# US 12,005,127 B2 · DNA-PK inhibitors

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- Number: US 12,005,127 B2
- Document ID: US12005127B2
- Status: Granted
- Kind: B2
- Application number: 16/962,442
- Filed: 2019-01-16
- Published: 2020-11-12
- Granted: 2024-06-11
- Earliest claimed: 2018-01-17
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Vertex Pharmaceuticals Incorporated
- Inventors: John Patrick Maxwell; Katrina Lee Jackson; Qing Tang; Mark A. Morris; Steven M. Ronkin; Jinwang Xu; Kevin M. Cottrell; Paul S. Charifson
- Web page: https://patentgrep.com/patent/US12005127B2

## CPC

- A61K 48/0066: {Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 35/00: Antineoplastic agents
- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- C07D 239/86: with hetero atoms directly attached in position 4
- C07D 239/88: Oxygen atoms
- C07D 239/94: Nitrogen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 491/048: the oxygen-containing ring being five-membered
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 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 C1-4alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH, and —OC1-2alkyl;
Ring C is a C4-6 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, C1-2 alkyl, —OH, and —OC1-2alkyl;
X is —NH—, —O—, —OC1-4 alkyl-, —S—, or —CH2—;
each of R1 and R2 is, independently, hydrogen, —C(O)NHR4, —C(O)OR4, —NHC(O)R4,
—NHC(O)OR4, —NHC(O)NHR4, —NHS(O)2R4, —NHR4, —C1-4 alkyl-NHR4, —OR4, or R7 wherein R1 and R2 cannot simultaneously be hydrogen;
each R3 independently is hydrogen, —C1-4alkyl,
halogen, —OC1-2alkyl, —C(O)OH, —C(O)OC1-2alkyl, —CN, —C(O)NHC1-2alkyl, —C(O)NH2, C3-4 cycloalkyl, or —NRR′, wherein each of said R3 alkyl and cycloalkyl independently is optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH and —OC1-2alkyl;
each R4 independently is hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 5-10-membered heteroaryl, or 4-10-membered heterocyclyl, wherein each of said R4 groups is optionally and independently substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, C1-4alkyl, CN, NO2, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, C0-4 alkyl-C3-5 cycloalkyl, C0-4 alkyl-O—C1-4 alkyl, C0-4 alkyl-O—C0-4 alkyl-C3-5 cycloalkyl, C(O)OC1-4 alkyl, C(O)OC0-4 alkyl-C3-5 cycloalkyl, C0-4 alkyl-C(O)NH2, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, C(O)NH(Co1-4 alkyl-C3-5 cycloalkyl), CH2OR5, C0-4 alkyl-C(O)R5, C0-4 alkyl-C(O)N(R5)2, C0-4 alkyl-C(O)OR5, C0-4 alkyl-NHC(O)R5, C0-4 alkyl-N(R5)2, 5-6 membered heterocyclyl, —O(C1-4 alkyl)OR5, —OR5, and oxo, and wherein each of said optional R4 substituents is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C1-4alkyl, —OH, —OC1-4alkyl, —SC1-4alkyl, —C(O)C1-4 alkyl, —C(O)OC1-4 alkyl, and —C(O)OC0-4 alkyl-C3-5 cycloalkyl; and
each R5 independently is hydrogen, C1-4alkyl, phenyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclyl, wherein each R5 is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C1-2alkyl, —CH2OH,
—CN, —OH, —OC1-2alkyl, 5-6-membered heteroaryl, and 4-7 membered heterocyclyl, or two R5 groups together with the intervening nitrogen atom optionally form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring; and
R6 is hydrogen or C1-4alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —CH2OH, —CN, —OH, and —OC1-2alkyl;
R7 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,
C1-2alkyl, —CH2OH, —CN, and —OR; and
each of R and R′ independently is hydrogen or C1-4alkyl, 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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein said aryl group for R4 is optionally substituted and selected from phenyl or naphthalene; the heteroaryl group for R4 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 R4 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.

### Claim 3 (depends on 1)

The compound of claim 1, wherein said heterocyclic group for the R4 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.

### Claim 4 (depends on 1)

The compound of claim 1, wherein said heteroaryl group for R5 is optionally substituted and selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, and wherein said heterocyclyl group for R5 is optionally substituted and selected from oxetane, tetrahydrofuran, or tetrahydropyran.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Ring C is optionally substituted C4-6 cycloalkyl or optionally substituted 5-6 membered heteroaryl.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The compound of claim 1, wherein
B is optionally substituted and selected from

### Claim 8 (depends on 1)

The compound of claim 1, wherein each R3 independently is hydrogen, —C1-4alkyl, halogen, —OC1-2alkyl, —CN, —C3-4 cycloalkyl, or —NRR′, wherein each of said R3 alkyl and cycloalkyl independently is optionally substituted.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
each R4 independently is hydrogen or an optionally substituted group selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-5cycloalkyl, or phenyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein each R4 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.

### Claim 11 (depends on 1)

The compound of claim 1, wherein each R4 independently is an optionally substituted group selected from imidazole, pyrazole, pyrimidine, furopyrimidine, oxetane or dihydrofuropyrimidine.

### Claim 12 (depends on 1)

The compound of claim 1, wherein each R4 independently is hydrogen or an optionally substituted group selected from C1-4 alkyl,
or a ring group selected from C3-5 cycloalkyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, or phenyl, wherein
X1 is Nor CR4d;
X2 is N or CR4c, wherein X1 and X2 cannot simultaneously be N;
each of R4a, R4b, and R4c independently is hydrogen, F, Cl, Br, CN, NO2, C1-4 alkyl,
C0-4 alkyl-C3-5 cycloalkyl, C0-4 alkyl-O—C1-4 alkyl, C0-4 alkyl-O—C0-4 alkyl-C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C(O)OC1-4 alkyl, C(O)OC0-4 alkyl-C3-5 cycloalkyl, C(O)NH2, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, C(O)NH(C0-4 alkyl-C3-5 cycloalkyl), a heterocyclic group selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, or piperazine, or a heteroaryl group selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, or tetrazole; or R4c and R4a, or R4c and R4b, together with the intervening atoms, optionally form a dihydrofuran, dihydropyran, or tetrahydropiperidine heterocyclic ring group;
R4d independently is hydrogen, F, Cl, Br, CN, NO2, C1-4 alkyl, C0-4 alkyl-O—C1-4 alkyl,
C2-4 alkenyl, C2-4 alkynyl, C(O)OC1-4 alkyl, C(O)NH2, C(O)NHC1-4 alkyl, or C(O)N(C1-4 alkyl)2;
wherein each of the R4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, NO2, C1-4 alkyl, C0-4 alkyl-C3-5 cycloalkyl, C0-4 alkyl-O—C1-4 alkyl, C0-4 alkyl-O—C0-4 alkyl-C3-5 cycloalkyl,
C2-4 alkenyl, C2-4 alkynyl, C(O)OC1-4 alkyl, C(O)OC0-4 alkyl-C3-5 cycloalkyl, C(O)NH2, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, C(O)NH(C0-4 alkyl-C3-5 cycloalkyl), a heterocyclic group selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, or piperazine, and a heteroaryl group selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, or tetrazole;
each of said heterocyclic and heteroaryl groups for R4a, R4b and R4c, and for the substituents of R4 is optionally and independently substituted with one or more substituents selected from the group consisting of —F, C1-4 alkyl, —OH, —C(O)C1-4 alkyl, —C(O)OC1-4 alkyl, or —C(O)OC0-4 alkyl-C3-5 cycloalkyl; and wherein each of said alkyl and cycloalkyl groups for R4a, R4b and R4c, and for the substituents of R4 is optionally and independently substituted with one or more substituents selected from the group consisting of —F and —OH.

### Claim 13 (depends on 1)

The compound of claim 1, wherein each R4 independently is C1-4 alkyl or a ring group selected from C3-5 cycloalkyl, pyrazole, imidazole, oxetane,
wherein said R4 C1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, and —O(C1-4 alkyl), and wherein each of said R4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, C1-4alkyl, —CN, —O(C1-4 alkyl), C3-6cycloalkyl, C0-4 alkyl-O—C1-4 alkyl, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, and a piperazine, wherein each of said optional R4 substituents is optionally and independently substituted with one or more substitutents selected from the group consisting of —F, C1-4alkyl, —OH, and —OC1-4alkyl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein said R4 C1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F and —O(C1-4 alkyl), and wherein each of said R4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of C1-4alkyl, —O(C1-4 alkyl), C0-4 alkyl-O—C1-4 alkyl, C(O)NHC1-4 alkyl, C(O)N(C1-4 alkyl)2, and a piperazine, wherein each of said optional R4 substituents is optionally substituted with one or more C1-4alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein each of R1 and R2 independently is hydrogen, —C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —C0-4 alkyl-NHR4, —OR4, or R7.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R7 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, benzoxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

### Claim 17 (depends on 16)

The compound of claim 16, wherein R7 is optionally substituted and selected from a pyrimidine, imidazole, pyrazole, thiazole, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, benzoxazole, oxetane, dihydrofuropyrimidine, or isoindoline-1,3-dione.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R7 is optionally substituted and selected from a pyrimidine, pyrazole, furopyrimidine, thiazole, or isoindoline-1,3-dione.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

The compound of claim 1, wherein Ring C is optionally substituted C4-6 cycloalkyl.

### Claim 21 (depends on 20)

The compound of claim 20, wherein Ring C is optionally substituted cyclohexane.

### Claim 22 (depends on 1)

The compound of claim 1, represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein
R1 is —C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —NHC(O)NHR4, —NHS(O)2R4, —C0-4 alkyl-NHR4, —OR4, or R7; and
R2 is hydrogen.

### Claim 23 (depends on 1)

The compound of claim 1, represented by the following formula:
(III-B-1), or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The compound of claim 23, wherein each R1 independently is
—C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —C1-4 alkyl-NHR4, —NHR4, —OR4, or R7.

### Claim 25 (depends on 24)

The compound of claim 24, wherein R1 is —C1-4 alkyl-NHR4, —NHR4, or —OR4.

### Claim 26 (depends on 1)

The compound of claim 1, represented by following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 26)

The compound of claim 26, wherein each R1 independently is
—C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —C0-4 alkyl-NHR4, —OR4, or R7.

### Claim 28 (depends on 1)

The compound of claim 1, wherein
each R3 independently is hydrogen, methyl, —Cl, —OCH3, —CN, cyclopropyl, —NHCH3, or —N(CH3)2; and
R6 is hydrogen or methyl.

### Claim 29 (depends on 1)

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

### Claim 30 (depends on 1)

The compound of claim 1, wherein
is optionally substituted

### Claim 31 (depends on 1)

The compound of claim 1, wherein Ring C is optionally substituted phenyl.

### Claim 32 (depends on 1)

The compound of claim 1, wherein X is —OC1-4 alkyl-.

### Claim 33 (depends on 32)

The compound of claim 32, represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, —C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —NHC(O)NHR4, —NHS(O)2R4, —C0-4 alkyl-NHR4, —OR4, or R7.

### Claim 34 (depends on 31)

The compound of claim 31, wherein
is optionally substituted

### Claim 35 (depends on 31)

The compound of claim 31, represented by the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 35)

The compound of claim 35, wherein
R3 is hydrogen, methyl, cyclopropyl, —F, —Cl, —OC1-2alkyl, —NRR′, or —CN, wherein each of said R3 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and —O(C1-2 alkyl);
each R4 independently is optionally substituted C1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and —O(C1-2 alkyl);
R and R′ are each and independently hydrogen or C1-2 alkyl.

### Claim 37 (depends on 36)

The compound of claim 36, wherein
each R3 independently is hydrogen, methyl, —Cl, —OCH3, —CN, cyclopropyl, —NHCH3, or —N(CH3)2; and
R6 is hydrogen or methyl.

### Claim 38

A compound selected from the list of compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 1)

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

### Claim 40 (depends on 1)

A method of sensitizing a cell to a therapeutic agent or a disease state that induces a DNA lesion comprising the step of contacting the cell with the compound of claim 1, or a pharmaceutical composition comprising said compound.

### Claim 41 (depends on 1)

A method of potentiating a therapeutic regimen for the treatment of cancer in a patient comprising the step of administering to said patient an effective amount of the compound of claim 1, or a pharmaceutical composition comprising said compound.

### Claim 42 (depends on 1)

A method of treating cancer or inhibiting cancer cell growth in a patient comprising administering to said patient an effective amount of the compound of claim 1, or a pharmaceutical composition comprising said compound, either alone or in combination with one or more additional therapeutic agent.

### Claim 43 (depends on 1)

A method of preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the method comprises:
reacting Compound (X-1) with Compound (Y-1) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
L1 of Compound (X-1) is a halogen, toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, and the other variables of Compound (X-1) are each and independently as described in claim 1; and
Compound (Y-1) is
wherein Ra is —H or two Ra, together with the oxygen atom to which they are attached, form a dioxane ring optionally substituted with one or more C1-2 alkyl.

### Claim 44 (depends on 1)

A method of preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —NHC(O)R4, —NHC(O)OR4, —NHC(O)NHR4, —NHS(O)2R4, —NHR4, or —OR4; and the other variables of Formula (I) are each and independently as described in claim 1; and wherein the method comprises:
reacting Compound (X-2) with Compound (Y-2) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:
Q1 of Compound (X-2) is —NH2 or —OH, and the other variables of Compound (X-2) are each and independently as described in claim 1; and
Compound (Y-2) is R4—C(O)-L2, R4—O—C(O)-L2, NHR4—C(O)-L2, R4S(O)2-L2, R4-L2, R4C(O)ORb, or R4—N═C═O, wherein each R4 is as described in claim 1, L2 is a halogen, toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, and Rb is C1-4 alkyl.

### Claim 45 (depends on 1)

A method of preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —NH— or —O—, and the other variables of Formula (I) are each and independently as described in claim 1, and wherein the method comprises:
(i) reacting Compound (X-3) with Compound (Y-3) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:
or
(ii) reacting Compound X-4 with Compound Y-4 to form a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein L3 is a halogen; L4 is a halogen, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate, and wherein the variables of each of Compounds (X-3), (X-4), (Y-3), and (Y-4) are each and independently as described in claim 1.

### Claim 46 (depends on 1)

A method of preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is —C(O)NHR4, —C(O)OR4, —NHC(O)R4, —NHC(O)OR4, —NHC(O)NHR4, —NHS(O)2R4, —NHR4,
—C1-4 alkyl-NHR4, —OR4, or R7; R2 is hydrogen; each of R4 independently is 5-10 membered heteroaryl substituted with —OR5; R7 independently is 5-10 membered heteroaryl substituted with —OR; R, R5, and the other variables of formula (I) are each and independently as described in claim 1, provided that both R and R5 are not hydrogen, and wherein the method comprises:
reacting Compound (X-5) with R5OH or ROH to form a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
Q2 is a bond, —C(O)NH—, —C(O)O—, —NHC(O)—, —NHC(O)O—, —NHC(O)NH—, —NHS(O)2—, —NH—, —C1-4 alkyl-NH—, or —O—,
Ring D is 5-10-membered heteroaryl;
L5 is a halogen; and
R of ROH, R5 of R5OH, and the other variables of Compound (X-5) are each and independently as described in claim 1, provided that both R and R5 are not hydrogen.

### Claim 47 (depends on 1)

A method of preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —O—, and the other variables of Formula (I) are each and independently as described in claim 1, and wherein the method comprises:
wherein L6 is —OH; L7 is —OH; and the remaining variables of each of Compounds (X-6), and (Y-6) are each and independently as described in claim 1.

### Claim 48 (depends on 1)

A kit or composition for editing one or more target genomic regions, comprising:
a genome editing system; and
a compound of claim 1 or a pharmaceutically acceptable salt thereof.