Substituted tetrahydropyrazolo[3,4-d]pyrimidines and tetrahydropyrazolo[4,3-d]pyrimidines as C5A receptor modulators

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or deuterium labelled form thereof,

wherein:

(i) X represents N;

Y represents NR 5 ; and

Z represents CH; or

(ii) X represents CH;

Y represents NR 5 ; and

Z represents N;

ring A represents piperidin-1,4-diyl, wherein ring A is optionally substituted in position 4 with one R A substituent;

R A represents CH 3 ;

R 1 represents phenyl;

wherein the phenyl is substituted with one or two substituents;

wherein the phenyl is substituted in the ortho position with one substituent selected from the group consisting of F, CH 3 , CHF 2 , and OCH 3 ; and

wherein the phenyl is optionally substituted in the other ortho position with one substituent selected from the group consisting of F, CH 3 , and OCH 3 ;

R 2 represents phenyl, wherein the phenyl is substituted in the ortho position with one substituent selected from the group consisting of F, Cl, CH(CH 3 ) 2 , CF 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OCF 3 , OCH 2 -cyclopropyl, O(cyclopropyl), and O(oxetan-3-yl);

R 3 represents hydrogen;

R 4 represents hydrogen; and

R 5 represents CH 2 CHF 2 , CH(CH 3 )CHF 2 , CH 2 CH(F)CH 3 , CH 2 CF 2 CH 3 , or CH 2 C(F)(CH 3 )CH 3 .

2. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound according to claim 1 , or a pharmaceutically acceptable salt or deuterium labelled form thereof.

3. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt or deuterium labelled form thereof.

4. The method of claim 3 , wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

5. The method of claim 3 , wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

6. The method of claim 5 , wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

7. The method of claim 6 , wherein the surgery is a surgery including transplantation.

8. The compound:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and the compound according to claim 8 , or a pharmaceutically acceptable salt thereof.

10. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 8 , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

12. The method of claim 10 , wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

13. The method of claim 12 , wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

14. The method of claim 13 , wherein the surgery is a surgery including transplantation.

15. The compound:

or a deuterium labelled form thereof.

16. The compound:

17. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and the compound according to claim 16 .

18. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 16 .

19. The method of claim 18 , wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

20. The method of claim 18 , wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

21. The method of claim 20 , wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

22. The method of claim 21 , wherein the surgery is a surgery including transplantation.