HUE035693T2 - A dipeptidil-peptidáz-IV inhibitorai - Google Patents

A dipeptidil-peptidáz-IV inhibitorai Download PDF

Info

Publication number
HUE035693T2
HUE035693T2 HUE10729125A HUE10729125A HUE035693T2 HU E035693 T2 HUE035693 T2 HU E035693T2 HU E10729125 A HUE10729125 A HU E10729125A HU E10729125 A HUE10729125 A HU E10729125A HU E035693 T2 HUE035693 T2 HU E035693T2
Authority
HU
Hungary
Prior art keywords
group
acetyl
methyl
mmol
carbonitrile
Prior art date
Application number
HUE10729125A
Other languages
English (en)
Inventor
Gopalan Balasubramanian
Sukumar Sakamuri
Gajendra Singh
Sivanesan Dharmalingam
Xavier Franklin Pooppady
Shridhar Narayanan
Jeyamurugan Mookkan
Jeganatha Balasubramanian
Agneeswari Rajalingam
Jayanarayan Kulathingal
Original Assignee
Orchid Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orchid Pharma Ltd filed Critical Orchid Pharma Ltd
Publication of HUE035693T2 publication Critical patent/HUE035693T2/hu

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/08—Preparation by ring-closure
    • C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
    • C07D213/12—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Nutrition Science (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Description

• DATABASE CAPLUS [Online] CHEMICAL · H.E. BAUMGARTEN ET AL: JOURNAL OF ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ORGANIC CHEMISTRY, vol. 40, no. 24, 1975, XP002674248, retrieved from STN Database pages 3554-3561, XP002674256,
accession no. 1976:84206 & P. SCHENONE ET · DATABASE CAPLUS [Online] CHEMICAL AL: EUROPEAN JOURNAL OF MEDICINAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; CHEMISTRY, vol. 10, no. 4, 1975, pages 412-417, XP002674257, retrieved from STN Database • DATABASE REGISTRY [Online] CHEMICAL accession no. 1944:31172 & T. COSCIUG: ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WIENER CHEMIKER-ZEITUNG, vol. 46, 1943, 13 March 2001 (2001-03-13), XP002674249, pages 145-149,
retrieved from STN Database accession no. RN · K. YAMADA ET AL: JOURNAL OF ORGANIC 326916-48-7 CHEMISTRY, vol. 52, no. 11, 1987, pages • DATABASE REGISTRY [Online] CHEMICAL 2327-2330, XP002674258,
ABSTRACTS SERVICE, COLUMBUS, OHIO, US; · DATABASE CAPLUS [Online] CHEMICAL 22 January 2002 (2002-01-22), XP002674250, ABSTRACTS SERVICE, COLUMBUS, OHIO, US; retrieved from STN Database accession no. RN XP002674259, retrieved from STN Database
385398-91-4 accession no. 1998:121726 & J.M. BLANCO ET
• DATABASE REGISTRY [Online] CHEMICAL AL: ORGANIC PREPARATIONS AND ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PROCEDURES INTERNATIONAL, vol. 30, no. 1, 26 November 2003 (2003-11-26), XP002674251, 1998, page 7178,
retrieved from STN Database accession no. · DATABASE REGISTRY [Online] CHEMICAL RN620937-78-2 ABSTRACTS SERVICE, COLUMBUS, OHIO, US; • DATABASE REGISTRY [Online] CHEMICAL XP002674260, retrieved from STN Database ABSTRACTS SERVICE, COLUMBUS, OHIO, US; accession no. RN 937650-05-0, 9376676-39-5
1 December 2003 (2003-12-01), XP002674252, · J. HOUBEN ET AL: JUSTUS LIEBIGS ANNALEN retrieved from STN Database accession no. RN DER CHEMIE, vol. 489, 1932, pages 193-224, 622354-46-5 XP002674261, • DATABASE REGISTRY [Online] CHEMICAL · HANYU N. ET AL:’New chiral 1,4-aminoalcohols ABSTRACTS SERVICE, COLUMBUS, OHIO, US; derived from (+)- camphor and (-)-fenchone for 9 April 2006 (2006-04-09), XP002674253, retrieved the enantioselective addition of diethylzinc to from STN Database accession no. RN aidehyde’TETRAHEDRON: ASYMMETRYvol. 11, 879794-27-1 2000, pages 4127 - 4136 • DATABASE REGISTRY [Online] CHEMICAL · NIETO Μ. I. ET AL: ’Synthetic Approaches to ABSTRACTS SERVICE, COLUMBUS, OHIO, US; (1S,3R)-3-Aminomethyl-2,2,3-trimethylcyclop 30 May 2008 (2008-05-30), XP002674254, entylmethanol and retrieved from STN Database accession no. RN (1S,3R)-3-Amino-2,2,3-trimethylcyclopentylm 1023877-62-4 ethanol from (+)-Camphoric Acid’ • DATABASE REGISTRY [Online] CHEMICAL TETRAHEDRON vol. 54, 1998, pages 7819 - 7830 ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 J une 2008 (2008-06-01 ), XP002674255, retrieved from STN Database accession no. RN 1024208-52-3 • M.l. NIETO ET AL: TETRAHEDRON, vol. 54, no. 27, 2 July 1998 (1998-07-02), pages 7819-7830, XP004122490, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(98)00416-5
Description
Field [0001] Described are compounds of the formula (I), their tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and pharmaceutical compositions thereof
[0002] Described herein is also a process for the preparation of the above said compounds and compositions containing them.
[0003] The compounds are dipeptidyl peptidase (DPP-IV) inhibitors and are used for treating conditions that are regulated or normalized via inhibition of DPP-IV such as treatment and /or prophylaxis of type II diabetes.
[0004] Described herein is also a method for delaying the onset of type II diabetes and alleviating the physiological consequences of type II diabetes. Diabetes is a disease in which the body does not produce or properly use insulin. Around 150 million people have diabetes mellitus worldwide and this number will be double by the year 2025. Much of this increase will occur in developing countries and will be due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years. Diabetes is the leading cause of blindness, lower limb amputations, and renal failure in the United States. The healthcare cost of diabetes is high, with the total estimated cost in the United States exceeding $100 billion. Estimated number of diabetes cases in India in 2002 was 31.7 million. A report by American Diabetes Association, April 2004 stated that by 2030, 79.4 million are going to be affected by diabetes. As of today, approximately 5% of world population is suffering from type II diabetes.
Background [0005] Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Therefore patients with Type II diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
[0006] Diabetes mellitus has serious effects on people’s health and accompanies various complications. There are two major types of diabetes mellitus: type I diabetes mellitus characterized by little or no insulin secretory capacity due to the destruction of the pancreatic cells, and type II diabetes mellitus characterized by insulin deficiency and insulin resistance due to other causes. The prevalence of type II diabetes mellitus is 90% or more of total patients with diabetes mellitus.
[0007] The worldwide epidemic of type II diabetes has been stimulating the search for new concepts and targets for the treatment of this incurable disease. Most current therapies were developed in the absence of defined molecular, targets. Increasing knowledge on the biochemical and cellular alterations occurring in NIDDM (Non-insulin dependent diabetes mellitus) has led to the development of novel and potentially more effective therapeutic approaches to treat the disease. The role of peroxisome proliferator activated receptor in the regulation of lipid metabolism, insulin and triglycerides led to the rational design of several PPAR agonists. However, these drugs have side effects such as hypoglycemia, weight gain and the like. Accordingly, there is a strong need to develop therapeutic agents with decreased side effects, which in particular would not induce hypoglycemia and weight gain.
The other targets are: Protein Tyrosine Phosphatase 1B (PTP1B); Glycogen Synthase Kinase-3 (GSK-3); Adiponectin; Insulin Receptor Mimetic and Glucagon-like Peptidei (GLP-1).
[0008] The serine protease DPP-IV is responsible for the rapid degradation of the insulinotropic hormone GLP-1 (glucagon like peptide 1). DPP-IV inhibition results in an increase of circulating GLP-1 levels and as a consequence, improves the insulin secretion in type II diabetic patients. Other physiological effects of enhanced GLP-1 levels, such as reduction of hepatic glucose output, delayed gastric emptying and possibly an increased insulin sensitivity as well as preservation of pancreatic beta cell function, are believed to contribute to the beneficial effects (Current Topics in Medicinal Chemistry, 2007, 7,579-595). Advantageously, since the incretins are produced by the body only when food is consumed, DPP-IV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DPP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secret-agogues.
[0009] Compounds, which are inhibitors of the dipeptidyl peptidase-IV ("DPP-4") enzyme, approved as drugs for the treatment of diabetes and particularly Type II diabetes are Sitagliptin of Merck and Vildagliptin of Novartis. To date, many candidate molecules, as DPP-IV inhibitors have been on clinical trials. A lot of research for developing DPP-IV inhibitors has been focused on molecules in which the cyano group is bonded to the pyrrolidine ring (Current Topics in Medicinal Chemistry, 2007, 7, 579-595). Representative examples of these DPP-IV inhibitors are cited in WO9819998, WOOO/34241, WO04/064778, W003/004498 and W003/082817. WO 2005/075426 discloses compounds of the general formula (A),
wherein Y is -S(O)m, -CH2-, CHF, or-CF2 ; X is NR3, O or S(O)m; m is 0, 1 or 2; the dotted line [—] in the carbocyclic ring represents an optional double bond (i.e., a single or double bond); R1 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl ; R2 is hydrogen, nitrile (-CN), COOH, or isosteres of carboxylic acids, including, but not limited to, SO3H, CONHOH, B(OH)2, PO3R4R5, SO2NR4R5, tetrazole, amides, esters and acid anhydrides; WO 2006/040625 discloses compounds of formula (B),
wherein Y is -S(O)n, -CH2-, CHF, or -CF2; n is 0, 1, or 2; X is a bond, C^Cg alkyl (eg, - CH2-), or -C(=O)-; the dotted line [—] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -CN, -COOR3, CONR3R4, -OR3, -NR3R4, or NR3COR3; R2 is hydrogen, cyano, COOH, or an isostere of a carboxylic acid (such as SO3H, CONOH, B(OH)2, PO3R3R4, SO2NR3R4, tetrazole, -COOR3, -CONR3R4, NR3COR4, or-COOCOR3). WO 2007/113634 discloses compounds of formula (C),
wherein X = CH2, CHF, CF2, CHCI, CHOH, CHOCH3, NH, NCOCH3, CHPh, O, or S, Y = CN; R-, and R5 are selected from hydrogen, C^4 alkyl and hydroxy, R2 is selected from hydrogen, C-|-C4 alkyl, substituted alkyl, C^4 alkoxy C^4 alkyl, C^4 hydroxyalkyl, R5NHC1_4 alkyl, and R5NHC(NH)NHC1_4 alkyl, R3 is selected from hydrogen and C.|-C4 alkyl, R4 is selected from hydrogen, C1-4 alkyl, substituted alkyl, CrC4 alkoxy, C1-C4 alkanoyloxy, hydroxy, amino, nitro, C2-C6 alkenyl, acyl and halogen, n =1 or 2, m = 0, 1, or 2, R is as defined in the patent. WO 2005095339 discloses compounds of formula (D),
wherein R is R1-X-Y-(CH2)m- or R1-X-Y-(CH2)n(C(CH3)2)-, (C3-C12)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C1-C3)hydroxyalkyl, (C^Cgjalkyl, or R1-X-Y-(CH2)p-, wherein p is zero, one, two, or three; R1 is heterocyclyl(C0-C8)alkyl. X is a bond, -O-, -S-, -CO-. Y is a bond or NR2. WO 2006/011035 describes DPP-IV inhibitors of formula (E),
wherein: Y is-S(O)m-, -CH2-, -CHF-, or-CF2-; Xand Z are independently-C(=O)-, -NR3-, -O-or-S(O)m-; each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [—] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cylcoalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; R2 is hydrogen, nitrile (-CN), COOH, or an isostere of carboxylic.
Objective [0010] Although DPP IV inhibitors such as Sitagliptin and Vildagliptin are approved as drugs and many more are in different stages of development, there is still a need for novel compounds that are selective over other members of the family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9 (G. Lankas, et al., "Dipeptidyl Peptidase-IV Inhibition for the Treatment of Type II Diabetes," Diabetes, 2005, 54, 2988-2994).
[0011] With an objective of developing novel DPP IV inhibitors for lowering blood glucose, free fatty acids, cholesterol and triglyceride levels in type II diabetes, treating food intake disorder (Scand. J. Immunol., 1999, 50, 536-540) and treating autoimmune diseases such as multiple sclerosis and rheumatoid arthritis we focused our research to develop potent, stable and selective novel DPP IV inhibitors; efforts in this direction have led to compounds having the general formula (I).
[0012] The main objective is to provide novel DPP IV inhibitors and their pharmaceutically acceptable salts useful for treatment of disorders associated with insulin resistance such as hyperglycemia, low glucose tolerance, insulin resistance (European Journal of Pharmacology, 2008, 588 325-332; European Journal of Pharmacology, 2000, 404, 239-245), obesity (69th scientific session ADA Abstract No: 543-P, 2009), lipid disorders (Diabetes. Vase. Dis. Res., 2006, 3, 159-65), dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, coronary artery disease, peripheral vascular disease [Clin. Res. Cardiol., 2009, 98, 75-79], and its sequelae, vascular restenosis, pancreatitis, abdominal obesity (69th scientific session, ADA, Abs No. 543-P, 2009), nonalcoholic fatty liver disease (Med. Sei. Mónit., 2009, 15(4): HY1-5), nonalcoholic steatohepatitis (Med Sei Mónit, 2009, 15(4): HY1-5), syndrome X, polycystic ovarian syndrome and other disorders where insulin resistance is a component.
[0013] Yet another objective is to provide novel DPP IV inhibitors and their pharmaceutically acceptable salts that are also useful for the treatment of diabetic complications ("Effects of Vildagliptin twice daily vs. Sitagliptin once daily on 24-hour acute glucose fluctuations"Journal of Diabetes and Its Complications, 2009, Article in Press) such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic cataract and the like.
[0014] Another objective herein is to provide novel DPP IV inhibitors and their pharmaceutically acceptable salts that are also useful for the treatment of irritable bowel syndrome, inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, other inflammatory conditions (Trends in Pharmacological Sciences, 2009, 30, 600-607), neuro-degenerative diseases cognition disorders, anxiolytic, analgesic (US 2009/0017015, US 7132104), Immune modulators (69th scientific session ADA Abstract No: 1948-P, 2009), Wound Healing (69th scientific session ADA, Abstract No: 596-P, 2009).
[0015] Another objective herein is to provide novel DPP IV inhibitors and their pharmaceutically acceptable salts having
enhanced activities, without toxic effects or with reduced toxic effects.
[0016] As most of the cyanopyrrolidine class of DPP IV inhibitors are associated with inherent chemical instability due to formation of inactive diketopiperazine (Current Topics in Medicinal Chemistry, 2005, 5,1623-1637), one of our objective is to provide novel DPP IV inhibitors devoid of such inherent chemical instability due to formation of inactive diketopiperazine.
[0017] Yet another objective herein is to provide a process for the preparation of novel DPP IV inhibitors of the formula (I) and their pharmaceutically acceptable salts.
Summary of the invention [0018] The present invention provides compounds of the formula (I),
their tautomeric forms, stereoisomers and pharmaceutically acceptable salts thereof; wherein Y represents -CH2- or -CHF-; m and n are 1 ; p is 0, 1 or 2; X represents a bond, C^Cg alkylene (e.g., -CH2-) or -C(=O)-; R1 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -N3, -S(O)pR1°, -NR1°S(O)pR11, -CN, -COOR10, -CONR10R11, - OR10, -NR10R11 or-NR10COR11 or a group selected from:
wherein R12 represents hydrogen or substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, hydrox-ylalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; R2 and R4 independently represent hydrogen or alkyl, or R2 and R4 can be combined together to form an optionally substituted 4-10 membered ring having 0-4 hetero atoms selected from N, O and S; R3 represents alkyl; R5 represents hydrogen; R6 represents hydrogen; R7 represents hydrogen; R8 is -CN; R10and R11 independentlyrepresenthydrogen, nitro, hydroxy, cyano,formyl, acetyl, halogenoroptionallysubstituted groups selected from amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl and heteroarylalkyl;
when the groups R1, R2, R4, R10, R11 and R12 are substituted or when the term "substituted" is used, the substituents are one or more and are selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=O), thioxo (=S), thioalkyl, amino, hydrazino, formyl, alkyl, haloalkyl, alkoxy, haloalkoxy, arylalkoxy, cycloalkyl, cycloalkyloxy, aryl, heterocycloalkyl, heteroaryl, alkylamino, tolyl, -COORa, - C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb, -NRaC(O)NRbRc, -NRaC(S)NRbRc, - N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb, -NRaC(O)Rb, -NRaC(S)Rb, - SONRaRb, -SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb, -OC(O)Ra, -RaNRbRc, -RaORb, -SRa, -SORa and -SO2Ra; the substituents are further optionally substituted by one or more substituents as defined above; wherein Ra, Rb and Rc independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl and cycloalkenyl; or Ra and Rb can be combined together to form a ring structures having 4-8 atoms.
[0019] The present invention also provides a process for the preparation of a compound of formula (I) according to the invention, by coupling of the compound of formula (II), which is in its free, salt or protected form, with a compound of formula (III)
wherein; L represents leaving groups selected from chloro, bromo, iodo, tosylates, mesylates and triflates; PG represents hydrogen or protecting groups comprising acetyl, trifluoroacetyl, arylsulphonyl, nosyl, tosyl, -Boc or -CBz; and n, R1, R2, R3, R4, R5, R6, R7, R8, X and Y are as defined above.
[0020] The present invention also provides a compound of formula (II) as defined above which is selected from compounds of formula (II-2) and (II-3)
wherein the group Y1 represents SO2 or CO; PG represents hydrogen or protecting group which is -Boc; n, R12 are as defined above.
[0021] The present invention also provides a compound of formula (II) as defined above, which is selected from compounds of formula (II-4), (II-5), (II-6), (II-7), (II-8), (II-9) and (11-10)
wherein the groups R1, R12 are as defined above and PG represents hydrogen or protecting group which is -Boc. [0022] The present invention also provides a compound of formula (II) as defined above, which is selected from: 1. tert-Butyl( 1 R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentylcarbamate;
2. ((1 S,3R)-3-(tert-Butoxycarbonylamino)-2,2,3-trimethylcyclopentyl)methyl methanesulfonate; 3. tert-Butyl( 1 R,3S)-3-(azidomethyl)-1,2,2-trimethylcyclopentylcarbamate; 4. tert-B uty l[(1 R,3S)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 5. (1S,3R)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentane carboxylic acid; 6. tert-B uty I [( 1 S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 7. tert-B uty I [( 1 S,3R)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl]carbamate; 8. Methanesulfonic acid (1 R,3S)-3-t-butoxycarbonylamino-2,2,3-trimethyl-1-cyclopentylmethyl ester; 9. tert-B uty I [( 1 S,3R)-3-(azidomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 10. tert-Butyl[(1 S,3R)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 11. (1 R,3S)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentane carboxylic acid; 12. tert-Butyl[(1S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 13. (1 R,5R)-1-Amino-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octane-2,4-dione; 14. (1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-amine; 15. (1 R,5R)-1-Amino-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one; 16. (1 R,SR)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine; 17. (1S,5S)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine; and 18. 3-(((1 S,3S)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-1,2,4-oxadiazol-5-yl)methanol hydrochloride.
[0023] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) according to the invention, or a pharmaceutically acceptable salt thereof as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate.
[0024] The present invention also provides the compound according to the invention for use in the treatment or prevention of diabetes or diabetic complications.
[0025] The present invention also provides the compound according to the invention for use in the treatment of a metabolic disorder; Type II diabetes; impaired glucose tolerance; insulin resistance; food intake disorder; obesity; impaired fasting glucose; dyslipidemia; hypercholesterolemia or diabetic complications comprising stroke, coronary artery disease, hypertension, peripheral vascular disease, neuropathy, retinopathy, non-alcoholic fatty liver disease and nonalcoholic steatohepatitis; neurodegenerative diseases; cognition disorders and anxiolytic diseases.
[0026] The present invention also provides the compound according to the invention for use in the (i) prevention or treatment of hyperglycemia (ii) reduction of body weight (iii) wound healing (iv) immuno modulation (v) reducing pain.
Detailed description [0027] Described are compounds of the formula (I),
their tautomeric forms, stereoisomers and pharmaceutical acceptable salts thereof; wherein Y represents -CH2- or-CHF-; m and n are 1 ; p is 0, 1, or 2; X represents a bond, C^Cg alkylene chain (e.g., -CH2-) or-C(=O)-; R1 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -N3, -S(O)pR10, -NR10S(O)pR11 -CN, -COOR10, -CONR10R11 - OR10, -NR10R11, or-NR10COR11 or a group selected from:
wherein R12 represents hydrogen or substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, hydrox-ylalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; R2 and R4 independently represent hydrogen or alkyl, or R2 and R4 can be combined together to form an optionally substituted 4-10 membered ring having 0-4 hetero atoms selected from N, O and S; [0028] Non-limiting examples include:
R3 represents alkyl; R5 represents hydrogen; R6 represents hydrogen; R7 represents hydrogen; R8 is -CN; R10 and R11 may be the same or different and are independently hydrogen, nitro, hydroxy, cyano, formyl, acetyl, halogen or optionally substituted groups selected from amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl and heteroarylalkyl.
[0029] The term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: halogens such as fluorine, chlorine, bromine and iodine; hydroxy; nitro; cyano; oxo (=O); thioxo (=S); azido; nitroso; amino; hydrazino; formyl; alkyl; alkoxy; aryl; haloalkyl groups such as trifluoromethyl, tribromomethyl, trichloromethyl and the like; haloalkoxy groups such as -OCH2CI, -OCHF2, -OCF3 and the like; arylalkoxy groups such as benzyloxy, phenylethoxy and the like; cycloalkyl; -O-cycloalkyl; heterocyclyl; heteroaryl; alkylamino; -O-CH2-cycloalkyl; -COORa; -C(O)Rb; -C(S)Ra; -C(O)NRaRb; -NRaC(O)NRbRc; -N(Ra)SORb; -N(Ra)SO2Rb; -NRaC(O)ORb; -NRaRb; -NRaC(O)Rb; -NRaC(S)Rb; -SONRaRb; -SO2NRaRb; -ORa; -ORaC(O)ORb; -OC(O)NRaRb; -OC(O)Ra; -RaNRbRc; -RaORb; -SRa; -SORa and -SO2Ra; Ra, Rb and Rc each independently represent hydrogen atom; substituted or unsubstituted groups selected from alkyl; alkylene; aryl; arylalkyl; cycloalkyl; heterocyclyl; heteroaryl and heteroarylalkyl and Ra, Rb and Rc are also combined to form a 3-7 membered ring having 0-2 hetero atoms. The substitutents may be optionally further substituted.
[0030] The term "alkyl" refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms that are attached to the rest of the molecule by a single atom. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl and the like.
[0031] The term "alkylene" refers to -(CH2)n-wherein n represents an integer. Non limiting examples of alkylene group include -CH2-, -CH2CH2-, -CH2CH2CH2- and the like.
[0032] The term "hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen has been replaced with an -OH group. Non -limiting examples of hydroxyalkyl groups include -CH2OH,
-CH2CH2OH, - CH2CH2CH2OH and the like.
[0033] The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Preferred aryl groups include, without limitation, phenyl, naphthyl, indanyl, biphenyl and the like. Substituted or unsubstituted arylene groups such as phenylene, biphenylene, naphthylene, anthracenylene, phenanthrylene, indanylene and the like.
[0034] The term "arylalkyl" refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Preferred arylalkyl groups include, without limitation, -CH2C6H5, -C2H4C6H5 and the like. [0035] The term "heterocyclyl" refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized and the ring radical may be partially or fully saturated. Preferred heterocyclyl groups include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carba-zolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahy-droisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxadiazolyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidine 1,1-dioxide, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tet-rahydropyranyl, chromanyl, isochromanyl, oxabicyclo[3.2.1]octane, 3-oxabicyclo [3.2.1]octanone, 3-azabicyclo[3.2.1]oc-tane-2,4-dione and 3-azabicyclo[3.2.1]octane. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
[0036] The term "heteroaryl" refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heterocycloalkyl" refers to a heterocyclic ring radical as defined above. The heterocycloalkyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
[0037] The term "heteroarylalkyl" refers to a heteroaryl ring radical as defined above, directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from an alkyl group.
[0038] The term "heterocyclylalkyl" refers to a heterocyclyl ring radical as defined above, directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from an alkyl group. [0039] The term "cycloalkyl" refers to non-aromatic mono or polycyclic ring systems of about 3 to 12 carbon atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like; preferred polycyclic rings include, without limitation, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g. spiro [4.4]-non-2-yl and the like.
[0040] The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched chain having about 2 to 10 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
[0041] The term "arylalkenyl" refers to an aromatic ring radical directly bonded to an alkenyl group. The aryl radical may be attached to the main structure at any carbon from the alkenyl group. Preferred arylalkenyl groups include, without limitation, phenylethenyl, phenylpropenyl and the like.
[0042] The term "heteroarylalkenyl" refers to a heteroaryl ring radical directly bonded to an alkenyl group. The heteroaryl radical may be attached to the main structure at any carbon from the alkenyl group. Preferred heteroarylalkenyl groups include, without limitation, thienylpropenyl, pyridinylethenyl and indolylpropenyl.
[0043] The term "alkylthio" refers to an alkyl group attached via a sulfur linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkylthio groups include, without limitation, -SCH3, -SC2H5 and the like.
[0044] The term "alkoxy" refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. Preferred alkoxy groups include, without limitation, -OCH3, - OC2H5 and the like.
[0045] The term "aryloxy" refers to an aryl group attached via an oxygen linkage to the rest of the molecule. Preferred aryloxy groups include, without limitation, -O-phenyl, -O-biphenyl and the like.
[0046] The term "alkylamino" refers to an alkyl group as defined above attached via an amino linkage to the rest of the molecule. Preferred alkylamino groups include, without limitation, -NHCH3, -N(CH3)2 and the like.
[0047] The term "alkynyl" refers to straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.
[0048] The term "arylalkynyl" refers to an aromatic ring radical directly bonded to an alkynyl group. The aryl radical may be attached to the main structure at any carbon atom from the alkynyl group.
[0049] The term "heteroarylalkynyl" refers to a heteroaryl radical directly bonded to an alkynyl group. The heteroaryl radical may be attached to the main structure at any carbon atom from the alkynyl group.
[0050] The term "ring" refers to substituted or unsubstituted monocyclic or polycyclic, saturated or partially saturated or aromatic containing 0 to 4 heteroatoms selected from O, S or N.
[0051] "Tautomers" are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).
[0052] Furthermore, the compound of formula (I) can be its tautomeric forms, stereoisomers, geometrical isomers, rotomers, polymorphs, solvates, pharmaceutically acceptable salts and pharmaceutical compositions.
[0053] It is understood that included in the family of compounds of formula (I) are isomeric forms including tautomers and stereoisomers (diastereoisomers, enantiomers and geometrical isomers in Έ" or "Z" configurational isomer or a mixture of E and Z isomers). It is also understood that some isomeric forms such as diastereomers, enantiomers and geometrical isomers can be separated by physical and/ or chemical methods and by those skilled in the art.
[0054] Compounds disclosed herein may exist as single stereoisomers, racemates and or mixtures of enantiomers and or/diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.
[0055] The active compounds disclosed can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form (different polymorph) and have any particle size. Furthermore, the compound particles may be micronized or nanoized, or agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.
[0056] The term "protecting group" or "PG" refers to a substituent that block or protects a particular functionality while permitting other functional groups on the compound to react. For example, an "amino-protecting group" is a substituent attached to an amino group that block or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethylen oxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups, but are not limited to, include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2-(trimeth-ylsilyl)ethyl, 2-(trimethylsilyl) ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenyl phos-phino)ethyl, nitroethyl and the like.
[0057] The term "treating" or "treatment" of a state, disorder or condition includes: (1) preventing or delaying the appearance of one or more clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of their clinical or subclinical symptoms.
[0058] The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician. The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
[0059] A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
[0060] Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn, salts of organic bases such as Λ/,Λ/’-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine, salts of chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine and serine, salts of non-natural amino acids such as D-isomers or substituted amino acids, salts of guanidine, salts of substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl, ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts where appropriate such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, and acetates such as trifluoroacetate, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. Yet other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of the invention with alkyl halides or alkyl sulphates such as Mel or (Me)2SO4. Preferred pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, hydrochloride, maleate, methanesulfonate, oxalate, succinate, 2-oxoglutarate, benzoate, salicylate, benzenesulfonate, and naphthalene-1,5-disulfonic acid.
[0061] Pharmaceutically acceptable solvates include hydrates and other solvents of crystallization such as alcohols. The compounds of the present invention may form solvates with standard low molecular weight solvents using methods known in the art.
[0062] The pharmaceutical compositions of the present invention comprise at least one compound of the present invention and a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent. For example, the compounds of the present invention may be associated with a pharmaceutically acceptable excipient such as a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
[0063] The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
[0064] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castoroil, peanutoil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
[0065] The pharmaceutical compositions may be in conventional forms, for example capsules, tablets, soft or hard gelatin, dragees containing the active ingredient in powder or pellet form, troches and lozenges, aerosols, solutions, suspensions or products for topical applications. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
[0066] The route of administration may be any route, which effectively transports the active compound of the invention, which inhibits the enzymaticactivity of DPP-IV to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic such as with an ophthalmic solution or topical such as with a topical ointment. The oral route is preferred.
[0067] Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
[0068] Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
[0069] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castoroil.
[0070] Described herein is also a method of treating a condition that is regulated or normalized via inhibition of DPP-IV in a subject by administering a therapeutically effective amount of a compound or pharmaceutical composition of present invention.
[0071] Described herein is also a method of: treating a metabolic disorder, lowering blood glucose, treating Type II diabetes, treating impaired glucose tolerance (IGT), treating impaired fasting glucose (IFG), preventing or treating hyperglycemia, delaying the progression of impaired glucose tolerance (IGT) to Type II diabetes, delaying the progression of non-insulin requiring Type II diabetes to insulin requiring Type II diabetes, increasing the number and/or the size of beta cells, preventing or treating beta cell degeneration, such as apoptosis of beta cells, treating food intake disorders, treating obesity, regulating appetite or inducing satiety, treating dyslipidemia, hypercholesterolemia, or diabetic complications comprising stroke, coronary artery disease, hypertension, peripheral vascular disease, neuropathy, retinopathy, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, treating functional dyspepsia, such as irritable bowel syndrome, treatment and/or prophylaxis of a disease selected from diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, pain, wound healing, ulcerative colitis, Crohn’s disease, obesity, metabolic syndrome, neurodegenerative diseases, cognition disorders and anxiolytic diseases in a subject by administering a therapeutically effective amount or pharmaceutical composition of compounds of formula (I).
[0072] The compounds offormula (I) may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g., Type II diabetes, IGT, IFG, obesity, appetite regulation or as a blood glucose lowering agent.
[0073] Use of a Compound of formula (I), for the manufacture of a medicament for the treatment of the above said diseases.
[0074] The compounds of formula (I) are effective over a wide dosage range. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated.
[0075] A term once described, the same meaning applies for it, throughout the patent.
Representative compounds include: [0076] 1. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolid-ine-2-carbonitrile; 2. (2S,4R)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrroli-dine-2-carbonitrile methanesulfonate; 3. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolid-ine-2-carbonitrile; 4. (2S,4S)-1-(2-((1S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrroli-dine-2-carbonitrile methanesulfonate; 5. (2S,4R)-1-(2-((1S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrroli-dine-2-carbonitrile methanesulfonate; 6. (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolidine-2-carbon-itrile; 7. (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)pyrrolidine-2-carbon-itrile methanesulfonate; 8. (S)-1-(2-((1 R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)pyrrolidine-2-carbon-itrile; 9. (S)-1-(2-((1 R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)pyrrolidine-2-carbon-itrile methanesulfonate; 10. (2S,4S)-1-(2-((1 R,3S)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrro-lidine-2-carbonitrile; 11. (2S,4S)-1-(2-((1 R,3S)-3-((1H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrro-lidine-2-carbonitrile; 12. (2S,4S)-1-(2-((1 S,3R)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrro-lidine-2-carbonitrile; 13. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrro-lidine-2-carbonitrile methanesulfonate; 14. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl)cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 15. (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 16. (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 17. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyljmethanesulfonamide; 18. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyljmethanesulfonamide; 19. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4-fluorobenzenesulfonamide; 20. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4-fluorobenzenesulfonamide; 21. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-2-fluorobenzamide; 22. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4,4-difluorocyclo hexanecarboxamide; 23. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4,4-difluorocyclohexanecarboxamide; 24. 6-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1 -yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)methyl- amino)nicotinonitrile; 25. 6-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)methyl-amino)nicotinonitrile; 26.2-(((1 S, 3R)-3-(2-((2S, 4S)-2-Cyano-4-fluoropyrrolidin-1 -yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)methyl-amino)nicotinonitrile; 27. (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 28. (2S,4S)-1-(2-((1 R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclo pentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 29. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclo pentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 30. (2S,4S)-1-(2-((1S,3R)-3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethyl cyclo pentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 31. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoropyrrolid-ine-2-carbonitrile methanesulfonate; 32. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino) acetyl)-4-fluoropyrrolid-ine-2-carbonitrile; 33. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(morpholinomethyl) cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 34. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholinomethyl)cyclopentylamino)acetyl)pyrrolidine-2-car-bonitrile; 35. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholinomethyl)cyclo pentylamino)acetyl)pyrrolidine-2-carbonitrile dimethanesulfonate; 36. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclo pentylamino)acetyl)pyrrolidine-2-carbonitrile; 37. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 38. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 39. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 40. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 41. (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-3-((4-hydroxypiperidin-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile; 42. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 43. (2S,4R)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 44. (S)-1-(2-((1 R,3S)-1,2,2-Trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylamino)acetyl)pyrroli-dine-2-carbonitrile; 45. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)metliyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 46. (S)-1-(2-((1 S,3R)-1,2,2-Trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylamino)acetyl)pyrroli-dine-2-carbonitrile; 47. (2S,4R)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 48. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 49. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 50. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile; 51. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile; 52. (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 53. (2S,4S)-1-(2-((1 R,3R)-3-(Cyanomethyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carboni- trile; 54. (2S,4S)-4-Fluoro-1-(2-((1 R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 55. (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 56. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl) pyrrolidine-2-carbonitrile; 57. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile methanesulfonate; 58. (2S,4S)-1-(2-((1 S,3S)-3-((5-ferf-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 59. (2S,4S)-1-(2-((1 S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 60. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 61. (2S,4S)-4-Fluoro-1 -(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile methanesulfonate; 62. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 63. (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 64. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile 65. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 66. (S)-1-(2-((1 S,3R)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile methanesulfonate; 67. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 68. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 69. (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 70. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 71. (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile 72. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 73. (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile; 74. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile; 75. (S)-1-(2-((1 R,5R)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-car-bonitrile; 76. (2S,4S)-4-Fluoro-1-(2-((1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-l-ylamino)acetyl)pyrrolidine-2-carbonitrile; 77. (2S,4R)-4-Fluoro-1-(2-((1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 78. (S)-1-(2-((1 R,5R)-3,5,8,8-Tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 79. (S)-1-(2-((1 R,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 80. (S)-1-(2-((1 R,5R)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 81. (2S,4S)-4-Fluoro-1-(2-((1 R,5R)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-car-bonitrile; 82. (2S,4S)-4-Fluoro-1-(2-((1S,5S)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbon-itrile; and 83. (2S,4S)-1-(2-((1S,3R)-3-(3-(1 H-1,2,4-triazol-1-yl)propyl)-2,2,3-trimethylcyclopentyl amino)acetyl) -4-fluoropyr-rolidine-2-carbonitrile [0077] According to another feature of the present invention, there is provided a process for the preparation of compounds of the formula (I), wherein all other symbols are as defined earlier, as shown in the scheme-1.
Scheme-I
[0078] Wherein; L represent suitable leaving groups selected from chloro, bromo, iodo, tosylates, mesylates, triflates and similar leaving groups; PG represents hydrogen or protecting groups such as acetyl, trifluoroacetyl, Fmoc, arylsulphonyl, nosyl, tosyl, Boc or CBz; m = 1 and all the other symbols are same as described above.
[0079] The reactions described in the processes outlined above are performed using the methods described herein:
Compound of formula (II) is coupled with compound of formula (III) in solvents selected from toluene, N, N-dimeth-ylformamide (DMF), tetra hydrofuran (THF), acetonitrile, ethyl acetate, /V-methyl-2-pyrrolidone, dimethylsulphoxide (DMSO), dichloroethane, chloroform or a mixture thereof, in the presence of a base such as triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, alkali hydroxides such as sodium hydroxide, potassium hydroxide, potassium carbonate, alkaline earth metal hydroxides, alkali carbonates such as, cesium carbonate and the like, and potassium iodide or sodium iodide to give the compound of formula (I). The reaction is carried out at a temperature ranging from room temperature to reflux temperature, mostly 0 °C-100 °C.
[0080] The compound of formula (III) can be prepared by the methods known in Journal of Medicinal Chemistry, 2003, 46, 2774-2789; Bioorganic Medicinal Chemistry, 2008, 16, 4093-4106; W02007/113634; W02003/002553 and WO98/19998.
[0081] The compound of formula (II) can be prepared by following reaction sequence as summarized in scheme (ll-IX)
Scheme II:
[0082] The reactions in the processes outlined in Scheme II are described in following steps Step I: Mono esterification of camphoric acid (la) by purging anhydrous hydrogen chloride to alcoholic solution of camphoric acid at ambient temperature gave (lb).
[0083] Step Ila: Carboxylic acid function of formula (lb) is converted to amine function of formula (Ic) by the usual methods known in the art. For example, first converting acid to acid chloride using oxalyl chloride or thionyl chloride in a solvent like dichloromethane, toluene, tetra hydrofuran, chloroform or a mixture thereof. The reaction is carried out at a temperature ranging from 0 °C to reflux temperature, mostly 0-100 °C. The acid chloride was treated with ammonia in organic solvents such as ethyl acetate, tetrahydrofuran, dichloromethane or aqueous ammonia to afford amide. Amide is converted to amine under conventional Hofmann conditions. Amine can also be prepared by phenyliodonium bis(tri-fluoroacetate) (PIFA) or phenyliodonium diacetate (PIDA)-promoted Hofmann rearrangement of amide.
[0084] Alternatively, acid is converted to amine by treatment with an azide like NaN3 or, diphenylphosphoryl azide (DPPA) under acidic conditions in presence of solvents like dichloromethane, chloroform, acetonitrile at a temperature range 30-50 °C.
[0085] Step lib: The amine thus formed is protected by conventional amine protecting groups like Boc, CBz, Fmoc etc. [0086] Alternatively, Boc protected amine of formula (Ic) is prepared by oxidative rearrangement of amide with lead tetraacetate in t-BuOH as described in J. Org. Chem., 1975, 40, 3554-3561.
[0087] Step III: Reduction of compound of formula (Ic) using suitable reducing agents such as LiAIH4, NaBH4 and DIBAL-H in inert solvent like THF, ether or mixture thereof at a temperature ranging from 0 °C- 70 °C to afford alcohol of formula (Id).
Scheme III:
[0088] The reactions in the processes outlined in Scheme III are described in following steps Step I: Compound of formula (le) is prepared by transforming hydroxyl group of compound of formula (Id) to a leaving group L by mesylation, tosylation or halogenation in presence of organic base such as triethylamine, Ν,Ν-diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpyrrolidine in an inert solvent such as DCM, tetra hydrofuran (THF), CHCI3 orsimilar at about 0 °C-10 °C. Step Ila: Coupling of compound of formula (le) with a compound of formula R1H gave the Compound of formula (11-1) in the solvents selected from toluene, DMF, tetra hydrofuran, acetonitrile, ethyl acetate, /V-methyl-2-pyrro-lidone, DMSO, dichloroethane, chloroform ora mixture thereof, in the presence of a base such as triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, alkali hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides, alkali carbonates such as, potassium carbonate, cesium carbonate and the like, to give the compound of formula (11-1) (R1 is as defined earlier). The reaction is carried out at a temperature ranging from 0 °C to reflux temperature, mostly 0 -150 °C. Step lib: Amine deprotection of compound of formula (11-1) wherein PG is protecting group affords the compound of formula (11-1) wherein PG is hydrogen, in its salt or free base form. Deprotection may be carried out by conventional methods known in the art, using acids such as hydrochloric acid, acetic acid, trifluoroacetic acid or by hydrogenation using catalysts such as Pd/C, Rh/C, Pt/C, Raney Nickel in the presence of solvents such as dichloromethane, ethyl acetate, water and the like or a mixture thereof, at a temperature in the range of-10 °C to 50 °C.
[0089] Step Ilia: Azidation reaction is carried out by reacting compound of formula (le) with sodium azide in the solvents selected from toluene, DMF, dimethylacetamide (DMA), tetrahydrofuran, /V-methyl-2-pyrrolidone, DMSO or a mixture thereof at 50 -90 °C. Step 111 b: Azide compounds thus formed is reduced to amine of formula (If) by hydrogenation using catalysts such as Pd/C, Rh/C, Pt/C, Raney Nickel in the presence of solvents such as dichloromethane, ethylacetate, water and the like or a mixture thereof, at a temperature in the range of 0 °C to 50 °C.
[0090] Step IVa: The amine prepared in step lllb is reacted with X1CH2(CH2)nCH2Y1X1, wherein X1 is a halogen selected from F, Cl, Brand I ; Y1 is SO2orCO, in presence of organic bases like triethylamine, Ν,Ν-diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpyrrolidine in an inert solvent such as DCM, THF, CHCI3 and the like at about 0 -10 °C followed by cyclization in presence of bases like NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide in solvents such as methanol, ethanol gave compound of formula (I I-2), wherein PG represents a protecting group. Step IVb: Amine deprotection is carried out similar to step lib to afford compound of formula (I i-2) in its salt orfreebase form. [0091] Step V: Compound of formula (le) is treated with a cyanating agent like NaCN, KCN, CuCN in presence of aprotic solvents such as DMF at 80-100 °C to afford compound of formula (Ig).
[0092] Step VI: Compound of formula (Ig) on treatment with hydroxylamine (50% aqueous solution) gave amidoxime, which on coupling with appropriate acid followed by cyclization under acidic condition affords compound of formula (II-3) wherein PG represents protecting group. Amine deprotection is carried out similar to step lib to afford compound of formula (II-3) in its salt orfreebase form.
[0093] Compounds of formula (11-1), (I i-2) and (I I-3) were treated with compound of formula (III) as shown in scheme I to form final compound of formula (I).
Scheme IV:
[0094] The reactions in the processes outlined in Scheme IV are described in following steps Step I: Amination of compound offormula (Ih) as described in amination step of scheme II affords the compound offormula (11-4). Compound offormula (Ih) was prepared according to method described in Liebigs Ann. 1996, 1941 - 1948.
[0095] Step II: The amine formed in step I is protected by conventional amine protecting groups like Boc, Cbz, Fmoc, acetyl, benzoyl, and benzyl and the like to give compound offormula (li). The reaction can be carried out in presence of organic base like triethylamine, Ν,Ν-diisopropyl-ethylamine, pyridine, N-methylmorpholine, N-methylpyrrolidine in an inert solvent such as DCM, THF, CHCI3 and like at temperature ranging from 0 °C-50 °C.
[0096] Step III: Reduction of lactone to lactol is carried out by using suitable reducing agents selected from LiAIH4, NaBH4, LiBH4, LiEt3BH in an inert solvent like THF at temperature ranging from -78 °C to 70 °C to afford compound of formula (Ij).
[0097] Step IV: Lactol is deoxygenated to cyclic ether offormula (I I-5) using Et3SiH and BF3.Et2O in an inert solvent like THF, DCM at temperature ranging from -10 to 10 °C. Amine protected lactol is deprotected similar to deprotection step of scheme III to afford compound of formula (Ii-5) in its salt or freebase form. If protecting group is acetyl, it is deprotected by method described in Org. Lett., 2009, 11 (2), 433-436. Compounds offormula (II-4) and (II-5) were treated with compound offormula (III) as shown in scheme I to form final compound offormula (I).
Scheme V:
[0098] The reactions in the processes outlined in Scheme V are described in following steps Step I: Amination of compound offormula (Ik) as described in amination step of scheme II affords the compound offormula (I I-6). Compound offormula (Ik) prepared according to method described in Liebigs Ann. 1996, 1941-1948.
[0099] Step II: Reduction of imide to amine is carried out by using suitable reducing agents selected from LiAIH4, NaBH4, LiBH4 LiEt3BH in an inert solvent like THF at temperature ranging from 0 °C to 70 °C to afford compound of formula (II-7). Compounds offormula (Ii-6) and (II-7) were treated with compound offormula (III) as shown in scheme I to form final compound offormula (I).
Scheme VI:
[0100] The reactions in the processes outlined in Scheme VI are described in following steps Step la: Hydrolysis of ester is carried out in presence of suitable base like NaOH, KOH in solvents like tetrahydrofuran, methanol, ethanol,
1,4-dioxane or mixture thereof to afford acid.
[0101] Step lb: The above acid is coupled with appropriate amidoxime using coupling agents like N,N’-Dicyclohexyl-carbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), carbonyldiimidazole (CDI) and the like in suitable solvents like tetrahydrofuran, dichloromethane, toluene and the like followed by cyclization in presence of catalytic amount acid in refluxing toluene afforded the compound of formula (II-8).
[0102] Compound of formula (ll-8)was treated with compound of formula (III) as shown in scheme I to form final compound of formula (I).
Scheme VII:
[0103] The reactions in the processes outlined in Scheme VII are described in following steps Step I: The acid (lb) is transformed to compound of formula (II) as described in scheme VI.
[0104] Step II: Hydrolysis of ester function of compound of formula (II) followed by amination as described in amination step of scheme II affords the compound of formula (II-9).
[0105] Compounds of formula (II-9) was treated with compound of formula (III) as shown in scheme I to give final compound of formula (I).
Scheme VIII:
[0106] The reactions in the processes outlined in Scheme VIII are described in following steps Step I: Carboxylic acid function of compound of formula (lb) is selectively reduced by borane-dimethylsulfide complex in presence of ester to afford alcohol of formula (Im). Step II: Oxidation of alcohol (Im) to aldehyde is carried out using oxidizing agents like pyridinium chlorochromate, Jones reagent, Collins reagent, Dess-Martin periodinane orwith DMSO activated with oxalyl chloride (Swern oxidation) to give aldehyde of formula (In). Reaction can be carried out in inert solvents like DCM, THF and like at temperature ranging from -78 °C to room temperature.
[0107] Step III: Alkene of formula (Io) from aldehyde of formula (In) was prepared by means of Wittig reaction conditions. Reaction are carried out in solvents inert like DCM, THF and the like at temperature ranging from 0 °C to room temperature in presence of sodium hydride.
[0108] Step IVa: Alkene of formula (Io) was reduced by reducing agents such as Pd/C, Raney Nickel in presence of hydrogen in suitable solvents like THF, MeOH, ethylacetate and the like at temperature ranging from room temperature to reflux temperature of the solvent used.
[0109] Step IVb: Deprotection of the above reduced compound is carried out by the conventional methods known in
the art, for instance, by acids such as hydrochloric acid, trifluoroacetic acid or by catalytic amount hydrogenation conditions in suitable solvents like THF, MeOH, ethyl acetate and like at temperature ranging from room temperature to reflux temperature of the solvent used.
[0110] Step V: Compound offormula (Ip) is reduced to alcohol offormula (Iq) as described in step I.
[0111] Step VI: Compound offormula (Ir) is prepared by transforming hydroxyl group of compound offormula (Iq) to a leaving group L by mesylation, tosylation or halogenation in presence of organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpyrrolidine in an inert solvent such as DCM, THF, CHCI3 and the like at about 0 °C-10 °C.
[0112] Step VII: Coupling of compound offormula (Ir) with compound offormula R1H gave the compound offormula (Is) in solvents selected from toluene, DMF, tetra hydrofuran, acetonitrile, ethyl acetate, /\/-methyl-2-pyrrolidone, DMSO, dichloroethane, chloroform or a mixture thereof, in the presence of a base such as triethylamine, pyridine, diisopropyl-ethylamine, 4-dimethylaminopyridine, alkali hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides, alkali carbonates such as, potassium carbonate, cesium carbonate and the like, to give the intermediate offormula (Is). The reaction is carried out at a temperature ranging from 0 °C to reflux temperature, mostly 0 °C-150 °C. [0113] Step VIII: Hydrolysis of ester function of compound offormula (Is) followed by amination as described in amination step of scheme II affords the compound offormula (11-10).
[0114] Compound offormula (11-10) was treated with compound offormula (III) as shown in scheme I to form final compound offormula (I).
Scheme IX:
[0115] The reactions in the processes outlined in Scheme IX are described in following steps Step I: Compound of formula (Im) can be prepared similar to step I of scheme III.
[0116] Step II: Coupling of compound offormula (It) with compound offormula R1H according to Step II of scheme III gave the Compound offormula (lu).
[0117] Step III: Hydrolysis of ester function of compound offormula (lu) followed by amination as described in amination step of scheme II affords the compound offormula (11-11).
[0118] Compound offormula (11-11) was treated with compound offormula (III) as shown in scheme I to form final compound offormula (I).
[0119] The examples given below are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
Intermediate-1 : (1S,3R)-Methyl 3-(tert-butoxycarbonylamino)-2,2,3-trimethyl cyclopentanecarboxylate [0120]
[0121] The above intermediate was prepared as per the literature procedure (Journal of Organic Chemistry, 1975, 40, 3554-3561) following the procedure as described below. Step I: To a stirred solution of (1 R,3S)-(+)-camphoric acid (5 g, 25 mmol) in 30 mL of methanol, anhydrous HCI was bubbled for 2 h at room temperature. Methanol was evaporated and the residue was mixed with 5% sodium bicarbonate solution until the effervescence ceased and then 5% sodium hydroxide was added. The diester byproduct was removed by extraction with diisopropyl ether. The aqueous layer was acidified with 10% HCI and extracted with diisopropyl ether. The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to obtain (1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylicacid (4.38 g) in 83% yield. 1H NMR (400MHz, CDCI3) δ ppm 0.84 (s, 3H), 1.25 (s, 6H), 1.53-1.55 (m, 1H), 1.80-1.84 (m, 1H),
2.19-2.22 (m, 1H), 2.25-2.57 (m, 1H), 2.79-2.84 (m, 1H); 3.70 (s, 3H); m/z (M+1): 214.
[0122] Step II: To a solution of (1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid (4.1 g, 19.2 mmol) in 18 mL of DCM and oxalyl chloride (2.1 mL, 24.9 mmol), 2 drops of DMF were added. The solution was stirred for 5 hours at -15 °C. All the volatiles were removed by passing nitrogen gas. The residue was dissolved in THF and the solution added dropwise to 80 mL of anhydrous acetonitrile saturated with NH3gas maintained at-30 °C. The reaction mixture was stirred for another 15 minutes and the volatiles were removed under reduced pressure. The residue was taken in hot ethyl acetate and the solution was filtered; the crude product obtained after evaporation of the solvent was purified by column chromatography to furnish methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (3.45 g) in 84 % yield. 1H NMR (400MHz, CDCI3) δ ppm 0.85 (s, 3H), 1.22 (s, 3H), 1.30 (s, 3H), 1.45-1.48 (m, 1H), 1.80-1.91 (m, 1H), 2.20-2.27 (m, 1H), 2.35-2.43 (m, 1H), 2.79-2.84 (m, 1H), 3.69 (s, 3H), 5.60 (d, J=37.96, 2H) ; m/z (M+1): 213.
[0123] Step III: To a stirred solution of methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (2.6 g; 12.2 mmol) in 12 mL of f-butanol, 0.2 mL of stannic chloride was added followed by lead tetraacetate (7.02 g, 15.86 mmol). The reaction mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure; the residue was taken up in diethyl ether, washed with 10% K2CO3 solution. The ether extract was concentrated and the crude product was purified by column chromatography to obtain methyl (1 S,3R)-3-[(f-butoxycarbonyl)amino]-2,2,3-trimethylcyclopentanecarboxylate (2.58 g) in 74% yield. 1H NMR (400MHz, CDCI3) δ ppm 0.86 (s, 3H), 1.18 (s, 3H), 1.35 (s,3H),1.43 (s,9H), 1.8-1.9 (m,1H), 1.98-2.05 (m,3H), 2.72-2.76 (m, 1H), 3.71 (s, 3H), 4.73(bs, 1H); m/z (M+1 ): 285.
Intermediate-2: t-Butyl(1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl carbamate [0124]
[0125] To a suspension of methyl (1S,3R)-3-[(f-butoxycarbonyl)amino]-2,2,3-trimethyl cyclopentanecarboxylate (2.38 g, 8.3 mmol) in THF (50 mL) and water (5 mL), NaBH4 (2.52 g, 66.8 mmol) was added over a period of three hours. The reaction mixture was heated under reflux for 24 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and water. The organic layerwas separated, dried over anhydrous Na2SO4. The solvent was evaporated to obtain f-butyl [(1 R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl]carbamate (2 g) in 93% yield as a white solid. 1H NMR (400MHz, CDCI3) δ ppm 0.85 (s, 3H), 1.05 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.52 (m, 1H), 1.82-1.96 (m, 4H), 3.53-3.57 (dd, J=7.8 & 17.7 Hz,1H), 3.70-3.74 (dd, J=5.4 & 10.2 Hz, 1H), 4.63 (bs, 1H); m/z (M+1): 258.
Intermediate-3: ((1S,3R)-3-(t-Butoxycarbonylamino)-2,2,3-trimethylcyclopentyl) methylmethanesulfonate [0126]
[0127] To a stirred solution of f-butyl [(1 R,3S)-3-(hydroxymethyl)-1,2,2-trimethyl cyclopentyl]carbamate (2.0 g, 7.78 mmol) in 30 mL of dichloromethane maintained at 0 °C, triethylamine (5.4 mL, 38.9 mmol) was added. To this reaction mixture, methanesulphonyl chloride (1.91 mL, 23.3 mmol) was added dropwise over a period of 30 minutes and the stirring continued for two hours. Subsequently, the reaction mixture was diluted with dichloromethane and water. The layers were separated and the organic layerwas dried over anhydrous Na2SO4 concentrated and dried to give a light yellow colored crude sticky mass, which was purified by column chromatography to furnish methanesulfonicacid (1S,3R)-3-f-butoxycarbonylamino-2,2,3-trimethyl-cyclopentylmethyl ester (2.01 g) in 76% yield as an off-white solid. 1H NMR (400MHz, CDCI3)Ô ppm 0.85 (s, 3H), 1.05 (s, 3H), 1.32 (s, 3H), 1.43 (s, 9H), 1.49(m, 1H), 1.85-2.04 (m, 3H), 2.20-2.24 (m, 1H), 3.01 (s, 3H), 4.10-4.15 (dd, J=8 & 9.24 Hz, 1H), 4.24-4.29 (dd, J=6.44 & 9.52 Hz,1H), 4.47 (s, 1H); m/z (M-55): 280.1 ; [a] D +36.3° (C, 1.0, methanol).
Intermediate-4: t-Butyl(1 R,3S)-3-(azidomethyl)-1,2,2-trimethylcyclopentyl carbamate [0128]
[0129] To a solution of intermediate-3 (1.48 g, 4.41 mmol) in DMF (20 mL), NaN3 (0.57 g, 8.82 mmol) was added and stirred under N2 atmosphere for 12 hours, maintaining the temperature 60 °C. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2x100 mL). The ethyl acetate layers were combined, washed with water, brine, dried over Na2SO4 and concentrated to 0.65 g of azide. 1H NMR (400MHz, CDCI3) δ ppm 0.8 (s, 3H), 0.9(d, 3H), 1.15(s, 3H), 1.43 (s, 9H), 1.68-1.80(m, 1H), 1.90-2.04 (m, 4H), 3.15-3.20 (dd, J=8.64 & 8.88,1H), 3.31-3.42(dd, J=5.4 & 5.56, 1H), 3.08-3.41 (m, 2H), 4.51 (s, 1H).
Intermediate-5: f-Butyl[(1R,3S)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl] carbamate [0130]
The intermediate (4) azide (0.65 g) was dissolved in ethyl acetate and added 5% Pd/C (85 mg) and hydrogenated at 50 psi for 1 hourto give 0.6 g of amine as semi-solid. 1H NMR (400MHz, DMSO-d6) δ ppm: 400 MHz δ 0.69 (s, 3H), 0.98(d, 3H), 1.22(s, 3H), 1.37 (s, 9H), 1.71-1.78(m, 4H), 1.93-1.98(m, 1H), 2.45-2.76 (m, 2H), 6.37 (bs, 2H); m/z(M+H): 257.2.
Intermediate-6: (1S,3R)-3-[(f-Butoxycarbonyl)amino]-2,2,3-trimethyl cyclopentanecarboxylicacid [0131]
[0132] To a solution of intermediate-1 in methanol, NaOH solution was added and refluxed for 3 hours. The reaction mixture was concentrated and acidified with 0.1 N HCI and extracted with ethyl acetate (2x50 mL). Combined ethyl acetate layers were washed with brine, dried with anhydrous Na2SO4 and concentrated. 1H NMR (400MHz, CDCI3) δ ppm 0.93 (s, 3H), 1.18 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.8-1.9 (m, 1H), 1.98-2.05 (m, 3H), 2.72-2.76 (m, 1H), 4.73 (bs, 1H); m/z(M-H): 270.1.
Intermediate-7: f-Butyl [(1 S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl] carbamate [0133]
[0134] To a mixture of NaCN (1.18 g, 0.0287 mol) in DMF 70 mL, intermediate-3 (4.18 g, 0.0124 mol) was added and heated to 80-85 °C for six hours. After completion of reaction, it was diluted with ethyl acetate and water and the organic layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated on a rotavapor to give brown coloured sticky mass, which is purified by column chromatography.1.75 g, Off white solid ; 1H NMR (400MHz,
CDCI3)ô ppm: 0.81(s, 3H), 1.09(s, 3H), 1.32(s, 3H), 1.43 (s, 9H), 2.01-2.22(m, 5H), 2.33-2.39(dd, J=4.88 Hz & J= 4.68 Hz,1H), 2.38-2.41 (m, 1H), 4.47(m, 1H). m/z(M-1): 265.2.
Intermediate-8: Methyl (1/?,3S)-3-[(ferf-butoxycarbonyl)amino]-2,2,3-trimethyl cyclopentanecarboxylate [0135] Prepared similar to intermediate 1 starting from (1S, 3R)(-) camphoric acid) in step 1
[0136] 1H NMR(400MHz, CDCI3)δ ppm 0.86 (s,3H), 1.18(s,3H), 1.35(s,3H), 1.43(s,9H), 1.8-1.9(m, 1H), 1.98-2.05 (m, 3H), 2.72-2.76 (m, 1H), 3.71 (s, 3H), 4.73 (bs, 1H); m/z (M+1): 285.
Intermediate-9: f-Butyl[(1S,3R)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl] carbamate [0137] Prepared similar to intermediate 2 starting from intermediate 8
[0138] 1H NMR (400MHz, CDCI3) δ ppm 0.85 (s,3H), 1.02 (s,3H), 1.27 (s,3H), 1.43 (s,9H), 1.52 (m, 1H), 1.81-1.89 (m, 1H), 1.96-2.01(m, 3H), 3.53-3.57 (dd, J=7.8 Hz& 17.7 Hz,1H), 3.71-3.74 (dd, J=5.4 & 10.2 1H), 4.62 (bs, 1H); m/z (M+1): 258.
Intermediate-10: Methanesulfonic acid (1R,3S)-3-f-butoxycarbonylamino-2,2,3-trimethyl-1-cyclopentylmethyl ester [0139] Prepared similar to intermediate 3 starting from intermediate 9
[0140] 1H NMR (400MHz, CDCI3) δ ppm 0.85 (s, 3H), 1.06 (s, 3H), 1.32 (s, 3H), 1.43 (s, 9H), 1.49(m, 1H), 1.85-2.04 (m, 3H), 2.16-2.24 (m, 1H), 3.01 (s, 3H), 4.10-4.15 (dd, J=8 & 9.24, 1H), 4.25-4.29 (dd, J=6.44 & 9.52,1H), 4.48 (s, 1H).
Intermediate-11: f-Butyl [(1S,3R)-3-(azidomethyl)-1,2,2-trimethylcyclopentyl] carbamate [0141] Prepared similar to intermediate 4 starting from intermediate 10.
[0142] 1H NMR (400MHz, CDCI3) δ ppm 0.8 (s,3H),0.9(d,3H), 1.15(s,3H), 1.43(s,9H), 1.68-1.80(m, 1H), 1.90-2.04 (m, 4H), 3.08-3.41 (m, 2H), 4.51 (s, 1H).
Intermediate-12: f-Butyl[(1S,3R)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl] carbamate [0143] Prepared similar to intermediate 5 starting from intermediate 11 and used assuch without purification. m/z(M+H): 257.2.
Intermediate-13: (1/?,3S)-3-[(f-Butoxycarbonyl)amino]-2,2,3-trimethyl cyclopentanecarboxylic acid [0144]
[0145] Prepared similar to intermediate 6 starting from intermediate 8. 1H NMR (400MHz, CDCI3) δ ppm 0.94 (s, 3H), 1.17 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.82-1.89 (m, 1H), 1.98-2.05 (m, 3H), 2.72-2.76 (m, 1H), 4.73-4.75 (bs, 1H); m/z(M-H): 270.1.
Intermediate -14: f-Butyl [(1S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamate [0146] Prepared similar to intermediate 7 starting from intermediate 10
[0147] 1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 1.09(s, 3H), 1.32(s, 3H), 1.43 (s, 9H), 2.01-2.22(m, 5H), 2.33-2.39(dd, J=4.88 Hz & J= 4.68 Hz,1H), 2.38-2.41 (m, 1H),4.47(m, 1H). m/z(M-1): 265.2.
Intermediate-15: (1R,5R)-1 -Amino-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octane-2,4-dione [0148]
Step 1: (1R,3S)-1,2,2-Trimethyl-3-(methylcarbamoyl)cyclopentanecarboxylic acid [0149]
[0150] A mixture of 40% aqueous methylamine (70 mL) and camphoric anhydride (5 g) was stirred at room temperature for 30 minutes. To this N,N-dimethyl-4-aminopyridine (DMAP) (0.67 g, 5.4 mmol) was added and stirred further for 24 hours. The reaction mixture was allowed to cool to room temperature and acidified with con. HCI at 0-5 °C. White precipitate formed was filtered and dried (5.2 g). m/z(M+H): 214.1.
Step 2: (1R)-1,3,8,8-Tetramethyl-3-azabicyclo[3.2.1]octane-2,4-dione [0151]
[0152] To a solution of step 1 intermediate (4.5 g, 21 mmol) in ethyl acetate, acetyl chloride (5.25 mL, 73 mmol) was added and refluxed for 24 hours. After the reaction, ethyl acetate was removed under reduced pressure, crude material purified by column, using ethyl acetate and hexane. (3.7 g) 1H NMR (400MHz, CDCI3) δ ppm: 0.8(s, 3H), 0.9(s, 3H), 1.1(s, 3H), 1.60-1.61(m, 1H), 1.71-1.83(m, 1H), 1.88-1.95(m, 1H), 2.11-2.2(m, 1H),2.65(d, 1H),2.91(s, 3H). m/z(M+H): 196.1.
Step 3: (1R,5/?)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1]octane-1-carboxylic acid [0153]
[0154] To a solution of step 2 intermediate (2 g, 10.2 mmol) in THF maintained at -95 °C under N2 atmosphere, 1,2N Sec.BuLi in cyclohexane (9.5 mL, 13.3 mmol) was added. After stirring for 15 min at -95 °C, small pieces of dry ice (2 g) were added and the reaction mixture was kept at this temperature for 1 h before quenching with water (3 mL). The reaction mixture was allowed to warm to room temperature. To this 5% NaHCO3 solution (100 mL) and diethyl ether (50 mL) was added, the aqueous layer was separated and acidified with KHSO4 to pH 2. This was extracted again with diethyl ether, washed with brine, dried with anhydrous Na2SO4 and concentrated. (1.85 g). 1H NMR (400MHz, CDCI3) δ ppm: 1.0(s, 3H), 1.1(s, 3H), 1.26(s, 3H), 1.88-1.98(m, 2H), 2.64-2.72(m, 1H), 2.8(m, 1H), 3.13(s, 3H). m/z(M-H): 238.
Step 4: (1S,5R)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1]octane-1 -carboxamide [0155]
[0156] A solution of step 3 intermediate in thionyl chloride was refluxed for 2 hours. After that, thionyl chloride was removed completely by distillation. The residue was dissolved in dichloromethane and 23% aqueous NH3 (40 mL) was added maintaining the temperature at 0 °C. The reaction was stirred for another 2 hours, diluted with dichloromethane. The organic layer was separated, washed with water and brine, dried with anhydrous Na2SO4 and concentrated to get light brown solid (2.69 g). 1H NMR (400MHz, CDCI3) δ ppm: 0.95(s, 3H), 0.96(s, 3H), 1.21(s, 3H), 1.88-1,94(m, 2H), 1.97-2.02(m, 1H), 2.88-2.94(m, 1H), 3.13(s, 3H), 5.8-6.1(d, 1H). m/z(M+H): 239.1.
Step 5 :(1/?,5R)-1-Amino-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octane-2,4-dione [0157]
[0158] Step 4 intermediate (2.5 g) was dissolved in a 20 mL solvent mixture of ethyl acetate, acetonitrile and water in the ratio 1:1:0.5, respectively. To this PIFA (6.3 g, 14.6 mmol) was added and stirred at temperature at 45 °C for 5 hours. The reaction was further was stirred at room temperature for 8 hours. Excess PIFA was decomposed by heating at 70 °C for 10 minutes. Reaction mixture was concentrated under reduced pressure, acidified with dilute HCI, and washed with diethyl ether. Aqueous layerwas separated, basified with NaHCO3 and extracted with dichloromethane, washed with water, brine, dried and concentrated. Crude material was purified by column chromatography to get 1.5 g solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.76(s, 3H), 0.98(s, 3H), 1.23(s, 3H), 1.77-1,97(m, 4H), 3.11(s, 3H). m/z(M+H): 211.
Intermediate-16: (1R,5/?)-3,5,8,8-Tetramethyl-3-azabicyclo[3.2.1]octan-1-amine [0159]
[0160] To a stirred suspension of lithium aluminumhydride in dry THF at 0 °C, a solution of intermediate 15 in THF was added slowly. After completion of the reaction (monitored by TLC), water was added and the precipitate that separated out was filtered off. The filtrate was extracted with ethyl acetate (2x100 mL). Ethyl acetate layers were combined together, dried with anhydrous Na2SO4, filtered and concentrated. 65 mg of pure product was obtained by purification of the crude material by silica column chromatography. 1H NMR (400MHz, CDCI3) δ ppm: 0.8(s, 3H), 0.9(s, 6H), 1.21-1.29(m,4H), 1.67-1.72(m, 1H), 1.83-1.9(m, 1H), 2.19-2.2(d, J=10.8 Hz, 1H), 2.29(s, 3H), 2.32(d, J= 10.84 Hz, 1H), 2.39(s, 2H). m/z(M+H): 183.1.
Intermediate-17: (1R,5R)-1-Amino-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one [0161]
Stepl : (1S,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carboxylic acid [0162] This intermediate was prepared starting from (+)Camphoric anhydride using literature procedures (Liebigs Ann. 1996, 1941-1948)
[0163] Melting point 243 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.93(s, 3H), 0.98(s, 3H), 1.23(s, 3H), 1.78-1,98(m, 3H), 2.31-2.39(m, 1H), 3.93(d, J= 10.84 Hz, 1H), 4.17(d, J=10.88 Hz, 1H) 12.77(bs, 1H); m/z(M-H): 211.
Step 2: (1S,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carboxamide [0164]
[0165] To a solution of step 1 intermediate in dichloromethane (0.7 g, 3.29 mmol), oxalyl chloride (0.32 mL, 3.62 mmol) was added and stirred for 2 hours at -10 °C. The volatiles were removed by purging N2 gas. The residue was dissolved in 25 mL diethyl ether and to this 25 mL of 23% aqueous ammonia was added. The reaction mixture was stirred for 2 hours and extracted with dichloromethane (2x100 mL). The organic layers were combined, washed with brine, dried with Na2SO4 and concentrated. 1H-NMR (400MHz, CDCI3) δ ppm: 0.93(s, 6H), 1.15(s, 3H), 1.88-2.05(m, 3H), 2.73-2.82(m, 1H), 3.97(d, J=10.9 Hz,1H) 4.17(d, J=10.9 Hz, 1H), 5.85(bs, 1H), 6.25(bs, 1H); m/z(M+H): 212.3.
Step 3: (1R,5/?)-1-Amino-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one [0166]
[0167] Step 2 intermediate (0.4 g, 1.89 mmol) was dissolved in a 5 mL solvent mixture of ethyl acetate, acetonitrile and water in the ratio 1:1:0.5 respectively. To this PIFA (1.14 g, 2.65 mmol) was added and stirred maintaining the temperature 45 °C for 5 hours. The reaction was further stirred at room temperature for 8 hours. Excess PIFA was decomposed by heating at 70 °C for 10 minutes. Reaction mixture was concentrated under reduced pressure, acidified with dilute HCI, washed with dichloromethane. Aqueous layer was separated, basified with NaHCO3, extracted with dichloromethane, washed with water, brine, dried and concentrated. Crude material was purified by column chromatography to give 0.26 g of solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.9(s, 3H), 0.93(s, 3H), 0.94(s, 3H), 1.77-1.93 (m,3H), 2.06-2.12(m, 1H), 3.89(d, J= 10.76 Hz, 1H), 4.09(d, J=10.72 Hz, 1H); m/z(M+H): 184.1.
Intermediate-18: 1R,5/?)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine [0168]
Step 1: A/-[(1R,5/?)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]oct-1-yl]acetamide [0169]
[0170] To a stirred solution of intermediate 17 in 5 mL of dichloromethane maintained at 0 °C, triethylamine, (0.34 mL, 2.4 mmol) was added. To this reaction mixture, acetyl chloride (0.17 mL, 2.4 mmol) was added over a period of 15 minutes and stirred for further 1 hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane and water. The organic layerwas separated and dried over anhydrous Na2SO4. The solventwas evaporated to give 0.17 g of off-white solid product. 1H NMR(400MHz, CDCI3) δ ppm: 0.91 (s, 3H), 0.96(s, 3H), 1,0(s, 3H), 1.81-1,90(m,
1H), 1.96-2.29(m, 2H), 2.1(s, 3H), 3.1-3.2(m, 1H), 3.95 (d, J=10.84 Hz, 1H), 4.08(m, J=9.72 Hz, 1H), 5.96(bs, 1H). m/z(M+H): 226.2.
Step 2: A/-[(1R,5/?)-2-Hydroxy-5,8,8-trimethyl-3-oxabicyclo[3.2.1]oct-1-yl] acetamide [0171]
[0172] To a suspension of lithium aluminumhydride (0.253 g, 6.6 mmol) in dry THF, step 1 intermediate in 2 mL THF was added dropwise at room temperature and stirred for 30 minutes. After completion, the reaction mixture was quenched with a few drops of water maintaining the temperature below 0 °C and stirred until a white precipitate formed. Reaction was filtered and residue obtained was washed with ethyl acetate. The filtrate was dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica column chromatography to give a pair of diastereomeric mixture. 1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 0.95(s, 3H), 1.05(s, 3H), 1.68-1.92(m, 3H), 2.03(s, 3H), 2.34-3.36(m, 0.25H), 2.75-2.81(m, 0.75H), 3.06 (d, J= 10.8 Hz, 0.25H), 3.21 (d, J=11.32 Hz, 0.75H), 3.74(d, J= 11.32 Hz, 0.75H), 3.95(d, J=10.70 Hz, 0.25H), 5.2(d, J=6.4 Hz, 0.75H), 5.34(s, 0.25H), 5.50(bs, 1H), 5.73(d, J= 6.6 Hz, 1H). m/z(M+59; -ve mode): 286.2.
