DNA-PK inhibitors

Patent metadata

Field	Value
Publication number	US-12005127-B2
Application number	US-201916962442-A
Country	US
Kind code	B2
Filing date	Jan 16, 2019
Priority date	Jan 17, 2018
Publication date	Jun 11, 2024
Grant date	Jun 11, 2024

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 diseases, conditions, or disorders.

First claim

What is claimed is:

1. A compound represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein
Ring A is an aromatic ring system selected from

Ring B is a ring system selected from

wherein Ring B is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH, and —OC 1-2 alkyl;
Ring C is a C 4-6 cycloalkyl, 5-6-membered heteroaryl, or phenyl group, wherein Ring C is optionally further substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, —OH, and —OC 1-2 alkyl;
X is —NH—, —O—, —OC 1-4 alkyl-, —S—, or —CH 2 —;
each of R 1 and R 2 is, independently, hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 ,

—NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —NHR 4 , —C 1-4 alkyl-NHR 4 , —OR 4 , or R 7 wherein R 1 and R 2 cannot simultaneously be hydrogen;
each R 3 independently is hydrogen, —C 1-4 alkyl,

halogen, —OC 1-2 alkyl, —C(O)OH, —C(O)OC 1-2 alkyl, —CN, —C(O)NHC 1-2 alkyl, —C(O)NH 2 , C 3-4 cycloalkyl, or —NRR′, wherein each of said R 3 alkyl and cycloalkyl independently is optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH and —OC 1-2 alkyl;
each R 4 independently is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10-membered heteroaryl, or 4-10-membered heterocyclyl, wherein each of said R 4 groups is optionally and independently substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, C 1-4 alkyl, CN, NO 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 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)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(Co 1-4 alkyl-C 3-5 cycloalkyl), CH 2 OR 5 , C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-N(R 5 ) 2 , 5-6 membered heterocyclyl, —O(C 1-4 alkyl)OR 5 , —OR 5 , and oxo, and wherein each of said optional R 4 substituents is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C 1-4 alkyl, —OH, —OC 1-4 alkyl, —SC 1-4 alkyl, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, and —C(O)OC 0-4 alkyl-C 3-5 cycloalkyl; and
each R 5 independently is hydrogen, C 1-4 alkyl, phenyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclyl, wherein each R 5 is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C 1-2 alkyl, —CH 2 OH,

—CN, —OH, —OC 1-2 alkyl, 5-6-membered heteroaryl, and 4-7 membered heterocyclyl, or two R 5 groups together with the intervening nitrogen atom optionally form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring; and
R 6 is hydrogen or C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —CH 2 OH, —CN, —OH, and —OC 1-2 alkyl;
R 7 is 6-10-membered aryl, 5-10-membered heteroaryl, or 4-7-membered heterocyclyl, each of which is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl,

C 1-2 alkyl, —CH 2 OH, —CN, and —OR; and
each of R and R′ independently is hydrogen or C 1-4 alkyl, or R and R′ together with the nitrogen atom to which they are attached optionally form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring.

2. The compound of claim 1 , wherein said aryl group for R 4 is optionally substituted and selected from phenyl or naphthalene; the heteroaryl group for R 4 is optionally substituted and selected from a pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, furopyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinolone, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, or benzoxazole; and said heterocyclyl group for R 4 is optionally substituted and selected from a tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

3. The compound of claim 1 , wherein said heterocyclic group for the R 4 substituents is optionally substituted and selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine, piperazine, furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole.

4. The compound of claim 1 , wherein said heteroaryl group for R 5 is optionally substituted and selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, and wherein said heterocyclyl group for R 5 is optionally substituted and selected from oxetane, tetrahydrofuran, or tetrahydropyran.

5. The compound of claim 1 , wherein Ring C is optionally substituted C 4-6 cycloalkyl or optionally substituted 5-6 membered heteroaryl.

6. The compound of claim 1 , wherein X is —O— or —NH—.

7. The compound of claim 1 , wherein

B is optionally substituted and selected from

8. The compound of claim 1 , wherein each R 3 independently is hydrogen, —C 1-4 alkyl, halogen, —OC 1-2 alkyl, —CN, —C 3-4 cycloalkyl, or —NRR′, wherein each of said R 3 alkyl and cycloalkyl independently is optionally substituted.

9. The compound of claim 1 , wherein
each R 4 independently is hydrogen or an optionally substituted group selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, or phenyl.

10. The compound of claim 1 , wherein each R 4 independently is an optionally substituted group selected from a pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, furopyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinolone, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, benzoxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

11. The compound of claim 1 , wherein each R 4 independently is an optionally substituted group selected from imidazole, pyrazole, pyrimidine, furopyrimidine, oxetane or dihydrofuropyrimidine.

12. The compound of claim 1 , wherein each R 4 independently is hydrogen or an optionally substituted group selected from C 1-4 alkyl,

or a ring group selected from C 3-5 cycloalkyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, tetrahydrof

Assignees

• Vertex Pharma

Inventors

• Maxwell John Patrick
• Jackson Katrina Lee
• Tang Qing
• Morris Mark A
• Ronkin Steven M
• Xu Jinwang
• Cottrell Kevin M
• Charifson Paul S

Classifications

• C07D491/048 Primary

  the oxygen-containing ring being five-membered · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/94

  Nitrogen atoms · CPC title