DNA-PK inhibitors

• US 10,258,627 B2
• Filed: 07/25/2017
• Issued: 04/16/2019
• Est. Priority Date: 03/12/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Maxwell, John Patrick, Charifson, Paul S., Tang, Qing, Ronkin, Steven M., Jackson, Katrina Lee, Pierce, Albert Charles, Lauffer, David J., Li, Pan, Giroux, Simon, Xu, Jinwang, Cottrell, Kevin Michael, Morris, Mark A., Waal, Nathan D., Court, John J., Gu, Wenxin, Deng, Hongbo
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US15/659,306
• Publication Number:
  US 20180161336A1
• Time in Patent Office: 630 Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5386 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 241/40 Benzopyrazines
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 271/12 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 475/00 : Heterocyclic compounds containing pteridine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/052 : the oxygen-containing ring being six-membered
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 491/08 : Bridged systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of DNA-PK. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Claims

1. A method of sensitizing a cell to an agent that induces a DNA lesion comprising the step of contacting the cell with a compound having the formula:

2. The method of claim 1, wherein X is NH.

3. The method of claim 1, wherein the compound is of formula:

4. The method of claim 3, wherein the compound is of formula:

5. The method of claim 2, wherein the compound is of formula:

6. The method of claim 5, wherein the compound is of formula:

7. The method of claim 6, wherein

R³ is hydrogen, C_1-4alkyl, fluoro, chloro, OC_1-2alkyl, C(O)OH, C(O)OC_1-2alkyl, CN, C(O)NHC_1-2alkyl, or C(O)NH₂, wherein each of said R³ alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC_1-2alkyl groups;

R⁴ is hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-5cycloalkyl, phenyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinoline, oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine;

each of said R⁴ groups is optionally substituted with Br, Cl, up to three fluorine atoms, up to three C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, an oxetane ring, a tetrahydrofuran ring, a dihydropyran ring, a tetrahydropyran ring, a pyrrolidine ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxadiazole ring, CN, CH₂OR⁵, C(O)R⁵, C(O)N(R⁵)₂, C(O)OR⁵, NO₂, NHC(O)R⁵, N(R⁵)₂, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to 3 fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, or up to two SC_1-4alkyl groups; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, imidazole, triazole, thiazole, pyridine, pyrimidine, oxetane, tetrahydrofuran, or tetrahydropyran, and each R⁵ group is optionally substituted with chloro, up to three fluorine atoms, up to two C_1-2alkyl, CH₂OH, CN, up to two OH, up to two OC_1-2alkyl, pyrrolidine, or triazole, or two R⁵ groups together with the intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC_1-2alkyl groups.

8. The method of claim 6, wherein the compound is of formula:

9. The method of claim 1, wherein X is O.

10. The method of claim 9, wherein the compound is of formula:

11. The method of claim 10, wherein the compound is of formula:

12. The method of claim 10, wherein the compound is of formula:

13. The method of claim 9, wherein the compound is of formula:

14. The method of claim 13, wherein the compound is of formula:

15. The method of claim 13, wherein the compound is of formula:

16. The method of claim 13, wherein the compound is of formula:

17. The method of claim 16, wherein

R³ is hydrogen, C_1-4alkyl, fluoro, chloro, OC_1-2alkyl, C(O)OH, C(O)OC_1-2alkyl, CN, C(O)NHC_1-2alkyl, or C(O)NH₂, wherein each of said R³ alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC_1-2alkyl groups;

R⁴ is hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-5cycloalkyl, phenyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinoline, oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine;

each of said R⁴ groups except hydrogen is optionally substituted with Br, Cl, up to three fluorine atoms, up to three C_1-4alkyl, up to two C_0-4alkyl-R⁵, up to two C_0-4alkyl-O-C_0-4alkyl-R⁵, C_2-4alkenyl, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, CN NO₂, C(O)R⁵, C(O)N(R⁵)₂, C(O)OC_0-4alkyl-R⁵, NHC(O)R⁵, N(R⁵)₂, oxetane, azetidine tetrahydrofuran, dihydropyran, tetrahydropyran, pyrrolidine, pyrazole, triazole, tetrazole, or oxadiazole, wherein each of said optional R⁴ substituents is optionally substituted with up to 3 fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, or up to two SC_1-4alkyl groups; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, C_3-5cycloalkyl, imidazole, triazole, thiazole, pyridine, pyrimidine, oxetane, tetrahydrofuran, or tetrahydropyran, and each R⁵ group is optionally substituted with chloro, up to three fluorine atoms, up to two C_1-2alkyl, CH₂OH, CN, up to two OH, up to two OC_1-2alkyl, pyrrolidine, or triazole, or two R⁵ groups together with an intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC_1-2alkyl groups.

18. The method of claim 1, wherein

19. The method of claim 1, wherein the compound of formula (I) is of formula: