# US 10,308,627 B2 · Benzodiazepine derivatives as CCK2/gastrin receptor antagonists

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- Number: US 10,308,627 B2
- Document ID: US10308627B2
- Status: Granted
- Kind: B2
- Application number: 15/502,490
- Filed: 2015-08-07
- Published: 2018-08-02
- Granted: 2019-06-04
- Earliest claimed: 2014-08-08
- Assignees: Trio Medicines Ltd
- Applicants: Trio Medicines Ltd
- Inventors: Malcolm James Boyce; Liv Thomsen; Donald Alan Gilbert; David Wood
- Web page: https://patentgrep.com/patent/US10308627B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to benzodiazepine derivatives of formula (A) useful as CCK2/gastrin receptor antagonists, their preparation and their use in the treatment or prevention of disorders associated with CCK2/gastrin receptors, disorders caused by or associated with hypergastrinaemia, and gastric acid-related disorders.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound of formula (A):
or a pharmaceutically acceptable salt thereof,
wherein, R1 and R2 are each, independently, H or C1-3 aliphatic, halo, or C1-3 haloaliphatic, or wherein R1 and R2 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;
R3 is —OR6 or —SR6;
W and X are, independently, hydrogen, halo, C1-8 alkyl or C1-8 alkoxy; and
R4 and R5 are both, 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 alkyl)amino;
R6 is hydrogen, —C(O)R, alkyl, —P(O)(OH)2, —P(O)(O(C1-6)alkyl)2, an alkylcarbonyloxyalkyl, (C1-6)alkoxycarbonylaminomethyl, succinoyl, or a α-aminoalkylcarbonyl;
R is an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety;
and optionally one or more pharmaceutically acceptable excipient(s).

### Claim 2 (depends on 1)

The composition of claim 1, wherein at least one of R4 and R5 is unsubstituted or substituted phenyl or pyridyl.

### Claim 3 (depends on 1)

The composition of claim 1, wherein at least one of R4 and R5 is unsubstituted, monosubstituted or disubstituted phenyl or unsubstituted, monosubstituted or disubstituted 2-, 3- or 4-pyridyl.

### Claim 4 (depends on 1)

The composition of claim 1, wherein R5 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 R4 is 2-, 3- or 4-pyridyl or phenyl.

### Claim 5 (depends on 1)

The composition of claim 1, wherein W and X are both H.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the compound of formula (A) is a compound of formula (B):
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The composition of claim 1, wherein R1 and R2 are each, independently, C1-2 alkyl, L is C1-3 alkylene and R3 is —OH.

### Claim 8 (depends on 1)

The composition of claim 1, wherein R3 is —OR6, —SR6, —OC(O)R7 or SC(O)R7, R6 is hydrogen or alkyl, and R7 is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt, ester, thioester, salt of an ester or thioester, or prodrug thereof;
wherein an ester is a compound in which the H of —OH is replaced by a moiety —C(O)R, wherein R is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
wherein a thioester is a compound in which the H of —SH is replaced by a moiety —C(O)R, wherein R is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; and
wherein a prodrug is a compound in which the H of —OH or H of —SH is replaced by —P(O)(OH)2, —P(O)(O(C1-6)alkyl)2, an alkylcarbonyloxyalkyl, (C1-6)alkoxycarbonylaminomethyl, succinoyl, or a α-aminoalkylcarbonyl.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the compound is a compound (TR):
or a pharmaceutically acceptable salt, ester, salt of an ester, or prodrug thereof;
wherein an ester is a compound in which the H of —OH is replaced by a moiety —C(O)R, wherein R is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; and
wherein a prodrug is a compound in which the H of —OH is replaced by —P(O)(OH)2, —P(O)(O(C1-6)alkyl)2, an alkylcarbonyloxyalkyl, (C1-6)alkoxycarbonylaminomethyl, succinoyl, or a α-aminoalkylcarbonyl.

### Claim 11 (depends on 10)

The composition of claim 10, wherein (TR) is provided as a racemic mixture of enantiomers (TR2) and (TR3), a non-racemic mixture of enantiomers (TR2) and (TR3), or as a single enantiomer (TR2) or (TR3) in optically pure form

### Claim 12 (depends on 11)

The composition of claim 11, wherein the compound (TR) is a compound (TR2)
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the compound is a compound of formula (C)
or a pharmaceutically acceptable salt thereof,
wherein:
Y is —O— or —S—; and
R7 is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety.

### Claim 14 (depends on 13)

The composition of claim 13, wherein the compound of formula (C) is a compound (TR-A):
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the compound (TR-A) is a compound (TR2-A)
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the composition is provided as an oral, sublingual, or parenteral dosage form.

### Claim 17 (depends on 1)

The composition of claim 1, further comprising an additional active agent.

### Claim 18

A compound of formula (C)
or a pharmaceutically acceptable salt thereof,
wherein, R1 and R2 are each, independently, H, C1-3 aliphatic, halo, or C1-3 haloaliphatic, or wherein R1 and R2 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;
Y is —O— or —S—;
W and X are, independently, hydrogen, halo, C1-8 alkyl or C1-8 alkoxy;
R4 and R5 are both, 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 alkyl)amino; and R7 is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety.

### Claim 19 (depends on 18)

The compound of claim 18, wherein at least one of R4 and R5 is unsubstituted, monosubstituted or disubstituted phenyl or unsubstituted, monosubstituted or disubstituted 2-, 3- or 4-pyridyl.

### Claim 20 (depends on 19)

The compound of claim 19, wherein (a) R5 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 R4 is 2-, 3- or 4-pyridyl or phenyl; and/or (b) wherein W and X are both H.

### Claim 21 (depends on 20)

The compound of claim 20, wherein the compound of formula (C) is a compound of formula (D):
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The compound of claim 21, wherein R1 and R2 are each, independently, C1-2 alkyl, L is C1-3 alkylene and Y is —O—.

### Claim 23 (depends on 18)

The compound of claim 18, wherein the compound is a compound of formula (E):
or a pharmaceutically acceptable salt thereof, wherein R8 is selected from

### Claim 24 (depends on 23)

The compound of claim 23, wherein the compound is a compound of formula (F):
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The compound of any of claim 24, R7 is substituted or unsubstituted C1-6 aliphatic.

### Claim 26 (depends on 18)

The compound of claim 18, wherein the compound is a compound (TR2-A):
or a pharmaceutically acceptable salt thereof.

### Claim 27

A process for preparing a compound of formula
said process comprising the step of coupling a compound of formula (A-i) with a compound of formula (A-ii) to form a compound of formula (A-iii); wherein,
R1 and R2 are each, independently, H or C1-3 aliphatic, halo, or C1-3 haloaliphatic, or wherein R1 and R2 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;
W and X are, independently, hydrogen, halo, C1-8 alkyl or C1-8 alkoxy;
R3 is —OR6, —SR6, —OC(O)R7 or —SC(O)R7;
R6 is hydrogen or alkyl (preferably methyl);
R7 is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; and
R4′ and R5′ are, 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(C1-8alkyl)amino; or a protected form thereof,
optionally wherein the process comprises the further step of deprotecting the compound of formula (A-iii) to form a compound of formula (A)
wherein, R1, R2 L, W, X and R3 are as defined for formula (A-i) and R4 and R5 are both, 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.

### Claim 28 (depends on 27)

The process of claim 27, wherein the compound of formula A-iii is:

### Claim 29 (depends on 27)

The process of claim 27, wherein the compound of formula A-i is: