# US 10,766,897 B2 · Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors

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- Number: US 10,766,897 B2
- Document ID: US10766897B2
- Status: Granted
- Kind: B2
- Application number: 16/542,792
- Filed: 2019-08-16
- Published: 2020-01-02
- Granted: 2020-09-08
- Earliest claimed: 2013-03-13
- Assignees: Proximagen Limited
- Applicants: Proximagen, LLC
- Inventors: Max Espensen; Lee Patient; David Evans; Iain Simpson; Edward Savory
- Web page: https://patentgrep.com/patent/US10766897B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/16: Central respiratory analeptics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 53/18: containing fluorine
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The compounds of formula (I) are inhibitors of SSAO activity wherein V, W, X, Y, Z, R1 and R2 are as defined in the claims.

## Claims

### Claim 1

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide thereof
comprising reacting a compound of formula (IIIb) with a compound of formula (IX) to form the compound of formula (I)
wherein:
Y is selected from hydrogen, hydroxyl, —NH2, —NH—C1-4-alkyl, —NH-halo-C1-4-alkyl, and —C1-4-alkoxy;
Z is selected from hydrogen, halogen, hydroxyl, cyano, C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, —CONH2, —SO2NH2, —NH2, —NHC1-4-alkyl, and —NHhalo-C1-4-alkyl;
R1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, a 3-7 membered cycloalkyl ring, —OR5, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —C(O)NR4AR4B, —C(O)R5, —C(O)OR5, and —NR6S(O)2R5;
R4A, R4B, R5, and R6 are each independently selected from hydrogen, C1-4-alkyl, and halo-C1-4-alkyl, or
R4A and R4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, —CONH2, —SO2NH2, —NH2, —NHC1-4-alkyl, and —NHhalo-C1-4-alkyl;
X is —C(R2)═;
R2 is selected from hydrogen, halogen, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR4AR4B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —SO2R5, —SO2NR4AR4B and —NR6S(O)2R5;
W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, oxo C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR7AR7B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR7AR7B, —C(O)NR7AR7B, —C(O)R5, —C(O)OR5, —SO2R5, —SO2NR7AR7B, and —NR6S(O)2R5;
R7A and R7B are independently hydrogen, C1-4-alkyl, or halo-C1-4-alkyl;
V is selected from a bond, —O—, —N(R6)—, —(C═O)—, —CONR6—, —NR6C(O)—, and —C1-4-alkylene-, wherein the C1-4-alkylene group is optionally substituted by halogen, and wherein any one of the carbon atoms of the C1-4-alkylene group may be replaced by —O— or —N(R6)—;
R3 is selected from hydrogen, —C1-4-alkyl, —C1-4-alkyl-C1-4-alkoxy, a 3-7 membered heterocyclic ring, a 3-7 membered cycloalkyl ring, and a 5 or 6-membered heteroaryl ring, any one of the rings being optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR4AR4B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —C(O)NR4AR4B, —C(O)R5, —C(O)OR5, —SO2R5, —SO2NR4AR4B, and —NR6S(O)2R5;
provided that groups —WVR3 and/or R1 are not:
wherein:
n is 0, 1, or 2;
R′ and R″ are independently selected from the group consisting of H, —C1-C6 alkyl, —(C═O)—C1-C6 alkyl, and —(C═O)OC(CH3)3; and
R′″ is H, OH, or C1-C6 alkyl; and
further provided that when —R3 is H, R1 is not a phenyl ring substituted with one —OCH3.

### Claim 2

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide thereof
comprising reacting a compound of formula (IIIb) with a compound of formula (IX) to form the compound of formula (I)
wherein:
Y is selected from hydrogen, hydroxyl, —NH2, —NH—C1-4-alkyl, —NH-halo-C1-4-alkyl, and —C1-4-alkoxy;
Z is selected from hydrogen, halogen, hydroxyl, cyano, C1-4-alkyl, halo-C14-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, —CONH2, —SO2NH2, —NH2, —NHC1-4-alkyl, and —NHhalo-C1-4-alkyl;
R1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C14-alkyl, —OR5, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —C(O)NR4AR4B, —C(O)R5, —C(O)OR5, and —NR6S(O)2R5;
R4A, R4B, R5, and R6 are each independently selected from hydrogen, C1-4-alkyl, and halo-C1-4-alkyl, or
R4A and R4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, —CONH2, —SO2NH2, —NH2, —NHC1-4-alkyl, and —NHhalo-C1-4-alkyl;
X is —C(R2)═;
R2 is selected from hydrogen, halogen, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR4AR4B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —C(O)NR4AR4B, —C(O)R5, —C(O)OR5, —SO2R5, —SO2NR4AR4B, and —NR6S(O)2R5,
W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR7AR7B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR7AR7B, —SO2R5, —SO2NR7AR7B, and —NR6S(O)2R5;
R7A and R7B are independently hydrogen, C1-4-alkyl, and halo-C1-4-alkyl;
V is selected from a bond, —O—, —N(R6)—, —(C═O)—, —CONR6—, —NR6C(O)—, and —C1-4-alkylene-, wherein the C1-4-alkylene group is optionally substituted by halogen, and wherein any one of the carbon atoms of the C1-4-alkylene group may be replaced by —O— or —N(R6)—;
R3 is hydrogen, or a 3-7 membered heterocyclic ring, or 3-7 membered cycloalkyl ring selected from cyclopropyl, cyclopentyl or cyclohexyl, or a 5 or 6-membered heteroaryl ring, any one of the rings being optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, —OR5, —NR4AR4B, —NR6C(O)OR5, —NR6C(O)R5, —NR6C(O)NR4AR4B, —C(O)NR4AR4B, —C(O)R5, —C(O)OR5, —SO2R5, —SO2NR4AR4B; and —NR6S(O)2R5;
provided that when —R3 is H, R1 is not a phenyl ring substituted with one —OCH3.

### Claim 3 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula (IIIb) is formed by reacting a compound of formula (IIb) with a compound of formula R1—I
wherein Z, Y, and R1 are as defined in claim 1.

### Claim 4 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula (IIIb) is converted into a boronate ester prior to its reaction with the compound of formula (IX).

### Claim 5 (depends on 4)

The process as claimed in claim 4, wherein the boronate ester is formed in a reaction that comprises lithium diisopropylamide and (iPrO)3B.

### Claim 6 (depends on 4)

The process as claimed in claim 4, wherein the compound of formula (I) is formed by reacting the boronate ester of the compound of formula (IIIb) with the compound of formula (IX) under Suzuki coupling conditions.

### Claim 7 (depends on 6)

The process as claimed in claim 6, wherein the Suzuki coupling conditions comprise Pd(PPh3)4 and Na2CO3.

### Claim 8 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula (IIIb) is reacted with the compound of formula (IX) in a reaction that comprises lithium diisopropylamide, (iPrO)3B, Pd(PPh3)4, and Na2CO3.

### Claim 9 (depends on 3)

The process as claimed in claim 3, wherein the compound of formula (IIb) is reacted with the compound R1—I in the presence of 1,2-dimethylethylenediamine, K3PO4, and CuI.

### Claim 10 (depends on 1)

The process as claimed in claim 1, wherein Z is hydrogen.

### Claim 11 (depends on 1)

The processes as claimed in claim 1, wherein R1 is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from halogen, C1-4-alkyl, and halo-C14-alkyl.

### Claim 12 (depends on 1)

The process as claimed in claim 1, wherein R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from F, Cl, and CH3.

### Claim 13 (depends on 1)

The process as claimed in claim 1, wherein R2 is hydrogen, halogen, cyano, C1-4-alkyl, or halo-C1-4-alkyl.

### Claim 14 (depends on 1)

The process as claimed in claim 1, wherein R2 is hydrogen.

### Claim 15 (depends on 1)

The process as claimed in claim 1, wherein W is a phenyl ring optionally substituted with one or more substituents as defined in claim 1.

### Claim 16 (depends on 1)

The process as claimed in claim 1, wherein W is a 6-membered heteroaryl ring selected from pyridine, pyridazine, pyrazine, and pyrimidine optionally substituted with one or more substituents as defined in claim 1.

### Claim 17 (depends on 1)

The process as claimed in claim 1, wherein W is a 5-membered heteroaryl ring selected from oxazole, thiazole, and imidazole optionally substituted with one or more substituents as defined in claim 1.

### Claim 18 (depends on 1)

The process as claimed in claim 1, wherein W is an imidazolyl ring optionally substituted as in claim 1, and wherein the imidazolyl ring is connected to the pyrrolopyridine core via an imidazolyl ring carbon atom.

### Claim 19 (depends on 1)

The process as claimed in claim 1, wherein W is optionally substituted with one or more substituents selected from fluoro, chloro, cyano, CH3, and CF3.

### Claim 20 (depends on 1)

The process as claimed in claim 1, wherein V is —CH2—, —(CH2)2, —N(R6)CH2—, or —CH2—N(R6)—.

### Claim 21 (depends on 1)

The process as claimed in claim 1, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted as defined in claim 1.

### Claim 22 (depends on 1)

The process as claimed in claim 1, wherein R3 is formed from NR4AR4B, wherein R4A and R4B, together with the nitrogen atom to which they are attached, join together to form a 4-7 membered heterocyclic ring optionally substituted as defined in claim 1.

### Claim 23 (depends on 1)

The process as claimed in claim 1, wherein R3 is selected from the group consisting of:
wherein R8 is selected from hydrogen, CH3, —CONH2, —NHCONH2, —S(O)2CH3, and —COCH3.

### Claim 24 (depends on 1)

The process as claimed in claim 1, wherein R1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more 3-7 membered cycloalkyl rings.

### Claim 25 (depends on 1)

The process as claimed in claim 1, wherein W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more oxo substituents.

### Claim 26 (depends on 1)

The process as claimed in claim 1, wherein R3 is selected from —C1-4-alkyl and —C1-4-alkyl-C1-4-alkoxy.

### Claim 27 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula (I) is selected from:
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;
2-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;
3-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidine;
2-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrazine;
1-({4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]phenyl}carbonyl)-4-methylpiperazine;
4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;
4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}piperazin-2-one;
4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine;
4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;
4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine;
4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-imidazole;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N,N-dimethylpyrimidin-2-amine;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-cyclopropyl-1,2-dihydropyridin-2-one;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-amine;
4-({5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}methyl)morpholine;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-amine;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1,2-dihydropyridin-2-one;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2-one;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-ethyl-1,2-dihydropyridin-2-one;
6-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2-one;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydropyridazin-3-one;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-amine;
3-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-5-fluoropyridine;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N-(cyclopropylmethyl)pyrimidin-2-amine;
3-Chloro-5-[1-(4-chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;
5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-2-(1H-pyrazol-1-yl)pyridine;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-3-fluoropyridine;
3-Chloro-4-[1-(4-chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;
4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine;
1-Cyclopropyl-4-{1-phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}-1,2-dihydropyridin-2-one; and
pharmaceutically acceptable salts thereof.