C5A receptor modulators

Patent metadata

Field	Value
Publication number	US-11739070-B2
Application number	US-201916963101-A
Country	US
Kind code	B2
Filing date	Jan 18, 2019
Priority date	Jan 19, 2018
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The present invention relates to derivatives of formula (I)

wherein ring A, X, Y, Z, R 1 , R 2 , R 3 and R 4 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.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein
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 independently is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of (C 1-3 )alkyl, fluoro, and (C 1-4 )alkoxy-carbonyl; or
ring A represents a saturated 7- or 8-membered bridged bi-cyclic carbocyclic ring containing the ring nitrogen atom to which R 1 is attached, wherein said ring is unsubstituted;

X and Z independently represent CR 5 or N; and Y represents CR 5 ; or, in case both X and Z represent CH, Y may in addition represent N; wherein each R 5 independently represents hydrogen, or (C 1-3 )alkyl;
R 1 represents
(C1-4)alkyl;
CO—R 11 wherein R 11 represents (C 1-4 )alkyl; (C 1-4 )alkoxy; phenyl, phenoxy; (C 3-6 )cycloalkyl; or (C 3-6 )cycloalkoxy optionally containing one ring oxygen and optionally mono-substituted with methyl or trifluoromethyl;
benzyl wherein the phenyl ring of said benzyl is optionally mono- or di-substituted with halogen; or
phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of
(C 1-4 )alkyl;
(C 1-4 )alkoxy;
(C 1-3 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
halogen;
cyano;
nitro;
hydroxy;
hydroxy-(C 1-3 )alkyl;
(C 1-4 )alkoxy-(C 1-3 )alkyl;
hydroxy-(C 2-3 )alkoxy;
(C 1-4 )alkoxy-(C 2-3 )alkoxy;
(C 3-6 )cycloalkyl-X 12 —, wherein X 12 represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl independently contains one optional ring oxygen;
R 13 —CO—X 13 —, wherein X 13 represents a direct bond or (C 1-3 )alkylene, and R 13 represents hydrogen or (C 1-4 )alkyl);
3-(morpholin-4-yl)-prop-1-ynyl;
R 14a R 14b N—X 14 —, wherein X 14 represents a direct bond or (C 1-3 )alkylene; and wherein R 14a and R 14b independently represent hydrogen, (C 1-4 )alkyl, hydroxy-(C 2-4 )alkyl, (C 1-3 )alkoxy-(C 2-4 )alkyl; or R 14a and R 14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C 1-4 )alkyl, hydroxy, (C 1-4 )alkoxy, or dimethylamino; and
benzyloxy, wherein the phenylring of benzyloxy is optionally mono- or di-substituted with halogen or methyl;

R 2 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of
(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 independently contains one optional ring oxygen;

R 3 represents hydrogen, or (C 1-3 )alkyl; and
R 4 represents
(C 1-4 )alkyl;
hydroxy-(C 1-3 )alkyl;
—O—R 41 , wherein R 41 represents
hydrogen;
(C 1-4 )alkyl;
(C 2 - 4 )alkyl which is substituted with one or two hydroxy;
R 41a R 41b N—(C 2-3 )alkylene-, wherein R 41a and R 41b independently represent hydrogen or (C 1-4 )alkyl; or
(C 4-7 )heterocyclyl-X 41 —, wherein X 41 represents a direct bond or (C 1-3 )alkylene, and wherein the (C 4-7 )heterocyclyl independently contains one or two ring heteroatoms independently selected from the group consisting of nitrogen and oxygen; wherein said (C 4-7 )heterocyclyl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of:
(C 1-4 )alkyl; and/or
(C 1-4 )alkoxy-carbonyl attached to a ring nitrogen atom having a free valency;

—NR 42a R 42b wherein R 42a and R 42b independently represent hydrogen, (C 1-4 )alkyl, (C 1-3 )alkoxy-(C 2-3 )alkyl, hydroxy-(C 2-3 )alkyl, or R 42a and R 42b together with the nitrogen to which they are attached form a 4- to 7-membered saturated ring optionally containing one further ring heteroatom selected from the group consisting of oxygen and nitrogen, wherein said ring is unsubstituted or mono-substituted with (C 1-3 )alkyl or (C 1-3 )alkoxy; or
—CO—R 43 wherein R 43 represents (C 1-4 )alkoxy, or —NR 43a R 43b wherein R 43a and R 43b independently represent hydrogen, (C 1-4 )alkyl, (C 1-3 )alkoxy-(C 2-3 )alkyl or hydroxy-(C 2-3 )alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
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 independently is unsubstituted, or mono-substituted with (C 1-3 )alkyl, fluoro, or (C 1-4 )alkoxy-carbonyl, or di-substituted wherein the substituents are two (C 1-3 )alkyl substituents, or two fluoro substituents; or
ring A represents a saturated 7- or 8-membered bridged bi-cyclic carbocyclic ring containing the ring nitrogen atom to which R 1 is attached, wherein said ring is unsubstituted.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof; wherein 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 independently is unsubstituted, or mono-substituted with (C 1-3 )alkyl, fluoro, or (C 1-4 )alkoxy-carbonyl, or di-substituted wherein the substituents are two (C 1-3 )alkyl substituents, or two fluoro substituents.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof; wherein
X represents CR 5 ; Z represents CR 5 ; and Y represents CR 5 ; wherein each R 5 independently represents hydrogen, or (C 1-3 )alkyl;
X represents CH; Z represents N; and Y represents CR 5 ; wherein each R 5 independently represents hydrogen, or (C 1-3 )alkyl;
X represents N; Z represents CR 5 ; and Y represents CR 5 ; wherein each R 5 independently represents hydrogen or (C 1-3 )alkyl;
X represents N; Z represents N; and Y represents CR 5 ; wherein R 5 represents hydrogen, or (C 1-3 )alkyl.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof; wherein one of X and Z represents CH or N; the other represents CH; and Y represents CR 5 , wherein R 5 represents hydrogen or (C 1-3 )alkyl.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof; wherein R 1 represents
(C 1-4 )alkyl;
—CO—R 11 wherein R 11 represents (C 1-4 )alkyl; (C 1-4 )alkoxy; phenyl, phenoxy; or (C 3 - 6 )cycloalkoxy optionally containing one ring oxygen and optionally mono-substituted with methyl or trifluoromethyl;
benzyl wherein the phenyl ring of said benzyl is optionally mono- or di-substituted with halogen;
phenyl which is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of
(C 1-4 )alkyl;
(C 1-4 )alkoxy;
(C 1-3 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
halogen;
cyano;
nitro;
hydroxy;
hydroxy-(C 1-3 )alkyl;
(C 1-4 )alkoxy-(C 1-3 )alkyl;
hydroxy-(C 2-3 )alkoxy;
(C 1-4 )alkoxy-(C 2-3 )alkoxy;
(C 3-6 )cycloalkyl-X 12 —, wherein X 12 represents a direct bond, —O—, or —(C 1-3 )alkylene-O—, and wherein the (C 3-6 )cycloalkyl independently contains one optional ring ox

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Froidevaux Sylvie
• Hubler Francis
• Murphy Mark
• Renneberg Dorte
• Stamm Simon

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title