Substituted quinoxaline DNA-PK inhibitors

• US 9,340,557 B2
• Filed: 03/12/2014
• Issued: 05/17/2016
• 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 M., Morris, Mark A., Waal, Nathan D., Court, John J., Gu, Wenxin, Deng, Hongbo
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/205,657
• Publication Number:
  US 20140275024A1
• Time in Patent Office: 797 Days
• Field of Search: 514/249, 544/116, 544/278, 544/322, 544/353
• US Class Current: 1/1
• 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 compounds represented by Formula (I) and pharmaceutically acceptable salts thereof are useful as inhibitors of DNA-PK:

where each of R¹, R², X, Ring A, Ring B and Ring C is as described herein. Pharmaceutically acceptable compositions comprise said compounds. These compounds and pharmaceutical compositions are used in the treatment of various disease, conditions, or disorders.

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, represented by Formula (II) or a pharmaceutically acceptable salt thereof:

3. The compound of claim 2, represented by Formula (II-A-1) or a pharmaceutically acceptable salt thereof:

4. The compound of claim 3, wherein R² is —

C_0-4 alkyl-NHR⁴.

5. The compound of claim 4, wherein X is —

O—

or —

OC_1-4 alkyl-.

6. The compound of claim 5, wherein

7. The compound of claim 6 wherein

8. The compound of claim 7, wherein R³ is hydrogen.

9. The compound of claim 8, wherein

R⁴ is hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-5cycloalkyl, phenyl, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl, C_0-4 alkyl-O—

C_0-4 alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O)R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵, C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC_0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

10. The compound of claim 8, wherein

R⁴ is a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl,

C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl,

C_0-4 alkyl-O—

C_0-4 alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl,

C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O)R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵,

C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC_0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

11. The compound of claim 8, wherein R⁴ is a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl, C_0-4 alkyl-O—

C_0-4 alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O)R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵, C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC_0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

12. The compound of claim 2, represented by Formula (II-B-1) or a pharmaceutically acceptable salt thereof:

13. The compound of claim 12, wherein R¹ is —

C_0-4 alkyl-NHR⁴.

14. The compound of claim 13, wherein X is —

O—

or —

OC_1-4 alkyl-.

15. The compound of claim 14, wherein

16. The compound of claim 15 wherein

17. The compound of claim 16, wherein R³ is hydrogen.

18. The compound of claim 17, wherein

R⁴ is hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-5cycloalkyl, phenyl, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl, C_0-4 alkyl-O—

C_0-4alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O) R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵, C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC_0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

19. The compound of claim 17, wherein

R⁴ is a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl, C_0-4 alkyl-O—

C_0-4 alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O)R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵, C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC_0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

20. The compound of claim 17, wherein

R⁴ is a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine, wherein each of said R⁴ groups is optionally substituted with up to four Br, Cl, F, or C_1-4alkyl, up to three CN, NO₂, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloalkyl, C_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-O—

C_1-4 alkyl, C_0-4 alkyl-O—

C_0-4 alkyl-C_3-5 cycloalkyl, C(O)OC_1-4 alkyl, C(O)OC_0-4 alkyl-C_3-5 cycloalkyl, C_0-4 alkyl-C(O)NH₂, C(O)NHC_1-4 alkyl, C(O)N(C_1-4 alkyl)₂, C(O)NH(C_0-4 alkyl-C_3-5 cycloalkyl), CH₂OR⁵, C_0-4 alkyl-C(O)R⁵, C_0-4 alkyl-C(O)N(R⁵)₂, C_0-4 alkyl-C(O)OR⁵, C_0-4 alkyl-NHC(O)R⁵, C_0-4 alkyl-N(R⁵)₂, a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine or piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole, or up to two OR⁵, wherein each of said optional R⁴ substituents is optionally substituted with up to four fluorine atoms, up to two C_1-4alkyl groups, up to two OH groups, up to two OC_1-4alkyl groups, up to two SC_1-4alkyl groups, a C(O)C_1-4 alkyl, a C(O)OC_1-4 alkyl, or a C(O)OC _0-4 alkyl-C_3-5 cycloalkyl; and

each R⁵ is, independently, hydrogen, C_1-4alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a spirooxetane, 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.

21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable excipient.

23. A pharmaceutical composition comprising a compound of any one of claims 3-4 and 5-11, and a pharmaceutically acceptable excipient.

24. A pharmaceutical composition comprising a compound of any one of claims 12-20, and a pharmaceutically acceptable excipient.

25. A compound, wherein the compound is:

26. A pharmaceutical composition comprising a compound of claim 25, and a pharmaceutically acceptable excipient.