IP Library › Granted Patent US 12,258,366
Granted Patent B2
US 12,258,366 · App. 18/045,647 · Granted Mar 25, 2025

Bicyclic heteroaryl compounds and uses thereof

Inventors: Adrian L. Gill (Menlo Park, CA); Andreas Buckl (San Francisco, CA); Elena S. Koltun (Foster City, CA); Naing Aay (San Mateo, CA); Arlyn A. Tambo-ong (South San Francisco, CA); Severin Thompson (Belmont, CA); Micah James Gliedt (Fremont, CA); John E. Knox (Emerald Hills, CA); James Cregg (Belmont, CA); Anne V. Edwards (San Mateo, CA); Yang Liu (Foster City, CA); G. Leslie Burnett (San Mateo, CA)
Assignee: Revolution Medicines, Inc.
C07F9/6584A61K31/519A61K31/5377C07D471/04C07D519/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,258,366
App. No.
18/045,647
Granted
Mar 25, 2025
Kind
B2
Abstract

The present disclosure is directed to modulators of SOS1 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.

Claims (122)

1. A method of treating a disease, wherein treating the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-8-methyl-6-morpholinopyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-6-(3,6-dihydro-2H-pyran-4-yl)-8-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-{[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino}-8-methyl-6-(morpholin-4-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

8-methyl-6-(morpholin-4-yl)-4-{[(1R)-1-[3-(trifluoromethyl)phenyl]-ethyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-6-(1-methanesulfonyl-3-methylazetidin-3-yl)-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-amino-2-fluoro-5-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(pyridazin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-imino-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-(methylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxidotetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]-ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxy-1λ 6 -thiane-1,1-dione;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]-pyrimidin-6-yl)-4-fluoro-1λ 6 -thiane-1,1-dione;

4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-6-(phenylsulfanyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(4-aminooxan-4-yl)-4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido-[2,3-d]pyrimidin-7-one;

4-(4-{[(1R)-1-[3-(difluoro-methyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-methoxy-1λ 6 -thiane-1,1-dione;

6-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimi-din-6-yl)-2λ 6 -thiaspiro[3.3]heptane-2,2-dione;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3-hydroxypiperidin-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-imino-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

1-acetyl-4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl) piperidine-4-carbonitrile;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-1λ 6 -thiane-1,1-dione;

6-(1-acetylpiperidin-4-yl)-4-{[(1R)-1-[2,3-bis(difluoromethyl)phenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetylpiperidin-4-yl)-4-{[(1R)-1-[3-(difluoromethyl)-2-(fluoromethyl)phenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

2-{3-[(1R)-1-{[6-(1,1-dioxo-3,6-dihydro-2H-1λ 6 -thiopyran-4-yl)-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]phenyl}-2,2-difluoroacetonitrile;

2-{3-[(1R)-1-{[6-(1,1-dioxo-3,6-dihydro-2H-1λ 6 -thiopyran-4-yl)-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroacetonitrile;

4-(4-{[(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-1λ 6 -thiopyran-1,1-dione;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-(difluoromethyl)-5-(3-fluoroazetidin-3-yl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-6-yl]-1-oxo-3,6-dihydro-2H-thiopyran-1-ylidene]cyanamide;

[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-6-yl]-1-oxo-thian-1-ylidene]cyanamide;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1S,4s)-1-imino-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1R,4r)-1-imino-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1S,4s)-4-fluoro-1-(methylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1R,4r)-4-fluoro-1-(methylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-{3-acetyl-3-azabicyclo[3.1.0]hexan-1-yl}-4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-[(4-cyclopropylmorpholin-2-yl)-difluoro-methyl]-2-fluoro-phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-((1R,4r)-1-(cyclopropylimino)-4-fluoro-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-((1S,4s)-1-(cyclopropylimino)-4-fluoro-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

(1R,4r)-1-(cyclopropylimino)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl) hexahydro-1λ 6 -thiopyran-4-carbonitrile 1-oxide;

(1S,4s)-1-(cyclopropylimino)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl) hexahydro-1λ 6 -thiopyran-4-carbonitrile 1-oxide;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-6-[1-(oxetan-3-ylimino)-1-oxo-thian-4-yl]pyrido[2,3-d]pyrimidin-7-one;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-[1-[(4-methoxyphenyl)methoxy]cyclopropyl]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

2-[2-(difluoromethyl)-6-[(1R)-1-[[6-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-4-yl]amino]ethyl]phenyl]acetonitrile;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((1R,4r)-1-(methylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((S)-1-(oxetan-3-ylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((R)-1-(oxetan-3-ylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(1-imino-1-oxo-thian-4-yl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-((1R,4r)-1-(cyclopropylimino)-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-((1S,4s)-1-(cyclopropylimino)-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; and

N-[3-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl) bicyclo[1.1.1]pentan-1-yl]acetamide;

or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

2. The method of claim 1 , wherein the disease is cancer.

3. The method of claim 1 , wherein the disease is a RASopathy.

4. The method of claim 2 , wherein the cancer comprises a Ras MUT or an NF1 LOF mutation.

5. The method of claim 1 , comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof.

6. The method of claim 2 , comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof.

7. A method of treating a disease, wherein treating the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from among the compounds in the following table:

Structure

8. The method of claim 7 , wherein the compound or a pharmaceutically acceptable salt or a stereoisomer thereof is selected from among the compounds in the following table:

Structure

9. The method of claim 7 , wherein the disease is a RASopathy.

10. The method of claim 7 , wherein the disease is cancer.

11. The method of claim 10 , wherein the compound or a pharmaceutically acceptable salt or a stereoisomer thereof is selected from among the compounds in the following table:

Structure

12. The method of claim 10 , wherein the cancer comprises a Ras MUT or an NF1 LOF mutation.

13. A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, the method comprising administering to the cell an effective amount of a compound selected from the group consisting of:

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-8-methyl-6-morpholinopyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-6-(3,6-dihydro-2H-pyran-4-yl)-8-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-{[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino}-8-methyl-6-(morpholin-4-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

8-methyl-6-(morpholin-4-yl)-4-{[(1R)-1-[3-(trifluoromethyl)phenyl]-ethyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-6-(1-methanesulfonyl-3-methylazetidin-3-yl)-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-amino-2-fluoro-5-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(pyridazin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-imino-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-(methylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxidotetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]-ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxy-1l6-thiane-1,1-dione;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]-pyrimidin-6-yl)-4-fluoro-1λ 6 -thiane-1,1-dione;

4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-6-(phenylsulfanyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(4-aminooxan-4-yl)-4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido-[2,3-d]pyrimidin-7-one;

4-(4-{[(1R)-1-[3-(difluoro-methyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-methoxy-1λ 6 -thiane-1,1-dione;

6-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimi-din-6-yl)-2λ 6 -thiaspiro[3.3]heptane-2,2-dione;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3-hydroxypiperidin-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

1-acetyl-4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl) piperidine-4-carbonitrile;

4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-1λ 6 -thiane-1,1-dione;

6-(1-acetylpiperidin-4-yl)-4-{[(1R)-1-[2,3-bis(difluoromethyl)phenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetylpiperidin-4-yl)-4-{[(1R)-1-[3-(difluoromethyl)-2-(fluoromethyl)phenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

2-{3-[(1R)-1-{[6-(1,1-dioxo-3,6-dihydro-2H-1λ 6 -thiopyran-4-yl)-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]phenyl}-2,2-difluoroacetonitrile;

2-{3-[(1R)-1-{[6-(1,1-dioxo-3,6-dihydro-2H-1λ 6 -thiopyran-4-yl)-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroacetonitrile;

4-(4-{[(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-1λ 6 -thiopyran-1,1-dione;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-(difluoromethyl)-5-(3-fluoroazetidin-3-yl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-6-yl]-1-oxo-3,6-dihydro-2H-thiopyran-1-ylidene]cyanamide;

