SOS1 inhibitor containing phosphorus

Patent metadata

Field	Value
Publication number	US-12565511-B2
Application number	US-202117998244-A
Country	US
Kind code	B2
Filing date	May 10, 2021
Priority date	May 9, 2020
Publication date	Mar 3, 2026
Grant date	Mar 3, 2026

Abstract

The present application relates to the field of pharmaceutical chemistry, relates to an SOS1 inhibitor containing phosphorus, i.e., a compound of formula (I) and a preparation method therefor, and a pharmaceutical composition containing the compound, and relates to use thereof in the preparation of a drug for treating a disease and/or disorder related to SOS1 or regulated by SOS1.

First claim

The invention claimed is:

1 . A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein,
X and Y are each independently selected from the group consisting of CR a , C(O), N and NR b ;
“ ” represents a single bond or a double bond depending on X and Y;
R a is selected from the group consisting of hydrogen, hydroxy, halogen, cyano, C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more deuterium or halogens;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkoxy;
R 1 and R 2 are each independently selected from the group consisting of C 1-6 alkyl, NH(R c )—C 1-6 alkyl- and N(R c )(C 1-6 alkyl)-C 1-6 alkyl-, or R 1 , R 2 and the phosphorus atom to which they are both connected together form 5-10 membered heterocyclyl, wherein the C 1-6 alkyl or 5-10 membered heterocyclyl is optionally substituted with one or more R c ;
each R c is independently selected from the group consisting of hydrogen, O═, HN═, C 1-6 alkyl-N═, C 1-6 alkyl-, C 1-6 alkyl-C(O)—, C 1-6 alkyl-S(O) 2 —, 3-6 membered cycloalkyl-S(O) 2 —, C 1-6 alkyl OC(O)—, C 1-6 alkyl-O—C 1-6 alkyl-, C 1-6 alkyl-O—C 1-6 alkyl-C(O)—, amino-C(O)—, mono(C 1-6 alkyl)amino-C(O)—, di(C 1-6 alkyl)amino-C(O)—, amino-C 1-6 alkyl-C(O)—, mono(C 1-6 alkyl)amino-C 1-6 alkyl-C(O)—, di(C 1-6 alkyl)amino-C 1-6 alkyl-C(O)—, amino-C(O)—C 1-6 alkyl-, mono(C 1-6 alkyl)amino-C(O)—C 1-6 alkyl-, di(C 1-6 alkyl)amino-C(O)—C 1-6 alkyl-, 3-6 membered cycloalkyl-, 3-6 membered cycloalkyl-C(O)—, 3-6 membered cycloalkyl-C 1-6 alkyl-, 3-6 membered heterocycloalkyl-, 3-6 membered heterocycloalkyl-C(O)—, 3-6 membered heterocycloalkyl-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl- and C 1-6 alkyl-substituted with one or more hydroxy or cyano, wherein the R c is optionally substituted with one or more halogens when it is not hydrogen and O═;
ring A is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl, 8-12 membered fused ring and 8-12 membered fused heterocyclic ring;
n is 0, 1, 2 or 3;
each R 3 is independently selected from the group consisting of amino, nitro, halogen, C 1-8 alkyl-, 3-6 membered cycloalkyl- and phenyl, wherein the C 1-8 alkyl, 3-6 membered cycloalkyl or phenyl is optionally substituted with one or more R d ;
R d is selected from the group consisting of hydroxy, halogen and C 1-6 alkyl-NH—C 1-6 alkyl-;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens; and
R 6 is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens.

2 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein X is selected from the group consisting of CR a and NR b , and Y is selected from the group consisting of CR a , C(O), N and NR b ; or, X and Y are both selected from CR a ; or, X is selected from CH, and Y is selected from CR a ; or, X is selected from CH, and Y is selected from the group consisting of C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF and C(OCD 3 ); or, X is selected from CH, and Y is selected from N; or, X is selected from N(CH 3 ), and Y is selected from C(O); or, X is selected from the group consisting of CF and C(CN), and Y is selected from the group consisting of CH and N.

