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

A compound of formula (I)

• wherein
• Y represents NR5;
• and X and Z independently represent N or CH;
• Y represents CR6;
• one of X and Z represents NR7, O or S, and the other of X and Z represents N;
• or
• Y represents N;
• one of X and Z represents NR8, 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 R1 is attached, wherein said ring A is optionally mono-substituted with RA;
• wherein RA represents (C1-4)alkyl;
• R1 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 (C1-4)alkyl;
• (C1-4)alkoxy;
• (C1-3)fluoroalkyl;
• (C1-3)fluoroalkoxy;
• halogen;
• cyano;
• or (C3-6)cycloalkyl;
• R2 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
• (C1-4)alkyl;
• (C1-4)alkoxy;
• (C1-3)fluoroalkyl;
• (C1-3)fluoroalkoxy;
• halogen;
• (C3-6)cycloalkyl-X21—, wherein X21 represents a direct bond, —O—, or —(C1-3)alkylene-O—, and wherein the (C3-6)cycloalkyl optionally contains one ring oxygen atom;
• or
• R21aR21bN—, wherein R21a and R21b independently represent hydrogen or (C1-4)alkyl;
• R3 represents hydrogen or (C1-3)alkyl;
• R4 represents hydrogen, or (C1-4)alkyl;
• R5 represents
• hydrogen;
• (C1-4)alkyl;
• (C1-4)alkyl which is mono-substituted with hydroxy, (C1-4)alkoxy, cyano, or RN1RN2N—, wherein
• RN1 and RN2 together with the nitrogen atom form a 4- to 6-membered saturated ring optionally containing one further ring heteroatom selected from O and N;
• wherein said ring is optionally mono-substituted with (C1-4)alkyl, or (C1-4)alkoxy;
• RN1 and RN2 are independently selected from hydrogen, (C1-4)alkyl, (C3-6)cycloalkyl-(C0-4)alkylene-, or (C1-4)alkoxy-(C2-4)alkylene;
• RN1 represents (C1-4)alkyl-C(O)—;
• and RN2 represents hydrogen, or (C1-4)alkyl;
• or
• RN1 represents phenylsulfonyl-, wherein the phenyl is optionally substituted by one to three substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, or nitro;
• and RN2 represents hydrogen, or (C1-4)alkyl;
• (C2-4)alkyl which is di- or tri-substituted, wherein the substituents are independently selected from hydroxy, (C1-4)alkoxy, or RN1RN2N—, wherein
• RN1 and RN2 together with the nitrogen atom form a 4- to 6-membered saturated ring;
• or
• RN1 and RN2 are independently selected from hydrogen, or (C1-4)alkyl;
• (C2-4)fluoroalkyl;
• (CH3)3Si—(CH2)2—O—(C1-4)alkylene-;
• (C2-5)alkynyl;
• (C2-5)alkenyl;
• RN3RN4N—C(O)—(C0-4)alkylene-, wherein RN3 and RN4 independently are hydrogen or (C1-4)alkyl;
• (C1-4)alkoxy-C(O)—(C0-4)alkylene-;
• (C1-4)alkoxy-C(O)—(C2-4)alkylene-, wherein the (C2-4)alkylene is mono-substituted by RN5RN6N—, wherein RN5 and RN6 independently are hydrogen or (C1-4)alkyl
• (C1-4)alkoxy-C(O)—(C2-4)alkylene-, wherein the (C2-4)alkylene is substituted by one to three halogen;
• (C1-4)alkoxy-C(O)—NH—(C2-4)alkylene-, wherein the (C2-4)alkylene- is optionally substituted by one to three halogen;
• (C3-6)cycloalkyl-(C0-4)alkylene-, wherein the cycloalkyl is optionally substituted by one or two substituents independently selected from fluoro, (C1-4)alkyl, nitro, or (C1-4)alkoxy-C(O)—NH—;
• or
• ringB-XB—;
• wherein XB is a direct bond, or (C1-4)alkylene-;
• and wherein ringB is a 4- to 6-membered saturated heterocyclyl containing one or two ring heteratom independently selected from O, S, and NRB, wherein said ringB is attached to XB at a ring carbon atom;
• wherein said ringB is optionally substituted by one or two substituents independently selected from oxo, hydroxy, fluoro, (C1-4)alkyl or (C1-4)alkoxy;
• and wherein
• RB independently represents
• hydrogen;
• (C1-4)alkyl;
• (C2-4)fluoroalkyl;
• (C1-4)alkyl-C(O)—;
• (C1-4)alkoxy-C(O)—;
• (C1-4)alkyl-SO2—;
• RN7RN8N—SO2— wherein RN7 and RN8 are independently hydrogen or (C1-4)alkyl;
• RN9RN10N—C(O)— wherein RN9 and RN10 are independently hydrogen or (C1-4)alkyl;
• RingC-O—C(O)—, and wherein ringC is (C3-6)cycloalkyl optionally containing one ring oxygen atom, wherein ringC is optionally substituted with one R, wherein RC is (C1-4)alkyl or (C1-4)fluoroalkyl;
• or
• RingD, wherein ringD is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N or S, wherein ringD is unsubstituted or mono-substituted with RD, wherein RD is (C1-4)alkyl or (C1-4)fluoroalkyl;
• R6 represents
• hydrogen;
• (C1-4)alkyl;
• (C1-4)fluoroalkyl;
• or
• (C3-6)cycloalkyl-(C0-4)alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C1-4)alkyl;
• R7 represents
• hydrogen;
• (C1-4)alkyl;
• or
• (CH3)3Si—(CH2)2—O—(C1-4)alkylene-;
• and
• R8 represents
• hydrogen;
• (C1-4)alkyl;
• (C2-4)fluoroalkyl;
• (C3-6)cycloalkyl-(C0-4)alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C1-4)alkyl;
• (C1-4)alkoxy-C(O)—(C1-4)alkylene-;
• or
• (CH3)3Si—(CH2)2—O—(C1-4)alkylene-;
• or a pharmaceutically acceptable salt thereof.