# US 2023/0055040 A1 · Synthesis Of Benzodiazepine Derivatives

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- Number: US 2023/0055040 A1
- Document ID: US20230055040A1
- Status: Published application
- Kind: A1
- Application number: 17/818,517
- Filed: 2022-08-09
- Published: 2023-02-23
- Earliest claimed: 2015-08-07
- Assignees: Trio Medicines Ltd
- Applicants: Trio Medicines Limited
- Inventors: Malcolm James Boyce; Liv Thomsen; Donald Alan Gilbert; David Wood
- Web page: https://patentgrep.com/patent/US20230055040A1

## CPC

- C07D 243/26: Preparation from compounds already containing the benzodiazepine skeleton
- C07C 259/10: having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
- C07C 271/28: to a carbon atom of a non-condensed six-membered aromatic ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to processes for the synthesis of benzodiazepine derivatives of Formula I: (I)

## Claims

### Claim 1

A process for producing a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R1 is:
—CH2C(O)C(R2)(R3)-L-R4 or —CH2CHOHC(R2)(R3)-L-R4, (i)
in which:
R2 and R3 are each, independently, H or C1-3 aliphatic, halo, or C1-3 haloaliphatic, or wherein R2 and R3 together with the intervening carbon atom to which they are bonded, form a C3-6 carbocyclic moiety;
L is a bond or C1-3 alkylene; and
R4 is —OR5 or —SR5, wherein R5 is hydrogen, optionally substituted alkyl, a protecting group or —C(O)R6, wherein R6 is optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
W and X are, independently, hydrogen, halo, C1-8 alkyl or C1-8 alkoxy; and
rings A and B are each, independently, a monocyclic aryl or heteroaryl, optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, nitro, carboxyl, carboxamido, cyano, —SO3H, and optionally substituted C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino or di(C1-8 alkyl)amino,
wherein any one or more substituent on R1, ring A or ring B may be unprotected or in a protected form;
wherein the process comprises:
providing a reaction mixture by adding a compound of formula (I-A), a compound of formula (I-B) and a phosgene synthetic equivalent or phosgene to an aprotic solvent, to form a compound of formula (I)
wherein the phosgene synthetic equivalent is carbonyldiimidazole (CDI), diphosgene, triphosgene, a chloroformate or disuccinimidyl carbonate.

### Claim 2

(canceled)

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The process of claim 1, wherein the phosgene synthetic equivalent or phosgene is carbonyldiimidazole.

### Claim 5 (depends on 1)

The process of claim 1, wherein the process comprises the additional step of deprotection to remove one or more protecting groups, wherein any one or more substituents on R1, ring A or ring B is in a protected form.

### Claim 6 (depends on 1)

The process of claim 1, wherein the process comprises step (a) of providing a reaction mixture by adding a compound of formula (I-A), a compound of formula (I-B) and a phosgene synthetic equivalent or phosgene to an aprotic solvent, to form a compound of formula (I), wherein the compound of formula (I-A) and the phosgene synthetic equivalent or phosgene are added to the solvent prior to addition of the compound of formula (I-B).

### Claim 7 (depends on 1)

The process of claim 1, wherein the aprotic solvent is ethyl acetate, dichloromethane, acetonitrile or toluene.

### Claim 8 (depends on 1)

The process of claim 1, wherein R1 is —CH2C(O)C(R2)(R3)-L-R4.

### Claim 9 (depends on 1)

The process of claim 1, wherein:
(a) at least one of ring A and ring B is unsubstituted or substituted phenyl or pyridyl; and/or
(b) W and X are, independently H, halo, C,1-3 alkyl or C1-3 alkoxy.

### Claim 10 (depends on 1)

The process of claim 1, wherein:
(a) at least one of ring A and ring B is unsubstituted, monosubstituted or disubstituted phenyl or unsubstituted, monosubstituted or disubstituted 2-, 3- or 4-pyridyl: and/or
(b) W and X are both H.

### Claim 11 (depends on 1)

The process of claim 1, wherein ring A is phenyl having a meta substituent chosen from NHMe, NMeEt, NEt2, F, Cl, Br, OH, OCH3, NH2, NMe2, NO2, Me, (CH2)n—CO2H, CN, CH2NMe2, NHCHO and (CH2)n—SO3H where n is 0-2; unsubstituted phenyl or 2-, 3- or 4-pyridyl optionally with a substituent selected from F, Cl, CH3 and CO2H; and Ring B is 2-, 3- or 4-pyridyl or phenyl.

### Claim 12 (depends on 1)

The process of claim 1, wherein the compound of formula (I) is a compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, L and R4 are as defined in claim 1, the compound of formula (I-A) is a compound of formula (II-A), and the compound of formula (I-B) is a compound of formula (II-B)
wherein PG is a protecting group, optionally a Boc protecting group.

### Claim 13 (depends on 1)

The process of claim 1 any preceding claim, wherein R2 and R3 together with the intervening carbon atom to which they are bonded, form a C3-4 carbocyclic moiety, or wherein R2 and R3 are each, independently, H or C1-2 alkyl; and L is a bond or C1-3 alkylene.

### Claim 14 (depends on 1)

The process of claim 1, wherein R2 and R3 are each, independently, C1-2 alkyl and L is —CH2—.

### Claim 15 (depends on 1)

The process of claim 1, wherein R1 is —CH2C(O)C(R2)(R3)-L-R4, R4 is —OR5 or —SR5, R5 is hydrogen, methyl or —C(O)R6, and R6 is optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety.

### Claim 16 (depends on 1)

The process of claim 1, wherein R6 is substituted or unsubstituted C1-6 aliphatic.

### Claim 17 (depends on 1)

The process of claim 1, wherein R6 is methyl.

### Claim 18 (depends on 1)

The process of claim 1, wherein R4 is —OR5 and R5 is —C(O)R6.

### Claim 19 (depends on 1)

The process of claim 1, wherein the compound of formula (I) or (II) is a compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The process of claim 19, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

The process of claim 1, wherein the compound of formula (I) or (II) is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein R11 is selected from

### Claim 22 (depends on 21)

The process of claim 21, wherein the compound is a compound of formula (IV):
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The process of claim 1, wherein the compound of formula (I) or (II) is a compound (TR) or (TR-A):
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The process of claim 23, wherein the compound is a compound (TR2) or (TR2-A):
or a pharmaceutically acceptable salt thereof.

### Claim 25

(canceled)

### Claim 26 (depends on 1)

A process according to claim 1 for producing a compound of formula (TR2-A):
wherein the process comprises:
(a) providing a reaction mixture by adding a compound of formula (II-A), a compound of formula (II-Ba) and a phosgene synthetic equivalent or phosgene to an aprotic solvent, to form a compound of formula (TR2-A-PG)
wherein PG is a protecting group, optionally a Boc protecting group; and
(b) deprotecting the compound of formula (TR2-A-PG) to form a compound of formula (TR2-A).

### Claim at position 27

27-29. (canceled)