US 2021/0070731 A1Published application

Tricyclic kinase inhibitors and use thereof

OwnerNivedita Namdev, Reena Zutshiinventors

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Abstract

The present application provides novel compounds that are inhibitors of kinases, including AMPK-related kinases like NUAK1, NUAK2, SIK1, SIK2, SIK3, MARK1, MARK2, MARK3, MARK4, as well as AURKA, AURKB, AURKC, CLK1, CLK2, DCAMKL2, MAPK7, MKNK2, PIK3CD, PKN3, RET, TAOK1, TAOK2, TAOK3, ULK2 and their mutants. The application also provides compositions, including pharmaceutical compositions, kits that include compounds, and methods of making and using compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by these kinases.

Claims1

Dependent claims

A compound of formula:

Each G1, G2, G3, G4, G7, G8, G9 and G10 is independently selected from N and CR10;
G5 is selected from —S—, —O—, —NRa—, —C(O)—, —C(O)O—, —C(O)NRa—, S(O)NRa—, —S(O)2NRa—, —S(O)—, —S(O)2—, C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene;
wherein each C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene is substituted with one to six R100;
G6 is selected from C4-7 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
R1 is selected from absent, hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Ra, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Ra, —S(O)2Ra, — NRaRb, —ORa, —SRb, C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycly is optionally substituted with one to four R100;
R2 is selected from absent, hydrogen, halogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Ra, —S(O)2Ra, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycly is optionally substituted with one to four R100;
R3 is selected from hydrogen, halogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rb, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
and optionally R2 and R3 together with the carbon atom to which it is attached may form a group selected from —C(O) and —C═CRaRb;
R4 is selected from hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocycly containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
Each R10 is independently selected from hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rb, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
Each Ra and Rb is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
wherein each CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R200;
Each Rc and Rd is independently selected from hydrogen, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
Each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
Each Rg is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;
each R100 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Rc, —C(O)ORc, —C(O)NRcRd, —N(Rc)C(O)Rd, —S(O)NRcRd, —S(O)2NRcRd, —S(O)Rc, —S(O)2Rc, NRcRd, —ORc, —SRc, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;
each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R201 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Re, —C(O)ORe, —C(O)NReRf, —N(Re)C(O)Rf, —S(O)NReRf, —S(O)2NReRf, —S(O)Re, —S(O)2Re, —NReRf, —ORe, —SRe, C1-6 alkyl, C2-4 alkenyl and C2-6 alkynyl;
each R200 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Re, —C(O)ORe, —C(O)NReRf, —N(Re)C(O)Rf, —S(O)NReRf, —S(O)2NReRf, —S(O)Rg, —S(O)2Rg, —NReRf, —ORe, —SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
and, each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

25 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula:

Each G1, G2, G3, G4, G7, G8, G9 and G10 is independently selected from N and CR10;
G5 is selected from —S—, —O—, —NRa—, —C(O)—, —C(O)O—, —C(O)NRa—, S(O)NRa—, —S(O)2NRa—, —S(O)—, —S(O)2—, C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene;
wherein each C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene is substituted with one to six R100;
G6 is selected from C4-7 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
R1 is selected from absent, hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Ra, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Ra, —S(O)2Ra, — NRaRb, —ORa, —SRb, C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycly is optionally substituted with one to four R100;
R2 is selected from absent, hydrogen, halogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Ra, —S(O)2Ra, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycly is optionally substituted with one to four R100;
R3 is selected from hydrogen, halogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rb, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
and optionally R2 and R3 together with the carbon atom to which it is attached may form a group selected from —C(O) and —C═CRaRb;
R4 is selected from hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocycly containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
Each R10 is independently selected from hydrogen, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rb, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;
Each Ra and Rb is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
wherein each CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R200;
Each Rc and Rd is independently selected from hydrogen, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
Each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
Each Rg is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;
each R100 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Rc, —C(O)ORc, —C(O)NRcRd, —N(Rc)C(O)Rd, —S(O)NRcRd, —S(O)2NRcRd, —S(O)Rc, —S(O)2Rc, NRcRd, —ORc, —SRc, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;
each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R201 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Re, —C(O)ORe, —C(O)NReRf, —N(Re)C(O)Rf, —S(O)NReRf, —S(O)2NReRf, —S(O)Re, —S(O)2Re, —NReRf, —ORe, —SRe, C1-6 alkyl, C2-4 alkenyl and C2-6 alkynyl;
each R200 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Re, —C(O)ORe, —C(O)NReRf, —N(Re)C(O)Rf, —S(O)NReRf, —S(O)2NReRf, —S(O)Rg, —S(O)2Rg, —NReRf, —ORe, —SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
and, each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

25 more elements