# US 10,501,439 B2 · DNA-PK inhibitors

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- Number: US 10,501,439 B2
- Document ID: US10501439B2
- Status: Granted
- Kind: B2
- Application number: 15/912,074
- Filed: 2018-03-05
- Published: 2018-07-12
- Granted: 2019-12-10
- Earliest claimed: 2012-04-24
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Vertex Pharmaceuticals Incorporated
- Inventors: Paul S. Charifson; Kevin Michael Cottrell; Hongbo Deng; John P. Duffy; Huai Gao; Simon Giroux; Jeremy Green; Katrina Lee Jackson; Joseph M. Kennedy; David J. Lauffer; Mark Willem Ledeboer; Pan Li; John Patrick Maxwell; Mark A. Morris; Albert Charles Pierce; Nathan D. Waal; Jinwang Xu
- Web page: https://patentgrep.com/patent/US10501439B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 495/04: Ortho-condensed systems
- C07D 521/00: Heterocyclic compounds containing unspecified hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

A method of potentiating a therapeutic regimen for the treatment of breast cancer, colorectal cancer, gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellular cancer, head and neck cancer, melanoma, lung cancer, pancreatic cancer, or prostate cancer in a patient comprising administering to said patient an effective amount of a compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
Q is N or CH;
R1 is hydrogen, CH3, or CH2CH3, or R1 and the carbon to which it is bound form a C═CH2 group;
Ring A is a ring system selected from
RA1 is hydrogen, halogen, C1-4 alkyl, C0-4 alkyl-C3-6cycloalkyl, C0-4 alkyl-ORA1a, C0-4 alkyl-SRA1a, C0-4 alkyl-C(O)N(RA1a)2, C0-4 alkyl-CN, C0-4 alkyl-S(O)—C1-4 alkyl, C0-4 alkyl-S(O)2—C1-4 alkyl, C0-4 alkyl-C(O)ORA1b, C0-4 alkyl-C(O)C1-4 alkyl, C0-4 alkyl-N(RA1b)C(O)RA1a, C0-4 alkyl-N(RA1b)S(O)2RA1a, C0-4 alkyl-N(RA1a)2, C0-4 alkyl-N(RA1b)(3-6 membered-cycloalkyl), C0-4 alkyl-N(RA1b)(4-6 membered-heterocyclyl), N(RA1b)C2-4 alkyl-N(RA1a)2, N(RA1b)C2-4 alkyl-ORA1a, N(RA1b)C1-4 alkyl-(5-10 membered heteroaryl), N(RA1b)C1-4 alkyl-(4-6 membered heterocyclyl), N(RA1b)C2-4 alkyl-N(RA1b)C(O)RA1a, C0-4 alkyl-N(RA1b)C(O)C1-4 alkyl, C0-4 alkyl-N(RA1b)C(O)OC1-4 alkyl, C0-4 alkyl-(phenyl), C0-4 alkyl-(3-10 membered-heterocyclyl), C0-4 alkyl-C(O)-(4-6 membered-heterocyclyl), C0-4 alkyl-O—C0-4 alkyl-(4-6 membered-heterocyclyl), C0-4 alkyl-(5-6 membered-heteroaryl), C0-4 alkyl-C(O)-(5-6 membered-heteroaryl), C0-4 alkyl-O—C0-4 alkyl-(5-6 membered-heteroaryl), C0-4 alkyl-N(RA1a)(4-6 membered-heterocyclyl), or C0-4 alkyl-N(RA1b)(5-6 membered-heteroaryl), wherein each of said RA1 heterocyclyl is a ring system selected from aziridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, tetrahydrothiophenedioxidyl, 1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.4]octanyl, and isoindolinonyl wherein each of said RA1 heteroaryl is a ring system selected from furanyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, and tetrazolyl, and wherein each of said RA1 alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to three 2H atoms, up to two C1-2 alkyl groups, a C3-6cycloalkyl group, a phenyl group, a benzyl group, an alkenyl-C0-2 alkyl group, an alkynyl-C0-2 alkyl group, up to two C0-2 alkyl-ORA1b groups, a C0-2 alkyl-N(RA1b)2 group, a SC1-4 alkyl group, a S(O)2C1-4 alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, a —CN group, or a C4-6heterocyclic ring system selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl;
each RA1a is, independently, hydrogen, C1-4 alkyl, C3-6cycloalkyl, C4-6heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two RA1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl, wherein each of said RA1a alkyl, cycloalkyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to two C1-2 alkyl groups, a C3-6cycloalkyl group, up to two C0-2 alkyl-ORA1b groups, a C0-2 alkyl-N(RA1b)2 group, a SC1-4 alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, or a —CN group;
each RA1b is, independently, hydrogen, C1-2 alkyl, or C3-4cycloalkyl;
RA2 is hydrogen, C1-4 alkyl, C0-4 alkyl-C3-6cycloalkyl, C0-2 alkyl-(4-6 membered)heterocyclyl, C2-4 alkyl-ORA2a, C0-2 alkyl-C(O)N(RA2a)2, C0-2 alkyl-S(O)2—C1-4 alkyl, C0-2 alkyl-C(O)OC1-4 alkyl, or C0-2 alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of said heterocyclyl is selected from oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, and 1,1-dioxothietanyl, and each of said RA2 groups except hydrogen is optionally substituted with up to three F atoms, up to two C1-2 alkyl groups, a C3-6cycloalkyl group, an alkenyl-C0-2 alkyl group, an alkynyl-C0-2 alkyl group, up to two ORA2b groups, a C0-2 alkyl-N(RA2b)2 group, a SC1-4 alkyl group, a S(O)2C1-4 alkyl group, a C(O)RA2b group, a C(O)ORA2b group, a C(O)N(RA2b)2 group, or a —CN group;
each RA2a is, independently, hydrogen, C1-4 alkyl, a C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, eo and pyrazinyl, or two RA2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl;
each RA2b is, independently, hydrogen, C1-4 alkyl, or C3-4cycloalkyl;
RA3 is hydrogen or C1-2 alkyl;
each RA4 is, independently, deuterium, halogen, CN, C1-4 alkyl, or OC1-4 alkyl, wherein each RA4 alkyl is optionally substituted with up to 3 F atoms, up to three 2H atoms, two non-geminal OH groups, or one OC1-2 alkyl, or two RA4 together with an intervening saturated carbon atom form a spiro-linked cyclopropyl or cyclobutyl ring;
n is 0-3;
Ring B is a ring system selected from
RB1 is hydrogen, C1-4 alkyl, (CH2)0-1C3-6cycloalkyl, C(O)C1-2 alkyl, (CH2)0-1-(4-6 membered)heterocyclyl ring wherein said heterocyclic ring is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, and pyrrolidinonyl, phenyl, benzyl, or (CH2)1-2(5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, and pyrazolyl, and wherein each of said RB1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl and heteroaryl groups is optionally substituted with up to 3 F atoms, up to two C1-2 alkyl groups, two non-geminal OH groups, or one OC1-2 alkyl;
RB2 is hydrogen, C1-4 alkyl, or OC1-4 alkyl;
each RB3 is, independently, hydrogen, deuterium, halogen, C1-4 alkyl, C2-4alkenyl, C2-4alkynyl, CN, C(O)H, C(O)C1-4 alkyl, C(O)OC1-4 alkyl, C(O)C1-4 alkyl, C(O)NH2, C(O)NHC1-4 alkyl, C(O)NH(CH2)0-1C3-6cycloalkyl, C(O)NHCH2oxetanyl, C(O)NHCH2tetrahydrofuranyl, C(O)NHCH2tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC1-4alkyl, C(O)NHO(CH2)0-1C3-6cycloalkyl, C(O)NHO(CH2)0-1oxetanyl, C(O)NHO(CH2)0-1tetrahydrofuranyl, C(O)NHO(CH2)0-1tetrahydropyranyl, C(O)NHOphenyl, C(O)NHObenzyl, NH2, NHC(O)C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, S(O)C1-4 alkyl, or a 5-membered-heteroaryl ring system selected from furanyl, thiophenyl, imidazolyl, pyrrole, pyrazolyl, and oxadiazolyl, wherein each RB3 group except hydrogen or halogen is optionally substituted with Cl, up to three F atoms, up to three 2H atoms, up to two non-geminal OH groups, up to two OC1-2 alkyl, one NH2, one NHC1-2 alkyl, one NHC(O)C1-4 alkyl, or one N(C1-2 alkyl)2;
each RB4 is, independently, hydrogen, deuterium, halogen, C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(O)C1-4 alkyl, C(O)OH, C(O)OC1-4 alkyl, C(O)NH2, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, CN, a morpholinyl ring, or an imidazolyl ring, wherein each RB4 alkyl is optionally substituted with up to 3 F atoms, up to three 2H atoms, two non-geminal OH groups, or one OC1-2 alkyl;
RB5 is hydrogen, C1-4 alkyl, C(O)C1-4 alkyl, C(O)OC1-4 alkyl, C(O)NH2, C(O)NHC1-4 alkyl, or C(O)N(C1-4 alkyl)2, wherein said RB5 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2 alkyl and
RB6 is F or C1-2 alkyl, or two RB6 and an intervening carbon atom form a spiro-linked cyclopropyl or cyclobutyl ring.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is represented by Structural Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
X is N or CRA5;
RA1 is F, C1-4 alkyl, C3-5cycloalkyl, OC1-4 alkyl, OC1-4 alkyl-C3-5cycloalkyl, NH2, NHC1-4 alkyl, NHC0-4 alkyl-C3-5cycloalkyl, or C0-4 alkyl-heterocyclyl, wherein said heterocyclic ring system is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and each of said alkyl, cycloalkyl, and heterocyclyl is optionally substituted with up to three F atoms, up to three 2H atoms, up to two non-geminal OH groups, or up to two OC1-2 alkyl;
each RA4 is, independently, H or 2H;
RA5 is hydrogen, F, C1-4 alkyl, or OC1-4 alkyl, wherein each of said alkyl is optionally substituted with up to three F atoms or up to three 2H atoms;
RB3 is C(O)NHC1-4 alkyl, wherein said alkyl is optionally substituted with up to three F atoms, up to three 2H atoms, up to two non-geminal OH groups, or up to two OC1-2 alkyl; and
each RB4 is, independently, hydrogen, deuterium, F, or C1-4 alkyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the therapeutic regimen comprises radiation therapy or an anticancer chemotherapeutic agent.

### Claim 13 (depends on 12)

The method of claim 12, wherein the therapeutic regimen comprises radiation therapy.

### Claim 14 (depends on 12)

The method of claim 12, wherein the therapeutic regimen comprises an anti-cancer therapeutic agent.

### Claim 15 (depends on 4)

The method of claim 4, wherein the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, is orally administered to the patient.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, is comprised in a capsule, tablet, or aqueous suspension.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, is comprised in a capsule.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, is comprised in a tablet.