Colony stimulating factor-1 receptor (CSF-1R) inhibitors

Patent metadata

Field	Value
Publication number	US-11274108-B2
Application number	US-201615745223-A
Country	US
Kind code	B2
Filing date	Jul 19, 2016
Priority date	Jul 20, 2015
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

Compounds of the formulas

which are useful as colony stimulating factor-1 receptor inhibitors (“CSF-1R inhibitors”).

First claim

The invention claimed is:

1. A compound of Formula (VII):

or the pharmaceutically acceptable salt thereof, wherein:
the dashed lines represent optional double bonds;
p is 1;
n is 1;
X 2 is N,
X 3 , X 4 , and X 5 , are each independently selected from CR 7 ,
wherein each R 7 is independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkylnyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, (C 2 -C 9 )heteroalkyl-C(O)—, COOH—(C 1 -C 10 )alkyl-, COOH—(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 2 -C 9 )heterocycloalkyl-, R 8 -(C 1 -C 10 )alkyl-, R 8 -(C 3 -C 10 )cycloalkyl, R 8 -(C 2 -C 9 )heterocycloalkyl, R 8 -(C 6 -C 14 )aryl, R 8 -(C 2 -C 9 )heteroaryl, R 8 -(C 2 -C 10 )alkylnyl, R 8 -(C 1 -C 10 )alkylamine, R 8 -((C 1 -C 10 )alkyl) 2 amine, R 8 -(C 2 -C 10 )alkynylamine, R 8 —C(O)—, R 8 -(C 1 -C 10 )alkyl-C(O)O—, R 8 -(C 1 -C 10 )-alkoxy-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, R 8 -(C 3 -C 10 )cycloalkyl-O—, R 8 -(C 2 -C 9 )heterocycloalkyl-O—, R 8 -(C 6 -C 14 )aryl-O—, R 8 -(C 2 -C 9 )heteroaryl-O—, HO—, halo, cyano, H 2 N—, (CH 3 )HN—, (CH 3 ) 2 N—, R 8 R 9 N—, R 8 R 9 N(O)C—, R 8 (R 9 C(O))N—, R 8 R 9 NC(O)O—, R 8 C(O)—, R 8 R 9 NC(O)R 8 N—, (C 1 -C 10 )alkyl-OC(O)R 8 N—, (C 3 -C 10 )cycloalkyl-OC(O)R 8 N—, (C 2 -C 9 )heterocycloalkyl-OC(O)R 8 N—, (C 6 -C 14 )aryl-OC(O)R 8 N—, (C 2 -C 9 )heteroaryl-OC(O)R 8 N—, F 3 C—, F 2 HC—, CH 3 F 2 C—, FH 2 C—, CH 3 FHC—, (CH 3 ) 2 FC—; NC—, (C 1 -C 10 )alkyl(O)P—, (C 1 -C 10 )alkyl-S-, (C 1 -C 10 )alkyl-S—(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 1 -C 10 )alkyl-S(O)—, (C 3 -C 10 )cycloalkyl-S(O)—, (C 6 -C 14 )aryl-S(O)—, (C 2 -C 9 )heterocycloalkyl-S(O)—, (C 2 -C 9 )heteroaryl-S(O)—, (C 3 -C 10 )alkyl-S(O) 2 —, (C 3 -C 10 )cycloalkyl-S(O) 2 —, (C 6 -C 14 )aryl-S(O) 2 —, (C 2 -C 9 )heterocycloalkyl-S(O) 2 —, (C 2 -C 9 )heteroaryl-S(O) 2 —, R 8 R 9 NS(O) 2 —, (C 1 -C 10 )alkyl-S(O) 2 R 8 N—, (C 3 -C 10 )cycloalkyl-S(O) 2 R 8 N—, (C 6 -C 14 )aryl-S(O) 2 R 8 N—, (C 2 -C 9 )heterocycloalkyl-SO 2 R 8 N—, and (C 2 -C 9 )heteroaryl-S(O) 2 R 8 N—;
wherein R 8 and R 9 are each independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, HO—, halo, (CH 3 ) 2 N—, and H 2 N—;
or R 8 and R 9 are taken together to form a 3 to 10 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

wherein each (C 1 -C 10 )alkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl are further optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, HO—, halo, or H 2 N—;

T 1 , T 2 , and T 3 are each independently selected from N or CR 10 ,
wherein each R 10 is independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 10 )alkylnyl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 2 -C 10 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl-, COOH—(C 3 -C 10 )cycloalkyl-, (C 1 -C 10 )alkoxy-, R 10A -(C 1 -C 10 )alkyl-, R 10A -(C 3 -C 10 )cycloalkyl, R 10A -(C 2 -C 9 )heterocycloalkyl, R 10A -(C 6 -C 14 )aryl, R 10A -(C 2 -C 9 )heteroaryl, R 10A -(C 2 -C 10 )alkylnyl, R 10A -(C 1 -C 10 )alkylamine, R 10A -((C 1 -C 10 )alkyl) 2 amine, R 10A -(C 2 -C 10 )alkynylamine, R 10A -C(O)—, R 10A -(C 1 -C 10 )alkyl-C(O)O—, R 10A -(C 1 -C 10 )alkoxy-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, R 10A -(C 3 -C 10 )cycloalkyl-O—, R 10A -(C 2 -C 9 )heterocycloalkyl-O—, R 10A -(C 6 -C 14 )aryl-O—, R 10A -(C 2 -C 9 )heteroaryl-O—, HO—, halo, cyano, H 2 N—, (CH 3 )HN—, (CH 3 ) 2 N—, R 10A R 11 N—, R 10A R 11 N(O)C—, R 10A (R 11 C(O))N—, R 10A R 11 NC(O)O—, R 10A C(O)—, R 10A R 11 NC(O)R 10A N—, (C 1 -C 10 )alkyl-OC(O)R 10A N—, (C 3 -C 10 )cycloalkyl-OC(O)R 10A N—, (C 2 -C 9 )heterocycloalkyl-OC(O)R 10A N—, (C 6 -C 14 )aryl-OC(O)R 10A N—, (C 2 -C 9 )heteroaryl-OC(O)R 10A N—, F 3 C—, F 2 HC—, CH 3 F 2 C—, FH 2 C—, CH 3 FHC—, (CH 3 ) 2 FC—; NC—, (C 1 -C 10 )alkyl(O)P—, (C 1 -C 10 )alkyl-S—, (C 1 -C 10 )alkyl-S-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 1 -C 10 )alkyl-S(O)—, (C 3 -C 10 )cycloalkyl-S(O)—, (C 6 -C 14 )aryl-S(O)—, (C 2 -C 9 )heterocycloalkyl-S(O)—, (C 2 -C 9 )heteroaryl-S(O)—, (C 3 -C 10 )alkyl-S(O) 2 —, (C 3 -C 10 )cycloalkyl-S(O) 2 —, (C 6 -C 14 )aryl-S(O) 2 —, (C 2 -C 9 )heterocycloalkyl-S(O) 2 —, (C 2 -C 9 )heteroaryl-S(O) 2 —, R 10A R 11 NS(O) 2 —, (C 1 -C 10 )alkyl-S(O) 2 R 10A N—, (C 3 -C 10 )cycloalkyl-S(O) 2 R 10A N—, (C 6 -C 14 )aryl-S(O) 2 R 10A N—, (C 2 -C 9 )heterocycloalkyl-SO 2 R 10A N—, and (C 2 -C 9 )heteroaryl-S(O) 2 R 10A N—;
wherein R 10A and R 11 are each independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, HO—, halo, (CH 3 ) 2 N—, and H 2 N—;
or R 10A and R 11 are taken together to form a 3 to 10 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
wherein each (C 1 -C 10 )alkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl are further optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloalkyl-O—, (C 2 -C 9 )heterocycloalkyl-O—, (C 6 -C 14 )aryl-O—, (C 2 -C 9 )heteroaryl-O—, HO—, halo, or H 2 N—

Y 1 is O, S, or CR 12 R 13 ,
wherein R 12 is absent or R 12 and R 13 are each independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, ((C 1 -C 10 )alkyl) 2 amine, (C 1 -C 3 )alkynylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy-, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl-, (C 3 -C 10 )cycloal

Assignees

• Genzyme Corp

Inventors

• Kane Jr John L
• Barberis Claude
• Czekaj Mark
• Erdman Paul
• Giese Barret
• Kothe Michael
• Le Tieu-Binh
• Liu Jinyu
• Ma Liang
• Metz Markus
• Patel Vinod
• Scholte Andrew
• Shum Patrick Wai-Kwok
• Wei Linli

Classifications

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title