3 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein R a is selected from the group consisting of hydrogen, hydroxy, halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted with one or more deuterium or halogens; or, R a is selected from the group consisting of hydrogen, hydroxy, halogen, cyano and C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted with 3 deuterium, or one or more fluorine; or, R a is selected from the group consisting of hydrogen, hydroxy, halogen, cyano and C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted with 3 deuterium, or 1 or 2 fluorine; or, R a is selected from the group consisting of hydrogen, hydroxy, fluorine, cyano, methoxy, monofluorinemethoxy and difluorinemethoxy, wherein the methoxy is optionally substituted with 3 deuterium; or, R a is selected from the group consisting of hydrogen, hydroxy, fluorine, cyano, CH 3 O—, CD 3 O—, CH 2 FO— and CHF 2 O—.

4 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein R b is selected from C 1-6 alkyl; or, R b is selected from C 1-4 alkyl; or, R b is selected from C 1-3 alkyl; or, R b is selected from methyl.

5 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of C 1-3 alkyl, NH(R c )—C 1-3 alkyl- and N(R c )(C 1-3 alkyl)-C 1-3 alkyl-; or, R 1 and R 2 are each independently selected from C 1-3 alkyl; or, R 1 and R 2 are each independently selected from the group consisting of methyl and ethyl.

6 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 , R 2 and the phosphorus atom to which they are both connected together form 5-10 membered heterocyclyl, wherein the ring atoms of the 5-10 membered heterocyclyl optionally contain one or more heteroatoms selected from the group consisting of N, O and S atoms, and the 5-10 membered heterocyclyl is optionally substituted with one or more R c , and when the ring atoms contain an N atom, N is connected to R c ; or, R 1 , R 2 and the phosphorus atom to which they are both connected together form 5-8 membered heterocyclyl, wherein the ring atoms of the 5-8 membered heterocyclyl optionally contain one heteroatom selected from the group consisting of N and O atoms, and when the ring atoms contain an N atom, N is connected to R c ; or, R 1 , R 2 and the phosphorus atom to which they are both connected together form 5 membered or 6 membered heterocyclyl, wherein the ring atoms of the 5 membered or 6 membered heterocyclyl optionally contain one heteroatom selected from the group consisting of N and O atoms, and when the ring atoms contain an N atom, N is connected to R c ; or, structural unit

is selected from the group consisting of structural units

or, structural unit

is structural unit

7 . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of claim 1 , wherein each R c is independently selected from the group consisting of C 1-3 alkyl-, C 1-3 alkyl-C(O)—, C 1-3 alkyl-S(O) 2 —, 3-5 membered cycloalkyl-S(O) 2 —, C 1-3 alkyl OC(O)—, C 1-3 alkyl-O—C 1-3 alkyl-, C 1-3 alkyl-O—CH 2 —C(O)—, di(C 1-3 alkyl)amino-C(O)—, di(C 1-3 alkyl)amino-CH 2 —C(O)—, di(C 1-3 alkyl)amino-C(O)—CH 2 —, 3-5 membered cycloalkyl-, 3-5 membered cycloalkyl-C(O)—, 3-5 membered cycloalkyl-CH 2 —, 3-5 membered heterocycloalkyl-, phenyl-CH 2 — and C 1-3 alkyl-substit

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Zhang Yinsheng
• Liu Baomin
• Chen Zhengbang
• Hu Jinfa
• Chen Yuchen
• Sun Kewen
• Wang Jinan
• Zhu Lijuan

Classifications

• C07F9/6584

  having one phosphorus atom as ring hetero atom · CPC title

• C07F9/657163

  the ring phosphorus atom being bound to at least one carbon atom · CPC title

• C07F9/6568

  having phosphorus atoms as the only ring hetero atoms · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title