, or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; and (C 3-6 )cycloalkyl-X 21 —, wherein X 21  represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl contains one optional ring oxygen atom; or   6-membered heteroaryl containing one or two nitrogen atoms; wherein said 6-membered heteroaryl independently is mono-, or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; halogen; and (C 3-6 )cycloalkyl-X 21 —, wherein X 21  represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl contains one optional ring oxygen atom;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound according to  claim 6 , wherein R 2  represents 2-chloro-phenyl, 2-cyclopropyl-phenyl, 2-isopropyl-phenyl, 2-ethoxy-phenyl, 2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl, 2-cyclopropoxy-phenyl, 2-(oxetan-3-yloxy)-phenyl, 2-cyclopropylmethoxy-phenyl, 2-fluoro-6-trifluoromethyl-phenyl, 2-bromo-6-trifluoromethyl-phenyl, 2-trifluoromethoxy-phenyl, 2,4-difluoro-6-isopropoxy-phenyl, 4-isopropyl-pyramid-5-yl, 3-trifluoromethyl-pyrazin-2-yl, 3-trifluoromethyl-pyridin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 6-chloro-3-trifluoromethyl-pyridin-2-yl, 6-fluoro-3-trifluoromethyl-pyridin-2-yl, 6-methylamino-3-trifluoromethyl-pyridin-2-yl, 6-methoxy-3-trifluoromethyl-pyridin-2-yl, 6-dimethylamino-3-trifluoromethyl-pyridin-2-yl, 4-trifluoromethyl-pyridin-3-yl or 2-methyl-4-trifluoromethyl-thiazol-5-yl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The compound according to  claim 1 , wherein R 4  represents hydrogen or methyl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         13 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising, as active principle, a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. 
     
     
         16 . A medicament comprising the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A method for the prevention or treatment of a disease or disorder comprising administering the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer. 
     
     
         18 . A method for the prevention or treatment of a disease or disorder comprising administering the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from the prevention or treatment of deleterious consequences of contact sensitivity and inflammation caused by contact with artificial surfaces; the prevention or treatment of increased leukocyte and platelet activation (and infiltration to tissues thereof); the prevention or treatment of pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation; the prevention or treatment of pathologic sequelae associated with insulin-dependent diabetes mellitus; the prevention of/the reduction of the risk of myocardial infarction or thrombosis; prevention or treatment of edema or increased capillary permeability; or the prevention of/the reduction of coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia. 
     
     
         19 . (canceled) 
     
     
         20 . A method of treatment of vasculitic diseases or disorders; inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders; neurodegenerative diseases or disorders; complement related inflammatory diseases or disorders; bullous diseases or disorders; diseases or disorders related to ischemia and/or ischemic reperfusion injury; inflammatory bowel diseases or disorders; autoimmune diseases or disorders; cancer; deleterious consequences of contact sensitivity and inflammation caused by contact with artificial surfaces; increased leukocyte and platelet activation (and infiltration to tissues thereof); pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation; pathologic sequelae associated with insulin-dependent diabetes mellitus; the risk of myocardial infarction or thrombosis; edema or increased capillary permeability; or coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia; comprising administering to a patient an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A method for the prevention or treatment of a disease or disorder comprising administering the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer. 
     
     
         22 . A pharmaceutical composition comprising, as active principle, a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. 
     
     
         23 . A method for the prevention or treatment of a disease or disorder comprising administering the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer.