# US 8,541,596 B2 · Inhibitors

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- Number: US 8,541,596 B2
- Document ID: US8541596B2
- Status: Granted
- Kind: B2
- Application number: 13/091,276
- Filed: 2011-04-21
- Published: 2011-10-27
- Granted: 2013-09-24
- Earliest claimed: 2010-04-21
- Assignees: Probiodrug AG
- Applicants: Ulrich Heiser; Daniel Ramsbeck; Torsten Hoffmann; Livia Boehme
- Inventors: Ulrich Heiser; Daniel Ramsbeck; Torsten Hoffmann; Livia Boehme
- Web page: https://patentgrep.com/patent/US8541596B2

## CPC

- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- 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 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt, tautomer, or stereoisomers thereof wherein:
X represents a bond or a —(CH2)m-group;
m represents an integer selected from 1 to 3;
R1 represents -aryl, —C1-6alkylaryl, -cycloalkyl, —C1-6alkylcycloalkyl, —C1-6alkyl-Het, -aryl fused to heterocyclyl, —C1-6alkylaryl fused to heterocyclyl, -aryl substituted by heteroaryl, —C1-6alkylaryl substituted by heteroaryl, -aryl substituted by phenyl, —C1-6alkylaryl substituted by phenyl, -aryl substituted by phenoxy or —C1-6alkylaryl substituted by phenoxy;
and in which any of aforesaid aryl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl);
R2 represents -aryl, —C1-6alkylaryl, -cycloalkyl, —C1-6alkylcycloalkyl, —C1-6alkyl- Het, -aryl fused to heterocyclyl, —C1-6alkylaryl fused to heterocyclyl, -aryl substituted by heteroaryl, —C1-6alkylaryl substituted by heteroaryl, -aryl substituted by phenyl, —C1-6alkylaryl substituted by phenyl, -aryl substituted by phenoxy or —C1-6alkylaryl substituted by phenoxy;
and in which any of aforesaid aryl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —S02C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl);
Het represents a bicyclic heteroaryl group;
in which said bicyclic heteroaryl group may be optionally substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)OC1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl).

### Claim 2 (depends on 1)

A compound as defined in claim 1, wherein R1 represents C1-6alkylaryl, —C1-6alkyl-Het, —C1-6alkylaryl fused to heterocyclyl or —C1-6alkylaryl substituted by heteroaryl.

### Claim 3 (depends on 1)

A compound as defined in claim 1, wherein R2 represents -aryl, —C1-6alkylaryl, —C1-6alkylcycloalkyl, —C1-6alkyl-Het, —C1-6alkylaryl fused to heterocyclyl or —C1-6alkylaryl substituted by heteroaryl.

### Claim 4 (depends on 1)

A compound as defined in claim 1, wherein R1 represents —C1-6alkylaryl and R2 represents —C1-6alkylaryl or —C1-6alkylcycloalkyl; wherein said aryl groups are optionally substituted by one or more halogen, cyano, C1-6alkyl, C1-6alkoxy, —C1-6thioalkyl or —N(C1-4alkyl)(C1-4alkyl) groups.

### Claim 5 (depends on 1)

A compound as defined in claim 1, wherein R1 and R2 both represent —C1-6alkylaryl; wherein said phenyl groups are optionally substituted by one or more halogen, cyano, C1-6alkyl, C1-6alkoxy, —C1-6thioalkyl or —N(C1-4alkyl)(C1-4alkyl) groups.

### Claim 6 (depends on 1)

A compound as defined in claim 1, wherein R1 and R2 both represent —C1-6alkylaryl substituted by to heteroaryl.

### Claim 7 (depends on 1)

A compound as defined in claim 1, wherein R1 and R2 both represent —C1-6alkylaryl substituted by heteroaryl.

### Claim 8 (depends on 1)

A compound as defined in claim 1, wherein R1 represents —C1-6alkyl-Het and R2 represents —C1-6alkyl-Het, C1-6alkylaryl, or —C1-6alkyl cycloalkyl; wherein said Het groups are optionally substituted by one or more halogen or C1-6alkyl groups; and wherein said aryl group is optionally substituted by one or more —C1-6thioalkyl, C1-6alkyl, C1-6alkoxy, halogen or —N(C1-4alkyl)(C1-4alkyl) groups.

### Claim 9 (depends on 1)

A compound as defined in claim 1, wherein R1 and R2 bothrepresent —C1-6alkyl-Het; wherein said Het groups are optionally substituted by one ormore halogen or C1-6alky groups.

### Claim 10 (depends on 1)

A compound as defined in claim 1, wherein R1 represents aryl and R2 represents —C1-6alkylaryl.

### Claim 11 (depends on 1)

A compound as defined in claim 1, wherein X represents a bondor a —CH2-group.

### Claim 12 (depends on 11)

A compound as defined in claim 11, wherein X representsa bond.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein saidcompound is selected from the group consisting of
N,N-Dibenzyl-1H- benzo[d]imidazol-5-amine;
N,N-Bis(2,4,5- trifluorobenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(4-cyanobenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis((4-methylbenzyl)- 1H-benzo[d]imidazol-5- amine;
N,N-Bis(4-isopropylbenzyl)- 1H-benzo[d]imidazol-5- amine;
N,N-Bis(4-tert-butylbenzyl)- 1H-benzo[d]imidazol-5- amine;
N,N-Bis(4-methoxybenzyl)- 1H-benzo[d]imidazol-5- amine;
N,N-Bis(2-fluoro-3- methylbenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(4-(thiophen-2- yl)benzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis((naphthalen-2- yl)methyl))-1H- benzo[d]imidazol-5-amine;
N,N-Bis((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis- ((benzo[c][1,2,5]thiadiazol-5- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis((5- chlorobenzo[b]thiophen-3- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis((2-methylquinolin-6- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- benzyl-1H-benzo[d]imidazol- 5-amine;
N,N-Bis(3-methoxybenzyl)- 1H-benzo[d]imidazol-5- amine;
N,N-Bis((3,4-dihydro-2H- benzo[b][1,4]dioxepin-9- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(4-bromobenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(3-bromobenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(2-fluorobenzyl)-1H- benzo[d]imidazol-5-amine;
N,N-Bis(3,5-difluorobenzyl)- 1H-benzo[d]imidazol-5- amine;
N-(4-(Methylthio)benzyl)-N- (4-methylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- (4-isopropylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- (4-methoxybenzyl)-1H- benzo[d]imidazol-5-amine;
N-(3-Methoxybenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(3,5-Dimethoxybenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(2-Fluoro-4,5- dimethoxybenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(2-Fluoro-3-methylbenzyl)- N-(4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(3,5-Difluorobenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(3,4,5-Trifluorobenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(2,4,5-Trifluorobenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(2,3,5,6-Tetrafluoro-4- methylbenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(2,5-Dichlorobenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- (4-bromobenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- ((5-chlorobenzo[b]thiophen- 3-yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- ((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Ethylbenzyl)-N-(4- methylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- (4-ethylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(2,3,5,6-Tetrafluoro-4- methylbenzyl)-N-(4- ethylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(3,4,5-Trifluorobenzyl)-N- (4-ethylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Cyanobenzyl)-N-(4- ethylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Ethylbenzyl)-N-((5- chlorobenzo[b]thiophen-3- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Ethylbenzyl)-N- ((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Ethylbenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Methoxybenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Chlorobenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4- (Dimethylamino)benzyl)-N- (4-methylbenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4- (Dimethylamino)benzyl)-N- (4-methoxybenzyl)-1H- benzo[d]imidazol-5-amine;
N-(4- (Dimethylamino)benzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine;
N-(4- (Dimethylamino)benzyl)-N- ((benzo[c][1,2,5]thiadiazol-5- yl)methyl)-1H- benzo[d]imidazol-5-amine;
N-(4-(Methylthio)benzyl)-N- (cyclohexylmethyl)-1H- benzo[d]imidazol-5-amine;
N-(4-Methoxybenzyl)-N- benzyl-3H-benzo[d]imidazol- 5-amine;
N-(4-Methoxybenzyl)-N- ((naphthalen-2-yl)methyl)- 3H-benzo[d]imidazol-5- amine;
N-(4-Methoxybenzyl)-N- phenethyl-1H- benzo[d]imidazol-5-amine;
N-(4-Methoxybenzyl)-N-(3- phenylpropyl)-3H- benzo[d]imidazol-5-amine; and
N-Benzyl-N-phenyl-1H- benzo[d]imidazol-5-amine;
or a pharmaceutically accepted salt thereof, including all tautomers and stereoisomers.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising acompound according to claim 1, optionally in combination with one or moretherapeutically acceptable diluents or carriers.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, which comprisesadditionally at least one compound, selected from the group consisting ofneuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, betaamyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs andanti-multiple sclerosis drugs.

### Claim 16 (depends on 14)

The pharmaceutical composition of claim 14, which comprisesadditionally at least one compound, selected from the group consisting of PEP-inhibitors,LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes,acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases,inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors ofPhosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptorantagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agentselected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR),campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel,Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.

### Claim 17 (depends on 1)

A process for preparation of a compound of formula(I) according to claim 1, which comprises:
(a) preparing a compound of formula (I) wherein X represents a bond by reacting a compound of formula (II)
with a compound of formula NHR1R2, wherein l1 represents a suitable leaving group and R1 and R2 are as defined in claim 1;
(b) preparing a compound of formula (I) wherein X represents a bond, R1 is as defined in claim 1 and R2 represents —C1-6alkylaryl, —C1-6alkyl-Het, —C1-6alkylaryl fused to heterocyclyl, —C1-6alkylaryl substituted by heteroaryl,—C1-6alkylaryl substituted by phenyl or —C1-6alkylaryl substituted by phenoxy, by alkylatinga compound of formula (III):
wherein Cy1 represents the aryl or Het group of R2;
(c) preparing a compound of formula (I) wherein X represents a bond, R1 is as defined in claim 1 and R2 represents —C1-6alkyl, —C1-6alkylaryl, —C1-6alkylcycloalkyl, —C1-6alkyl-Het, —C1-6alkylaryl fused to heterocyclyl, —C1-6alkylaryl substituted by heteroaryl, —C1-6alkylaryl substituted by phenyl or —C1-6alkyaryl substituted by phenoxy, by reacting a compound of formula (IV):
with a compound of formula H—CO—R2, wherein R2 is as defined in claim 1;
(d) preparing a compound of formula (I) wherein: X represents a bond, R1 is as defined in claim 1 and R2 is as defined in claim 1; or X represents a bond and R1 and R2 represent identical groups, by reacting a compound offormula (IV):
or an optionally protecting derivative thereof with a compound of formula L2-R2, whereinL2 represents a suitable leaving group and R2 is as defined in claim 1;
(e) preparing a compound of formula (I) wherein X represents a —(CH2)m-group,by reacting a compound of formula (VI):
with a compound of formula HNR1R2, wherein R1 and R2 are as defined in claim 1;
(f) interconversion of compounds of formula (I), such as preparing acompound of formula (I) wherein R1 is as defined in claim 1 by reacting a compound of formula (V):
with a compound of formula L4—R1a, wherein R2 is as defined in claim1, L4 represents a suitable leaving group such as bromine and R1a represents an R1 group as defined in claim1; and/or
(g) deprotecting a compound of formula (I) which is protected.

### Claim 18 (depends on 17)

The process of claim 17, wherein L1 is bromine, L2 is bromine, or L4 bromine.