# US 11,028,070 B2 · Isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them

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- Number: US 11,028,070 B2
- Document ID: US11028070B2
- Status: Granted
- Kind: B2
- Application number: 16/865,799
- Filed: 2020-05-04
- Published: 2020-08-20
- Granted: 2021-06-08
- Earliest claimed: 2013-07-23
- Assignees: Les Laboratoires Servier; Vernalis (R&D) Ltd
- Applicants: Les Laboratoires Servier; Vernalis (R&D) Ltd
- Inventors: James Edward Paul Davidson; James Brooke Murray; I-Jen Chen; Claire Walmsley; Mark Dodsworth; Johannes W. G. Meissner; Paul Brough; Imre Fejes; János Tatai; Miklós Nyerges; András Kotschy; Zoltán Szlávik; Olivier Geneste; Arnaud Le Tiran; Thierry Le Diguarher; Jean-Michel Henlin; Jérôme-Benoît Starck; Anne-Françoise Guillouzic; Guillaume De Nanteuil
- Web page: https://patentgrep.com/patent/US11028070B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Compound of formula (I): wherein Het, R3, R4, R5, R7, R8, R9, t, p, p′, q, and q′ are as defined in the description. Medicinal products containing the same which are useful in treating conditions requiring pro-apoptotic agent.

## Claims

### Claim 1

A process for the preparation of a compound of formula (I):
wherein:
Het represents a heteroaryl group,
T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, an alkyl(C1-C4)—NR1R2 group or an alkyl(C1-C4)—OR6 group,
R1 and R2 independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
or R1 and R2, together with the nitrogen atom carrying them, form a heterocycloalkyl group,
R3 represents a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl group, a (C3-C10)cycloalkyl-(C1-C6)alkyl group wherein the alkyl group may be linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated,
R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (C1-C6)alkyl group, wherein one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated,
R5 represents a hydrogen atom or a halogen atom, a linear or branched (C1-C6)alky group, or a linear or branched (C1-C6)alkoxy group,
R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R7 represents a group selected from R′7, R′7—CO—, R′7—O—CO—, NR′7R″7—CO—, R′7—SO2—, R′7—NR″7—SO2— wherein R′7 and R″7, independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl,
R8 and R9 represent, independently of one another, an oxo group or a halogen atom,
p and p′ are, independently of one another, integers equal to 0, 1, 2, 3 or 4,
q and q′ are, independently of one another, integers equal to 1, 2 or 3,
wherein, when the compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups: —PO(OM)(OM′), —PO(OM)(O−M+), —PO(O−M1+)(O−M2+), —PO(O−)(O−)M32+, —PO(OM)(O[CH2CH2O]nCH3), or —PO(O−M1+)(O[CH2CH2O]nCH3), wherein M and M′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of the cycloalkyl and heterocycloalkyl being composed of from 5 to 6 ring members, M1+ and M2+, independently of one another, represent a pharmaceutically acceptable monovalent cation, M32+ represents a pharmaceutically acceptable divalent cation and n is an integer between 1 to 5,
wherein:
“aryl” means a phenyl, naphthyl, biphenyl or indenyl group,
“heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and having from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen,
“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group having from 3 to 10 ring members, which may include fused, bridged or spiro ring systems,
“heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and having from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO2 and nitrogen,
wherein bicyclic group may be fused or spiro type, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, may be substituted by from 1 to 3 groups selected from: optionally substituted linear or branched (C1-C6)alkyl; optionally substituted linear or branched (C2-C6)alkenyl group; optionally substituted linear or branched (C2-C6)alkynyl group; (C3-C6)spiro; optionally substituted linear or branched (C1-C6)alkoxy; (C1-C6)alkyl-S—; hydroxyl; oxo (or N-oxide where appropriate); nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C1-C6)polyhaloalkyl; trifluoromethoxy; (C1-C6)alkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, wherein R′ and R″, independently of one another, represent a hydrogen atom, an optionally substituted linear or branched (C1-C6)alkyl group or an aryl group,
its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
which process comprises subjecting a compound of formula (II):
wherein Alk represents a linear or branched (C1-C6) alkyl group,
the ester function of which compound of formula (II) is hydrolysed to yield the corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III):
to yield a compound of formula (IV):
which compound of formula (IV) is deprotected and subjected to an acylation or a sulfonylation reaction, and which can optionally be subjected to the action of a pyrophosphate or a phosphonate derivative in basic conditions, to yield the compound of formula (I),
which compound of formula (I) may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique,
wherein some groups (including hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis.

### Claim 2 (depends on 1)

The process according to claim 1, wherein Het represents one of the following groups: 5,6,7,8-tetrahydroindolizine, indolizine or 1,2-dimethyl-1H-pyrrole.

### Claim 3 (depends on 1)

The process according to claim 1, wherein q=1 and q′=1.

### Claim 4 (depends on 1)

The process according to claim 1, wherein q=2 and q′=1.

### Claim 5 (depends on 1)

The process according to claim 1, wherein T represents a hydrogen atom, a methyl group, a (morpholin-4-yl)methyl group, a 3-(morpholin-4-yl)propyl group, a dimethylaminomethyl group, or a (4-methylpiperazin-1-yl)methyl group.

### Claim 6 (depends on 1)

The process according to claim 1, wherein R3 represents a linear or branched (C1-C6)alkyl group, an aryl group or a heteroaryl group.

### Claim 7 (depends on 1)

The process according to claim 1, wherein R3 represents a group selected from phenyl, methyl, ethyl, propyl, butyl, 1-methyl-1H-pyrrolo[2,3-b]pyridine or 5-cyano-1,2-dimethyl-1H-pyrrole.

### Claim 8 (depends on 1)

The process according to claim 1, wherein R4 represents a linear or branched (C1-C6)alkyl group or an aryl group.

### Claim 9 (depends on 1)

The process according to claim 1, wherein R4 represents a phenyl or 4-hydroxyphenyl group.

### Claim 10 (depends on 1)

The process according to claim 1, wherein R7 represents a group R′7—CO— or R′7—O—CO—.

### Claim 11 (depends on 1)

The process according to claim 1, wherein R′7 represents an aryl optionally substituted, a cycloalkyl optionally substituted or an alkyl optionally substituted.

### Claim 12 (depends on 1)

The process according to claim 1, wherein p=p′=0.

### Claim 13 (depends on 1)

The process according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:
N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-1,2,3,4-tetrahydro isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-1-carboxamide;
Phenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydro isoquinoline-2-carboxylate;
Phenyl 6-{4-[(4-hydroxyphenyl)methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydro isoquinoline-2-carboxylate;
Phenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;
Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;
4-Methylphenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;
2-Methylphenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Methoxyphenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Chlorophenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Ethylphenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Cyanophenyl 6-(1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
2-Methoxyphenyl 6-{1-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Methylphenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Chlorophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Cyanophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Cyanophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-{[2-(Dimethylamino)ethyl]amino}phenyl 6-{1-[(4-hydroxyphenyl)(methyl) carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
Phenyl 6-{4-[(4-hydroxyphenyl)(propyl)carbamoyl]-1,5-dimethyl-1H-pyrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
Phenyl 6-{4-[butyl(4-hydroxyphenyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
N-Butyl-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide;
3-[2-(Dimethylamino)ethoxy]phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-{[2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Ethynylphenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
Naphthalen-2-yl 6-{4-[(4-hydroxyphenyl)methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
1H-Indol-5-yl 6-(4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
3-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-Bromophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
(1r,4r)-4-{[(tert-Butoxy)carbonyl]amino}cyclohexyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydro isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate; and
Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-7-[(3R)-3-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate.