Compounds and compositions for the inhibition of NAMPT

• US 9,676,721 B2
• Filed: 09/02/2011
• Issued: 06/13/2017
• Est. Priority Date: 09/03/2010
• Status: Active Grant

• Current Assignee: VALO Health Incorporated
• Original Assignee: Forma Tm, LLC
• Inventors: Bair, Kenneth W., Buckmelter, Alexandre J., Han, Bingsong, Lin, Jian, Reynolds, Dominic J., Smith, Chase C., Wang, Zhongguo, Zheng, Xiaozhang
• Primary Examiner(s): Rao, Savitha
• Assistant Examiner(s): Polansky, Gregg
• Application Number:
  US13/820,489
• Publication Number:
  US 20130295051A1
• Time in Patent Office: 2,111 Days
• Field of Search: None
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: 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
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below.

Claims

1. Compounds of the Formula II:

2. The compounds of claim 1, wherein Ar¹ is unsubstituted pyridine.

3. The compounds of claim 1, wherein Ar¹ is imidazopyridine.

4. The compounds of claim 1, wherein R¹ is heteroaryl that is unsubstituted or substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy, heterocycloalkyl, —

N(R^aR^b), wherein R^a and R^b are as defined in claim 1.

5. The compounds of claim 4, wherein the heteroaryl is 5 to 13 membered monocyclic or bicyclic heteroaryl comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O with the proviso that no two adjacent ring heteroatoms are both S or both O.

6. The compounds of claim 5, wherein the heteroaryl is selected from the group consisting of pyridine, quinolone, benzodioxole, and indazole.

7. A compound selected from the group consisting of:

2-cyano-1-[(4-{[3-(dimethylsulfamoyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

(E)-3-({4-[(3-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-1-(pyridin-4-yl)guanidine;

1-[(4-{[4-chloro-3-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(ethanesulfonyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-[4-(benzenesulfonyl)phenyl]-2-cyano-3-(pyridin-3-ylmethyl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[3-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-8-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-({4-[(3,5-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-6-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-[(4-{[2-(morpholin-4-ylmethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(2-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(6-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

4-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-ethylbenzamide;

2-cyano-1-[(4-{[4-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-({4-[(3-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methanesulfonylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[6-(morpholin-4-yl)pyridine-3-sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-4-(2,2,2-trifluoroethoxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(propan-2-yloxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-dichlorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[2-methoxy-4-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-cyclopentylbenzamide;

(E)-3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-3-ylmethyl)guanidine;

1-{[4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]methyl}-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,5-difluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[3-chloro-2-(morpholin-4-yl)pyridine-4-sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-ethylbenzamide;

2-cyano-1-({4-[(2-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(phenylsulfonyl)benzyl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-{imidazo[1,2-a]pyridin-7-yl}guanidine;

2-cyano-1-({4-[(3,4-dimethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-diethyl-4-fluorobenzamide;

2-cyano-1-{[4-(4-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-dimethylbenzamide;

2-cyano-1-({4-[2-(dimethylamino)pyrimidine-5-sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,5-dichlorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propan-2-yloxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-fluoro-2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(2,3-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(2, 6-dimethoxypyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

1-({4-[(4-acetylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-3-{[4-(phenylmethane)sulfonylphenyl]methyl}-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-cyanobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(2-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chloro-3-fluorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-({4-[(4-fluorobenzene)sulfonyl]phenyl}methyl)-1-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-5-methylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-{imidazo[1,2-a]pyridin-7-ylmethyl}guanidine;

2-cyano-1-({4-[(3-fluoro-5-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-({3-[(morpholin-4-yl)carbonyl]benzene}sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-fluoro-3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chloro-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-methylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(5-fluoro-2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-{[4-(2H-1,3-benzodioxole-4-sulfonyl)phenyl]methyl}-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(5-chloro-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-({4-[(pyrrolidin-1-yl)carbonyl]benzene}sulfonyl)phenyl]methyl}guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[4-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-5-fluoro-N,N-dimethylbenzamide;

2-cyano-1-{[4-(1-propyl-1H-pyrazole-4-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[4-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-1-({4-[(4-ethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methoxy-3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-propoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(naphthalene-1-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-cyanobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propane-1-sulfonamido)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

5-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-methylpyridine-2-carboxamide;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-cyclopropylbenzamide;

1-({4-[(3-chloro-5-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[3-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-3-yl)guanidine;

1-({4-[(3-chloro-5-fluorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-difluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(5-methoxypyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-{2-[4-(benzenesulfonyl)phenyl]ethyl}-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-3-[(4-{8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl}phenyl)methyl]-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-4-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-phenylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-5-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-1-{[4-(1-methyl-1H-indazole-6-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(5-fluoropyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(methoxymethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-({4-[(5-acetyl-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-3-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-({4-[(4-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(1-methyl-1H-indole-2-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(pyridine-3-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-[(4-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-chloro-5-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-diethylbenzamide;

2-cyano-1-[(4-{[2-methoxy-5-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(morpholin-4-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methoxy-4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-(pyridin-4-yl)-3-[(4-{[2-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-1-[(4-{[3-fluoro-5-(2,2,2-trifluoroethoxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-ethoxy-3-fluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-(propan-2-yl)benzamide;

2-cyano-1-({4-[(2,4-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-[(4-{[3-chloro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-2-cyano-3-(pyridin-4-yl)guanidine; and

2-cyano-1-({4-[(2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

and pharmaceutically acceptable salts thereof.