Phenyl-sulfamoyl-benzoic acid derivatives as ERAP1-modulators
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, Formula (I), wherein, the group X—Y is —NHSO 2 —; Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which is optionally substituted by one or more groups selected from haloalkyl, alkyl, alkenyl, alkynyl and —(CR 16 R 17 ) m R 18 , where m is 0 to 6; L is a direct bond or a group (CR 14 R 15 ) n , where n is 1 or 2; R 1 is H, CN, Cl or F or alkyl; R 2 is selected from COOH and a tetrazolyl group; R 3 is selected from H, halo, alkoxy and alkyl; R 4 is selected from H and halo; R 5 is selected from H, alkyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R 6 is H; R 7 is selected from H, CN, haloalkyl, halo, SO 2 -alkyl, SO 2 NR 12 R 13 , heteroaryl, CONR 10 R 11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R 9 is selected from H, alkyl and halo; R 10 , R 11 , R 12 and R 13 are each independently H or alkyl; R 14 and R 15 are each independently H, halo or alkyl; R 16 and R 17 are each independently H, halo, haloalkyl or alkyl; and each R 18 is independently selected from OH, CN, alkoxy and halo. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.
1 . A compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
the group X—Y is —NHSO 2 —;
Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which is optionally substituted by one or more groups selected from haloalkyl, alkyl, alkenyl, alkynyl and —(CR 16 R 17 ) m R 18 , where m is 0 to 6;
L is a direct bond or a group (CR 14 R 15 ) n , where n is 1 or 2;
R 1 is selected from H, Cl, F, CN and alkyl;
R 2 is selected from COOH and a tetrazolyl group;
R 3 is selected from H, halo, alkoxy and alkyl;
R 4 is selected from H and halo;
R 5 is selected from H, alkyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy;
R 6 is H;
R 7 is selected from H, CN, haloalkyl, halo, SO 2 -alkyl, SO 2 NR 12 R 13 , heteroaryl, CONR 10 R 11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH;
R 8 is selected from H, alkyl, haloalkyl and halo;
R 9 is selected from H, alkyl and halo;
R 10 , R 11 , R 12 and R 13 are each independently selected from H and alkyl;
R 14 and R 15 are each independently selected from H, halo and alkyl;
R 16 and R 17 are each independently selected from H, halo, haloalkyl and alkyl; and
each R 18 is independently selected from OH, CN, alkoxy and halo.
2 . The compound according to claim 1 , wherein L is a direct bond; (CH 2 ) n and n is 1 or 2; or CH(Me).
3 . The compound according to claim 1 , wherein Z is a 3- to 7-membered monocyclic cycloalkyl or a 3- to 7-membered monocyclic heterocycloalkyl group, each of which is optionally substituted.
4 . The compound according to claim 1 , wherein Z is a 4-membered monocyclic cycloalkyl or a 4-membered monocyclic heterocycloalkyl group, each of which is optionally substituted.
5 . The compound according to claim 1 , wherein Z is a 5-membered monocyclic cycloalkyl or a 5-membered monocyclic heterocycloalkyl group, each of which is optionally substituted.
6 . The compound according to claim 1 , wherein Z is an optionally substituted polycyclic cycloalkyl group or an optionally substituted polycyclic heterocycloalkyl group, wherein said polycyclic group is fused, unfused, bridged or spirocyclic.
7 . The compound according to claim 6 , wherein Z is a bicyclic cycloalkyl or a bicyclic heterocycloalkyl group, each of which is fused, unfused, bridged or spirocyclic, and each of which is optionally substituted.
8 . The compound according to claim 1 , wherein Z is selected from:
9 . The compound according to claim 1 , wherein L-Z is selected from:
10 . The compound according to claim 1 , wherein R 2 is COOH.
11 . The compound according to claim 1 , wherein R 4 is selected from H and F.
12 . The compound according to claim 1 , wherein R 5 is selected from alkyl, alkoxy and cycloalkyl.
13 . The compound according to claim 1 , wherein R 5 is cyclopropyl.
14 . The compound according to claim 1 , wherein R 7 is selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, CONR 10 R 11 , heteroaryl and alkyl, wherein the heteroaryl group is selected from pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazol-5-yl, tetrazol-1-yl, tetrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.
15 . The compound according to claim 1 , wherein R 7 is CN.
16 . The compound according to claim 1 , wherein R 8 is Cl.
17 . The compound according to claim 1 , wherein R 9 is H.
18 . The compound according to claim 1 , wherein R 1 is H.
19 . The compound according to claim 1 , wherein R 1 , R 3 , R 4 and R 9 are all H.
20 . The compound according to claim 1 , wherein:
X—Y is NH—SO 2 ;
R 1 is H;
R 2 is COOH;
R 3 is H or F;
R 4 is H or F;
R 5 is selected from OMe, cyclopropyl and Et;
R 6 is H;
R 7 is selected from CN, tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl;
R 8 is selected from H, Cl and F; and
R 9 is selected from H, Me, Cl and F.
21 . The compound according to claim 1 , which is of formula (Ia):
22 . The compound according to claim 1 , which is selected from the following:
or a pharmaceutically acceptable salt or hydrate thereof.
23 . A pharmaceutical composition comprising the compound of formula (I) as defined in claim 1 admixed with a pharmaceutically acceptable excipient, diluent or carrier, and optionally one or more additional active agents.
24 . A method of treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .
25 . The method according to claim 24 wherein the disorder is a proliferative disorder selected from cancer.
26 . An in vitro or in vivo method for producing an antigen-presenting cell which presents a neo-antigen, comprising contacting antigen-presenting cell with a compound of formula (I) as defined in claim 1 to induce a neo-antigen in said antigen-presenting cell.
27 . An immunogenic composition comprising an antigen-presenting cell obtained or obtainable by the method according to claim 26 .
28 . A method of treating or preventing cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an immunogenic composition according to claim 27 .
29 . The method according to claim 24 , wherein said compound is used in combination with an immunotherapy.
30 . The method according to claim 24 , wherein the disorder is an immune disorder selected from ankylosing spondylitis, Behcet's disease, psoriasis and birdshot chorioretinopathy.
31 . The method according to claim 24 , wherein the disorder is an inflammatory disorder.
32 . The method according to claim 24 , wherein the viral disorder is an infectious viral disease selected from HIV, HPV, CMV and HCV.
33 . A combination comprising a compound according to claim 1 and a further active agent.
34 . The method according to claim 24 , wherein the disorder is a proliferative disorder selected from leukemia.