[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-6-yl]-1-oxo-thian-1-ylidene]cyanamide;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1S,4s)-1-imino-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1R,4r)-1-imino-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1S,4s)-4-fluoro-1-(methylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1R,4r)-4-fluoro-1-(methylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-{3-acetyl-3-azabicyclo[3.1.0]hexan-1-yl}-4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one;

6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-[(4-cyclopropylmorpholin-2-yl)-difluoro-methyl]-2-fluoro-phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-((1R,4r)-1-(cyclopropylimino)-4-fluoro-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-((1S,4s)-1-(cyclopropylimino)-4-fluoro-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

(1R,4r)-1-(cyclopropylimino)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl) hexahydro-1λ 6 -thiopyran-4-carbonitrile 1-oxide;

(1S,4s)-1-(cyclopropylimino)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl) hexahydro-1λ 6 -thiopyran-4-carbonitrile 1-oxide;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-8-methyl-6-[1-(oxetan-3-ylimino)-1-oxo-thian-4-yl]pyrido[2,3-d]pyrimidin-7-one;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-[1-[(4-methoxyphenyl)methoxy]cyclopropyl]-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

2-[2-(difluoromethyl)-6-[(1R)-1-[[6-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-4-yl]amino]ethyl]phenyl]acetonitrile;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((1R,4r)-1-(methylimino)-1-oxidohexahydro-1l6-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((S)-1-(oxetan-3-ylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((R)-1-(oxetan-3-ylimino)-1-oxido-1,2,3,6-tetrahydro-1λ 6 -thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(1-imino-1-oxo-thian-4-yl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one;

6-((1R,4r)-1-(cyclopropylimino)-4-methoxy-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-((1S,4s)-1-(cyclopropylimino)-4-methoxy-1-oxidohexahydro-1l6-thiopyran-4-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; and

N-[3-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-yl) bicyclo[1.1.1]pentan-1-yl]acetamide;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

14. A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, the method comprising administering to the cell an effective amount of a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from among the compounds in the following table:

Structure

Assignments (2)
SECURITY INTEREST Recorded Jun 25, 2025
From: REVOLUTION MEDICINES, INC.
To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS AGENT
Reel/Frame 071721/0025 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2023
From: GILL, ADRIAN L.; BUCKL, ANDREAS; KOLTUN, ELENA S.; AAY, NAING; TAMBO-ONG, ARLYN A.; THOMPSON, STEVERIN; GLIEDT, MICAH JAMES; KNOX, JOHN E.; CREGG, JAMES; EDWARDS, ANNE V.; LIU, YANG; BURNETT, G. LESLIE
To: REVOLUTION MEDICINES, INC.
Reel/Frame 064889/0125 →
Continuity (5)
Continuation 17090342 · Nov 5, 2020
Provisional Application 63070593 · Aug 26, 2020
Provisional Application 63031318 · May 28, 2020
Provisional Application 62933141 · Nov 8, 2019
Related Publication 20230365605A1 · Nov 16, 2023
References Cited (103)
US 8637684B2 · Shen et al. · 2014 [cited by applicant]
US 11168102B1 · Gill · 2021 [cited by examiner]
US 20110281942A1 · Shen et al. · 2011 [cited by applicant]
US 20160030594A1 · Abrams et al. · 2016 [cited by applicant]
CN 105418632A · 2016 [cited by applicant]
WO 2005094314A2 · 2005 [cited by applicant]
WO 2006119504A2 · 2006 [cited by applicant]
WO 2007117699A2 · 2007 [cited by applicant]
WO 2008124815A1 · 2008 [cited by applicant]
WO 2009049098A2 · 2009 [cited by applicant]
WO 2009135000A2 · 2009 [cited by applicant]
WO 2010011666A2 · 2010 [cited by applicant]
WO 2010121212A2 · 2010 [cited by applicant]
WO 2011022440A9 · 2011 [cited by applicant]
WO 2012041524A1 · 2012 [cited by applicant]
WO 2012087881A1 · 2012 [cited by applicant]
WO 2014015291A1 · 2014 [cited by applicant]
WO 2014113584A1 · 2014 [cited by applicant]
WO 2014176488A1 · 2014 [cited by applicant]
WO 2015003094A2 · 2015 [cited by applicant]
WO 2015107493A1 · 2015 [cited by applicant]
WO 2015107494A1 · 2015 [cited by applicant]
WO 2015107495A1 · 2015 [cited by applicant]
WO 2016044772A1 · 2016 [cited by applicant]
WO 2021074227A1 · 2016 [cited by applicant]
WO 2016077793A1 · 2016 [cited by applicant]
WO 2016115434A1 · 2016 [cited by applicant]
WO 2016191328A1 · 2016 [cited by applicant]
WO 2016196591A1 · 2016 [cited by applicant]
WO 2016203404A1 · 2016 [cited by applicant]
WO 2016203405A1 · 2016 [cited by applicant]
WO 2016203406A1 · 2016 [cited by applicant]
WO 2017014323A1 · 2017 [cited by applicant]
WO 2017078499A1 · 2017 [cited by applicant]
WO 2017079723A1 · 2017 [cited by applicant]
WO 2017100279A1 · 2017 [cited by applicant]
WO 2017156397A1 · 2017 [cited by applicant]
WO 2017210134A1 · 2017 [cited by applicant]
WO 2017211303A1 · 2017 [cited by applicant]
WO 2018013597A1 · 2018 [cited by applicant]
WO 2018057884A1 · 2018 [cited by applicant]
WO 2018081091A1 · 2018 [cited by applicant]
WO 2018115380A1 · 2018 [cited by applicant]
WO 2018129402A1 · 2018 [cited by applicant]
WO 2018130928A1 · 2018 [cited by applicant]
WO 2018136264A1 · 2018 [cited by applicant]
WO 2018136265A1 · 2018 [cited by applicant]
WO 2018160731A1 · 2018 [cited by applicant]
WO 2018172250A1 · 2018 [cited by applicant]
WO 2018172984A1 · 2018 [cited by applicant]
WO 2018218133A1 · 2018 [cited by applicant]
WO 2019201848A1 · 2019 [cited by applicant]
WO 2019051084A1 · 2019 [cited by applicant]
WO 2019051469A1 · 2019 [cited by applicant]
WO 2019067843A1 · 2019 [cited by applicant]
WO 2019122129A1 · 2019 [cited by applicant]
WO 2019152454A1 · 2019 [cited by applicant]
WO 2019158019A1 · 2019 [cited by applicant]
WO 2019165073A1 · 2019 [cited by applicant]
WO 2019167000A1 · 2019 [cited by applicant]
WO 2019182960A1 · 2019 [cited by applicant]
WO 2019183364A1 · 2019 [cited by applicant]
WO 2019183367A1 · 2019 [cited by applicant]
WO 2019199792A1 · 2019 [cited by applicant]
WO 2019213318A1 · 2019 [cited by applicant]
WO 2019233810A1 · 2019 [cited by applicant]
WO 2020022323A1 · 2020 [cited by applicant]
WO 2020033286A1 · 2020 [cited by applicant]
WO 2020033828A1 · 2020 [cited by applicant]
WO 2020061101A1 · 2020 [cited by applicant]
WO 2020061103A1 · 2020 [cited by applicant]
WO 2020063760A1 · 2020 [cited by applicant]
WO 2020072656A1 · 2020 [cited by applicant]
WO 2020073945A1 · 2020 [cited by applicant]
