US-12624032-B2 - Pyrido[2,3-d]pyrimidin-7-ones and related compounds as inhibitors of protein kinases

Abstract

Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit.

Inventors

• Gregory Cuny
• Sameer Nikhar
• Alexei Degterev

Assignees

• UNIVERSITY OF HOUSTON SYSTEM
• TRUSTEES OF TUFTS COLLEGE

Dates

Publication Date

20260512

Application Date

20240220

Claims (7)

1. 1 . A compound demonstrating protein kinase inhibitory activity and having a structure of: wherein R is at one available ring position, wherein Me is methyl and Et is ethyl; A and D are independently N or CH; E is N, CH, or C—R; B and C are independently N, CH, or C—Cl; R 1 is H, or R 1 is Cl, F, OCH 3 , C(CH 3 ) 3 , or OH at one available ring position; and X-Y is C═C.
2. 2 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof.
3. 3 . A method of treating a protein kinase related disease or condition, wherein the condition is inflammatory bowel disease or multiple sclerosis, comprising administering the pharmaceutical composition of claim 2 .
4. 4 . A compound demonstrating protein kinase inhibitory activity and having a structure of: wherein R is H, wherein Me is methyl and Et is ethyl; R 1 is any alkyl or aryl group; A and D are independently N or CH; E is N, CH, or C—R; B and C are independently N, CH, or C—Cl; R 3 is H, or R 3 is Cl, F, OCH 3 , C(CH 3 ) 3 , or OH at one available ring position; and X-Y is C═C.
5. 5 . The compound of claim 4 , wherein R 1 is methyl, ethyl, or propyl.
6. 6 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof.
7. 7 . A method of treating a protein kinase related disease or condition, wherein the condition is inflammatory bowel disease or multiple sclerosis, comprising administering the pharmaceutical composition of claim 6 .

Description

This application is a divisional of and claims priority to U.S. patent application Ser. No. 17/499,995, filed Oct. 13, 2021, entitled “Pyrido[2,3-d]pyrimidin-7-ones and Related Compounds as Inhibitors of Protein Kinases,” which is a divisional of and claims priority to U.S. patent application Ser. No. 16/613,003, filed Nov. 12, 2019, entitled “Pyrido[2,3-d]pyrimidin-7-ones and Related Compounds as Inhibitors of Protein Kinases,” which claims priority to PCT Application No. PCT/US2018/032631, filed May 15, 2018, entitled “Pyrido[2,3-d]pyrimidin-7-ones and Related Compounds as Inhibitors of Protein Kinases,” which claims priority to U.S. Provisional Patent Application No. 62/506,394, filed May 15, 2017, entitled “Pyrido[2,3-d]pyrimidin-7-ones and Related Compounds as Inhibitors of Protein Kinases,” the entire contents of which are hereby incorporated by reference. This invention was made with government support under grant CA190542 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND This disclosure pertains to compounds that demonstrate protein kinase inhibitory activity. Protein kinases are important enzymes in cellular signal transduction. In many pathological conditions aberrant signal transduction occurs. Therefore, protein kinase inhibitors can be used as therapeutic agents for the treatment of various diseases. SUMMARY The present disclosure relates generally to compounds that demonstrate protein kinase inhibitory activity. More specifically, the compounds can inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). RIPK2 mediates pro-inflammatory signaling and is an emerging therapeutic target in autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD) and multiple sclerosis. RIPK2 inhibitors could provide therapeutic benefit in the treatment of these and other conditions. Activin-like kinase 2 (ALK2) has been implicated in a number of diseases, such as bone disease (e.g. fibrodysplasia ossificans progressiva, ankylosing spondylitis), cardiovascular diseases (e.g. atherosclerosis and vascular calcification), some cancers (e.g. diffuse intrinsic pontine gliomas) and burns. Many of these maladies also have an inflammatory component that could exacerbate the condition and/or worsen the clinical outcome. Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit in the treatment of these and other conditions. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a general overall synthetic scheme for compounds disclosed herein as inhibitors of protein kinases, in accordance with preferred embodiments. FIG. 2 shows synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 3 shows synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 4 shows the structures of intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 5 shows synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 6 shows the structures of intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 7 shows the structures of intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 8 shows synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 9 shows synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 10 shows the structures of intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase. FIG. 11 shows a synthetic scheme for exemplary inhibitors of protein kinase, in accordance with preferred embodiments. FIG. 12 shows structures for exemplary inhibitors of protein kinase, in accordance with preferred embodiments. FIG. 13 shows structures for exemplary inhibitors of protein kinase, in accordance with preferred embodiments. FIG. 14 shows structures for exemplary inhibitors of protein kinase, in accordance with preferred embodiments. FIG. 15 shows structures for exemplary inhibitors of protein kinase, in accordance with preferred embodiments. FIG. 16 shows a synthetic scheme for an exemplary inhibitor of protein kinase, in accordance with preferred embodiments. FIG. 17 shows a synthetic scheme for an exemplary inhibitor of protein kinase, in accordance with preferred embodiments. FIG. 18A shows a synthetic scheme for exemplary inhibitors of protein kinases, in accordance with preferred embodiments. FIG. 18B shows structures of intermediate compounds used in the synthesis of exemplary inhibitors of protein kinases, in accordance with preferred embodiments. FIG. 19 shows structures of exemplary inhibitors of protein kinases, in accordance with preferred embod