WO 2020073949A1 · 2020 [cited by applicant]
WO 2020076723A1 · 2020 [cited by applicant]
WO 2020081848A1 · 2020 [cited by applicant]
WO 2020180768A1 · 2020 [cited by applicant]
WO 2020180770A1 · 2020 [cited by applicant]
WO 2021249519A1 · 2020 [cited by applicant]
WO 2022170802A1 · 2022 [cited by applicant]
Golub et al., Science, vol. 286, Oct. 15, 1999, pp. 531-537. (Year: 1999). [cited by examiner]
Boehringer Ingelheim, A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) Bethesda (Md): U.S. National … [cited by applicant]
Boehringer Ingelheim. A Study to Test Different Doses of BI 1701963 in Combination With Irinotecan in People With Advanced Bowel Cancer With Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutation. Bethesda (Md): U… [cited by applicant]
Boehringer Ingelheim. A Study to Find a Safe and Effective Dose of BI 1701963 Alone and in Combination With BI 3011441 in Patients With Advanced Cancer and a Certain Mutation (KRAS) Bethesda (MD): U.S. National Library … [cited by applicant]
Hofmann et al., “B1-3406, a Potent and Selective SOS-1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition”, Cancer Discovery, Jan. 2021, pp. 142-157. [cited by applicant]
Lu et al., “Inhibitors of Ras-SOS Interactions”, Chem Med Chem, Dec. 2, 2015, vol. 11, No. 8, pp. 814-821. [cited by applicant]
Ramharter et al., One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS:, J. Med. Chem., 2021, vol. 64, pp. 6569-6580. [cited by applicant]
International Search Report for PCT US/2020/059024, mailed Feb. 8, 2021, 3 pages. [cited by applicant]
Berger et al., “S(+)-4-(1-Phenylethylamino)quinazolines as Inhibitors of Human Immunoglobuline E Synthesis: Potency is Dictated by Sterochemistry and Atomic Point Charges at N-1”, J. Med. Chem., Jan. 1, 2001, vol. 44, N… [cited by applicant]
Bullock et al., “Syntheses of 6-Substituted Purines”, Journal of the American Chemical Society, Aug. 5, 1956, vol. 78, No. 15, pp. 3693-3696. [cited by applicant]
Burns et al., “Approach for targeting RAS with small molecules that activate SOS-mediated nucleotide exchange”, PNAS, Mar. 4, 2014, vol. 111, No. 9, pp. 3401-3406. [cited by applicant]
Chakraborti et al., “3D-QSAR Stuies on Thieno[3,2-d]pyrimidines as Phosphodiesterase IV Inhibitors”, Bioorganic & Medicinal Chemistry Letters, vol. 13, No. 8, Jan. 1, 2003, pp. 1403-1408. [cited by applicant]
Chen et al., “Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor”, Molecular Pharmacology, 2006, vol. 70, No. 2, pp. 562-570. [cited by applicant]
Crespo et al., “Design, Synthesis, and Biological Activities of New Thieno[3,2- d]pyrimidines as Selective Type 4 Phosphodiesterase Inhibitors”, J. of Med. Chem., Jan. 1, 1998, vol. 41, pp. 4021-4035. [cited by applicant]
Hillig et al., “Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction”, PNAS, Feb. 12, 2019, vol. 116, No. 7, pp. 2551-2560. [cited by applicant]
Igbe et al., “Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellar carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase”, Oncotarget, 2… [cited by applicant]
Kaspersen et al., “Activity of 6-aryl-pyrrolo[2,3- d]pyrimidines-4-amines to Tetrahymena”, Bioorganic Chemistry, Jan. 1, 2012, vol. 44, pp. 35-41. [cited by applicant]
Kaspersen et al., “Sythesis and in vitro EGFR (ErbB1) tyrosine kinase inhibitory activity of 4-N-substituted 6-ary1-7Hpyrrolo[2,3-d]pyrimidine-4-amines”, European Journal of Medicinal Chemistry, Oct. 6, 2011, vol. 46, N… [cited by applicant]
Koshimizu et al., “Structure-Activity Relationships in Optically Active Cytokinins”, Phytochemistry, Jan. 1, 1968, vol. 7, pp. 1989-1994. [cited by applicant]
Ross et al., “Potential Anticancer Agents. XVIII. Synthesis of Substituted 4,5-Trimethylenephyrimidines”, J. American Chemical Society, Jan. 1, 1959, vol. 81, pp. 3108-3110. [cited by applicant]
Sarver et al., “6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors”, J. Med. Chem., 2019, vol. 62, pp. 1793-1802. [cited by applicant]
Xie et al., “Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment”, J. Med. Chem., 2017, vol. 60, pp. 10205-10219. [cited by applicant]