Step 3: A/-[(1R,5/?)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]oct-1-yl]acetamide [0173]
[0174] To a stirred solution of step 2 intermediate (0.2 g, 0.88 mmol) in dry dichloromethane (5 mL) under nitrogen atmosphere, was added Et3SiH (0.84 mL; 5.28 mmol) at 0 °C. To this boron trifluoride etherate (0.33 mL, 2.6 mmol) was added dropwise over a period of 10 minutes. Stirring was continued for 5 hoursatroom temperature. After completion, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with dichloromethane. Organic layer was separated and dried over anhydrous Na2SO4. Dichloromethane layerwas concentrated under reduced pressure to obtain 165 mg of title compound. 1H NMR(400MHz, CDCI3)ôppm: 0.78(s, 3H), 0.89(s, 3H), 1.1 (s, 3H), 1.60-1,64(m, 1H), 1.72-1,78(m, 2H), 1,85(s, 3H), 2.60-2.67(m, 1H), 3.06(d, J= 10.96 Hz, 1H), 3.67(d, J= 10.92 Hz, 1H), 3.78(d, J=10.48 Hz, 1H), 3.92(d, J= 10.48 Hz,1H) 5.16(bs, 1H). m/z(M+1): 212.2.
Step 4: (1R,5/?)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine [0175]
[0176] To a solution of step 3 intermediate (0.165 g, 0.78 mmol) in 3 mL of dry THF and pyridine (0.37 mL, 47 mmol) maintained at 0 °C, oxalyl chloride was added with stirring. After 30 minutes propylene glycol (0.46 mL, 63 mmol) was added to the above reaction mixture and reaction warmed to room temperature. Reaction mixture was concentrated after adding ethyl alcohol. The residue was partitioned between 1N HCI and tert-butyl ether. Aqueous layerwas separated and basified with 4N NaOH and extracted with ethyl acetate. Ethyl acetate layerwas separated, dried and concentrated. Crude material was carried to next step without further purification, m/z (M+1): 170.2.
Intermediate-19: (1S,5S)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine [0177] Prepared similar to intermediate 17 starting from (1S,3R)(-)Camphoric acid m/z(M+1): 170.2
Intermediate-20: (2S,4S)-1-(Chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile [0178]
[0179] This intermediate was prepared starting from frans-4-hydroxyproline using literature procedures (Bioorganic Medicinal Chemistry 2008, 16, 4093-4106; W02007/113634 and US2007/0112059) as a white solid, mp 139-141 °C; IRcnv1: 3031,3007, 2962, 2241, 1679, 1407, 1280, 1225, 1076, 860; 1H NMR (400MHz, CDCI3) δ ppm (3:1 mixture of two rotomers) 2.25-2.5 (m, 1H), 2.55-2.65 (m, 1H), 4.06 (s, 2H), 3.55-4.3(m, 2H), 4.96(d, 0.8H, J=9.2 Hz), 5.07 (d, 0.2H, J=9.2 Hz), 5.45 (d, 0.8H, J=51.5 Hz), 5.41 (d, 0.2H, J=51.5 Hz); m/z (M+18): 208; [a] D-120.6 ° (C, 1.0, methanol).
Intermediate-21 : (2S)-1-(Chloroacetyl)pyrrolidine-2-carbonitrile [0180]
[0181] This intermediate was prepared starting from L-proline using literature procedures (Journal of Medicinal Chemistry, 2003, 46, 2774-2789) as off-white solid; mp 53-57 °C; 1H NMR (400MHz, CDCI3) δ ppm (4 to 1 mixture of trans/cis amide rotomers)2.10-2.40 (m, 4H), 3.55-3.66 (m, 1H), 3.66-3.79 (m, 1H), 4.03-4.21 (m, 0.4H, CH2CI), 4.09 (s, 1.6H, CH2CI), 4.76 (m, 0.8H, CHCN), 4.87 (dd, 0.2H, J= 7.4 and 2.2 Hz, CHCN); m/z (M+18): 190; [a] D -150.31° (C, 1.0, methanol).
Intermediate-22: (2S,4R)-1-(Chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile [0182]
[0183] This intermediate was prepared according to procedure described in Tetrahedron letters 1998, 39, 1169-1172 and W02007/113634. Melting point: 97-100 °C. 1H NMR(400MHz, CDCI3) δ ppm 2.44-2.57(m, 1H), 2.77-2.83(m, 1H), 3.55-4.4(m, 4H), 4.81 (t, J=8.3 Hz, 0.8H), 5.01 (t, J=8.36 Hz, 0.2H)5.35(d, J=51.3 Hz, 0.2H), 5.38(d, J= 51 Hz, 0.8H); m/z (M+18): 190; [a] D-153.39° (C, 1.0, methanol), m/z (M+18): 208.1
Example 1 : (2S,4S)-1-(2-((1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,8,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0184]
Step 1: tert-Butyl (1 R,3S)-3-((1 H-1,2,4-triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylcarbamate: [0185]
[0186] To a suspension of 1/-/-1,2,4-triazole (0.232g , 3.36 mmol) and K2CO3 (0.556 g, 4.03 mmol) in 5 mL of DMF, intermediate 3 (1.01 g, 3.02 mmol) was added and reaction mixture was stirred at 80-85 °C for 5 hours. The reaction mixture was brought to room temperature and diluted with water, extracted with ethyl acetate. The combined organic extract was washed with water and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to afford 135 mg of the title compound as a white solid. 1H NMR (CDCI3): 400ΜΗζδ0.91 (s, 3H), 0.99 (s, 3H), 1.31 (s, 3H), 1.43 (s, 9H), 1.45(m, 1H), 1.67 (m, 1H), 1.98 (m,2H),2.40 (m, 1H), 3.95-4.01 (dd, J=10.3& 13.2 Hz, 1H), 4.23-4.28 (dd, J=4.76 & 13.4 Hz,1H), 4.48 (s, 1H), 7.93 (s, 1H), 8.05 (s, 1H); m/z (M+1): 309.2.
Step 2:(1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentanamine hydrochloride [0187]
[0188] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of the step 1 intermediate (0.130 g, 0.422 mmol) in ethyl acetate at 0 °C and the reaction mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure to afford 90 mg of desired product. 1H NMR (d6-DMSO): 400MHz δ 0.91 (s,6H), 1.19(s,3H), 1.53(m,2H), 1.65(m, 1H), 1.94(m, 1H),2.32(m, 1H), 4.10-4.15 (dd, J=9.88 and 13.1 Hz,1H), 4.24-4.28 (dd, J=4.96 and 13.4 Hz,1H), 8.00 (bs, 3H), 8.01(s, 1H), 8.62 (s, 1H); m/z (M+1): 209.2.
Step 3: (2S,4S)-1-(2-((1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile [0189]
[0190] To a stirred suspension of the step-2 intermediate (0.097 g, 0.40 mmol), K2CO3 (0.218 g, 1.59 mmol) and Kl (0.033 g, 0.2 mmol) in 1mL of DMSO was added a DMSO solution of intermediate 20 (0.076 g, 0.40 mmol) and the reaction mixture was stirred for 24 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 concentrated and purified by chromatography to yield the product as an off-white solid (0.042 g). mp: 186-188; IR(KBr): 2246 &1662 cm"1; 1H NMR (CDCI3): 400 MHz δ 0.93(s,
3H), 0.98 (s, 3H), 1.03(s, 3H), 1.40-1.44(m, 1H), 1.63-1.70 (m, 4H), 2.39-2.44(m, 2H), 2.66-2.74(m, 1H), 3.35-3.52 (m, 2H), 3.65-4.1 (m,2H), 4.10-4.14 (m, 1H), 4.25-4.30 (dd, dd, J=4.4 &13.6 Hz, 1H), 4.96(d, J=9.2 Hz, 0.8H, rotomer)5.12 (d, J=9.2 Hz, 0.2H, rotomer), 5.42(d, J=48 Hz, 0.2H rotomer), 5.50(d, J=48 Hz, 0.8H, rotomer), 8.07 (s, 1H), 8.09 (s, 1H); m/z (M+1): 363.2.
Example 2: (2S,4R)-1-(2-((1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrilemethane sulfonate [0191]
[0192] To a suspension of step 2 intermediate of example 1 (0.097g, 0.40 mmol), K2CO3 (0.218g, 1.59 mmol), Kl (0.033 g, 0.2 mmol) in DMSO and intermediate-22 (0.076 g, 0.40 mmol) were added and stirred for 12 h at room temperature. The free base was isolated as described in step 3 of example 1. The free base isolated (20 mg, 0.005 mmol) was dissolved in ethyl acetate and treated with methanesulfonic acid (5.3 mg, 0.005 mmol) in ethyl acetate and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to yield 0.02 g of titled compound as white hygroscopic solid. 1H NMR (400MHz, D2O) δ ppm: 1.07(s, 3H), 1.15(s, 3H), 1,4(s, 3H), 1.66-1,78(m, 2H), 1.86-1,87(m, 1H), 2.1-2.12(m, 1H), 2.50-2.55(m, 2H), 2.79(s, 3H), 2.85-2.92(m, 1H), 3.8-4.14(m, 3H), 4.1-4.3(m, 2H), 4.5-4.53(m, 1H), 4.97(t, J=8 Hz, 0.8H ), 5.25(t, J=8 Hz, 0.2H), 5.41 (d, J=48 Hz, 0.2H), 5.42(d, J=48 Hz, 0.8H), 8.08(s, 1H), 8.51(s, 1H).m/z(M+H): 363.2.
Example 3: (2S,4S)-1-(2-((1S,3R)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile: [0193]
Step 1: (1S,3R)-1,2,2-Trimethyl-3-[1,2,4]triazol-1-ylmethyl-cyclopentylamine hydrochloride [0194]
[0195] Prepared according to procedure described in example-1, using intermediate 10.1H NMR (d6-DMSO): 400MHz δ 0.92 (s, 6H), 1.20 (s, 3H), 1.52(m,2H), 1.62 (m, 1H), 2.01 (m, 1H), 2.30 (m, 1H), 4.09-4.15 (dd, J=9.7 & 13.4 Hz,1H), 4.24-4.30 (dd, J=5.1 &13.5 Hz,1H), 8.05 (bs, 3H), 8.07(s, 1H), 8.68 (s, 1H); m/z (M+1): 209.2.
Step 2: (2S,4S)-4-Fluoro-1-[2-((1S,3R)-1,2,2-trimethyl-3-[1,2,4]triazol-1-yl methyl -cyclopentylamino)-acetyl]-pyr-rol id i ne-2-carbon itri le [0196]
[0197] Coupling reaction of step 1 intermediate (0.048 g, 0.196 mmol) and intermediate-20 (0.037 g, 0.196 mmol), in the presence of K2CO3 (0.108 g, 0.78 mmol) and Kl (0.016 g, 0.098 mmol) in 2 mL of DMSO as described in step-3 of Example-1 afforded 38 mg of product as an off-white solid, mp: 132-135 °C; IR(KBr): 2241 &1655cm-1; 1H NMR (CDCI3): 400 MHz δ 0.97 (s, 3H), 0.98 (s, 3H), 1.07 (s, 3H), 1.36-1.41 (m, 1H), 1.59-1.70 (m, 4H), 2.36-2.40(m, 2H), 2.65-2,73 (m, 1H), 3.30 (d, J=15.5 Hz,1H), 3.48 (d, J=15.5 Hz,1H), 3.66-4.09 (m, 2H), 4.14(dd, J=8.8 & 11.1 Hz,1H), 4.28(dd, J=4.4 &11.1 Hz, 1 H), 4.94(d, J=9.8 Hz, 0.8H, rotomer), 5.01 (d, J=9.2 Hz, 0.2H, rotomer), 5.11 (d, J=51 Hz, 0.2H, rotomer), 5.50 (d, J=51 Hz, 0.8H, rotomer), 7.93 (s, 1H), 8.05 (s, 1H); m/z (M+1): 363.2.
Example 4: (2S,4S)-4-Fluoro-1-[2-((1S,3R)-1,2,2-trimethyl-3-[1,2,4]triazol-1-yl methylcyclopentylami-no)-acetyl]-pyrrolidine-2-carbonitrile methanesulphonate [0198]
[0199] Example 3 (20 mg, 0.005 mmol) was dissolved in ethyl acetate. To this was added (5.3 mg, 0.005 mmol) methanesulfonic acid diluted in ethyl acetate and stirred for 2 h. The solid that separated out was decanted, washed with ethyl acetate and dried to obtain 22 mg of product as an off-white solid, mp: 167-170 °C; 1H NMR (D2O): 400 MHz δ 1.08 (s, 3H), 1.14 (s, 3H), 1.38 (s, 3H), 1.62-1.75 (m, 2H), 1.87-1.89(m, 1H), 2.09-2.11(m, 1H), 2.49-2.52 (m, 2H), 2.69-2.72(m, 1H), 2.80(s,3H), 3.77-3.79 (dd, 1H), 3.92-4.12(m, 2H), 4.26-4.28(m, 2H), 4.50-4.59(m, 1H), 5.08(d, J=9.3 Hz, 0.8H rotomer) - 5.25(d, J=9.1 Hz, 0.2H rotomer), 5.50(d, J=50.8 Hz, 0.2H rotomer) 5.51 (d, J=50.8 Hz, 0.8H rotomer), 8.06(s, 1H), 8.48(s, 1H) m/z (M+1): 363.2.
Example 5:(2S,4R)-1-(2-((1S,3R)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrilemethanesulfonate [0200]
[0201] Coupling reaction of example 3, step 1 intermediate (0.048 g, 0.196 mmol) and intermediate 22 (0.037 g, 0.196 mmol), in presence of K2CO3 (0.108 g, 0.78 mmol) and Kl (0.016 g, 0.098 mmol) in 2 mL of DMSO as described in step 3 of examplel afforded 20 mg of product as an off-white solid. The product (20 mg, 0.005 mmol) was dissolved in ethyl acetate. To this methanesulfonic acid (5.3 mg, 0.005 mmol) diluted in ethyl acetate was added and stirred for 2 h. The solid that separated out was decanted washed with ethyl acetate and dried. (0.025 g), White hygroscopic solid. 1H NMR (400MHz, D2O) δ ppm: 0.92(s, 3H), 1.05(s, 3H), 1.25(s, 3H), 1.53-1.62(m, 2H), 1.71-1.76(m, 1H), 1.94-1.99(m, 1H), 2.39-2.42(m, 2H), 2.67(s, 3H), 2.7-2.74(m, 1H), 3.69-3.91(m, 2H), 4.0-4.13(m, 2H), 4.26-4.31(m, 1H), 4.32-4.35(dd, 1H), 4.85(d, J=8.5 Hz, 0.8H rotomer), 5.1 (d, J=8.4 Hz, 0.2H rotomer), 5.25(d,J=51.3, 0.2H rotomer), 5.30(d, J=51, 0.8H rotomer), 7.96(s, 1H), 8.4(s, 1H). m/z(M+H): 363.2.
Example 6: (S)-1-(2-((1S,3R)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile [0202]
[0203] Coupling reaction of Example 3 step 1 intermediate (0.048 g, 0.229 mmol) and intermediate-21 (0.039 g, 0.229 mmol), in presence of K2CO3 (0.108 g, 0.78 mmol) and Kl (0.016 g, 0.098 mmol) in 2 mL of DMSO as described in step-3 of Example-1 afforded 10 mg of product as off-white sticky mass. 1H NMR (400MHz, CDCI3) δ ppm: 0.94(s, 3H), 0.96(s, 3H), 1.06(s, 3H), 1.37-1.42(m, 1H), 1.6-1.71(m, 3H), 2.16-2.42(m, 5H), 3.33-3.62(m, 4H), 4.06-4.12(m, 1H), 4.24-4.29(m, 1H), 4.79-4.77(m, 1H), 8.05(s, 1H), 8.06(s, 1H). m/z(M+H): 345.2.
Example 7: (S)-1-(2-((1S,3R)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile methanesulfonate [0204]
[0205] Example 6 (25 mg, 0.072 mmol) was dissolved in ethyl acetate. To this was added a solution of methanesulfonic acid (6.8 mg, 0.072 mmol) in ethyl acetate(1 mL) and stirred for 2 h. The separated solid was decanted, washed with ethyl acetate and dried to obtain title compound 25 mg as white solid. Melting point: 150-154 °C, 1H NMR (400MHz, D2O) öppm: 1.08(s, 3H), 1.14(s, 3H), 1.37(s, 3H), 1.66-1.78(m, 2H), 1.86-1.87(m, 1H), 2.08-2.09(m, 1H), 2.16-2.22(m, 2H), 2.31-2.37(m, 2H), 2.51-2.55(m, 1 H), 2.81(s, 3H) 3.52-3.56(m, 1H), 3.68-3.71(m, 1H), 3.96-4.0(m, 1H), 4.13-4.19(m, 1H), 4.22-4.25(, 1H), 4.39-4.44(m, 1H), 8.07(s, 1H), 8.48(s, 1H), m/z(M+H): 345.2.
Example 8: (S)-1-(2-((1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile [0206]
[0207] Intermediate 21 (0.01 g, 0.06 mmol) was added to a stirred suspension of step 2 intermediate of Example 1 (0.020 g, 0.08 mmol), K2CO3, (0.033 g, 0.239 mmol), Kl (0.01 g, 0.06 mmol) in 2 mL THF and reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using 0.5% methanol in dichloromethane to afford 8 mg product as a semisolid. IR (KBr): 2242 and 1654cm-1; 1H NMR(CDCI3): 400 MHz δ 0.93 (s, 3H), 0.97(s, 3H), 1.04 (s, 3H), 1.35-1.45(m,2H), 1.62-1.68 (m, 3H), 2.17-2.30(m, 4H), 2.33-2.42 (m, 1H), 3.35-3.45(m, 3H), 3.55-3.60(m, 1H), 4.05-4.1 (m, 1H), 4.26 (dd, J=4.4 &13.6 Hz, 1H), 4.76(m, 1H), 7.93(s, 1H), 8.06(s, 1H); m/z (M+1): 345.1.
Example 9: (S)-1-(2-((1R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrilemethanesulfonate [0208]
[0209] To a solution of example 8 (0.022 g, 0.063 mmol) in acetone, methanesulphonic acid (0.0058 g. 0.0607 mmol) was added and stirred for 3 h to give a white precipitate. The precipitate was allowed to settle, the solvent was decanted and residue dried under vacuum to afford the title compound as off white solid. 0.025 g. mp: 150-155 °C; IR(KBr): 2246 &1663cm_1; 1H NMR (D2O): 400 MHz δ 1.10 (s, 3H), 1.15 (s, 3H), 1.37 (s, 3H), 1.66-1.75(m, 2H), 1.86-1.90(m, 1H), 2.10-2.23 (m, 3H), 2.33-2.36(m, 2H), 2.52-2.56(m, 1H), 2.81 (s, 3H), 3.54-3.58 (m, 1H), 3.68-3.72 (m, 1H), 4.02 (d, J=28.6, 1H), 4.12(d, J=16.2, 1H), 4.21-4.24 (m,1H), 4.39-4.45 (dd, J=4.4&13.6 1H), 4.76(m, 1H), 8.07(s, 1H), 8.49 (s, 1H); m/z (M+1): 345.2.
Example 10:(2S,4S)-1-(2-((1R,3S)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0210]
Step 1: tert-Butyl (1R,3S)-3-((2H-1,2,3-triazol-2-yl)methyl)-1,2,2-trimethyl cyclopentylcarbamate [0211]
[0212] To a suspension of 1/-/-1,2,3-triazole (0.5 g, 7.2 mmol) and K2CO3 (1.5 g, 10.86 mmol) in 5mL of DMF, intermediate 3 (2.0 g, 6.0 mmol) was added and the reaction mixture was stirred at 80-85 °C for five hours. The reaction mixture was brought to room temperature and diluted with water, extracted with ethyl acetate; the combined organic extracts were washed with water and dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain isomeric mixture of products. The mixture was separated by silica column chromatography using methanol in dichloromethane.
[0213] The less polar compound was characterized as
[0214] Off white sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 0.95(s, 3H), 1.27(s, 3H), 1.47 (s, 9H), 1.50-1.53(m, 1H), 1.60-1.64(m, 1H), 1.95-1.99(m, 2H), 2.51-2.55(m, 1H), 4.28-4.34(m, 1H), 4.48-4.50(m, 1H), 4.51(s, 1H),7.58(s, 2H), m/z(M-100)+ H: 209.2.
[0215] The polar compound was characterized as
[0216] Off white sticky mass, m/z (M-100)+ H: 209.2.
Step 2: (1R,3S)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethyl cyclopentan aminehydrochloride [0217]
[0218] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of the step 1 intermediate (0.130 g, 0.625 mmol) in ethyl acetate at 0 °C and reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure to afford desired product. White solid,1H NMR (400MHz, DMSO) δ ppm: 0.85(s, 3H), 0.95(s, 3H), 1.20(s, 3H), 1.51-1.68(m, 3H), 1.90-1.96(m, 1H), 2.39-2.43(m, 1H), 4.29-4.34(m, 1H), 4.48-4.53(m, 1H), 7.77(s, 2H), 8.00(bs, 3H), m/z(M+1): 209.2.
Step 3: (2S,4S)-1-(2-((1R,3S)-3-((2H-1,2,3-triazol-2-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile [0219]
[0220] Coupling reaction of less polar step 2 intermediate (0.048 g, 0.196 mmol) and intermediate-20 (0.037 g, 0.196 mmol), in presence of K2CO3 (0.108 g, 0.78 mmol) and Kl (0.016g, 0.098mmol) in 2 mL of DMSO as described in step-3 of Example-1 afforded the desired product solid as white solid. Yield: 0.025 g, Mp: 84-87 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.87(s, 3H), 0.98(s, 3H), 1.07(s, 3H), 1.49-1.52(m, 1H), 1.63-1.71(m, 3H), 2.25-2.41(m, 1H), 2.50-2.55(m, 1H), 2.64-2.75(m, 1H), 3.34-3.52(m, 2H), 3.52-3.78(m, 1H), 3.88-3.97(m, 1H), 4.38-4.49(m, 1H), 4.51-4.53(m, 1H), 4.93-4.96(d, J=9.2 Hz, 0.8H), 5.18(d, J=9.2 Hz, 0.2H), 5.32(d, J=50 Hz, 0.2H), 5.49(d, 0.8H, J=50 Hz), 7.57(s, 2H). m/z(M+H): 363.2.
Example 11 : (2S,4S)-1-(2-((1R,3S)-3-((1H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0221]
Step-1 : (1 R,3S)-1,2,2-Trimethyl-3-(1 H-1,2,3-triazol-1 -ylmethyl)cyclopentanamine [0222]
[0223] Asolution of saturated HCI in ethyl acetate (2mL) was added to a solution of the more polar step 1 intermediate from example 9 in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure to afford the desired product as white solid, 1H NMR (400MHz, DMSO) δ ppm: 0.86(s, 3H), 0.88(s, 3H), 1.19(s, 3H), 1.52-1.54(m, 2H), 1.66-1.68(m, 1H), 1.90-1.94(m, 1H), 2.33-2.36(m, 1H), 4.25- 4.31(m, 1H), 4.46-4.50(m, 1H), 7.77(s, 1H), 8.00(bs, 3H), 8.16(s, 1H), m/z (M+1): 209.2.
Step-2: (2S,4S)-1-(2-((1R,3S)-3-((1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile [0224]
[0225] Coupling reaction of step-1 intermediate (0.024 g, 0.098 mmol) and intermediate 20 (0.037 g, 0.098 mmol), in presence of K2CO3 (0.108 g, 0.78 mmol) and Kl (0.016 g, 0.098 mmol) in 2 mL of DMSO as described in step-3 of Example-1 afforded the desired product 0.007 g as white solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.93(s, 3H), 0.96(s, 3H), 0.99(s, 3H), 1.49-1,59(m. 1H), 1.59-1,66(m, 2H), 1.60-1,78(m, 3H), 2.38-2.46(m, 2H), 2.65-2.73(m, 1H), 3.3-3.52(m, 2H), 3.68-3.88(m, 1H), 3.99-3.94(m, 1H), 4.23-4.29(m, 1H), 4.49-4.54(m, 1H), 4.94(d, J=9.2 Hz, 0.8H), 5.18(d, 0.2H, J=9.2 Hz), 5.35(d, J=51.2 Hz, 0.2H), 5.5(m, J=51.2 Hz, 0.8H). m/z(M+H): 363.2.
Example 12: (2S,4S)-1 -(2-((1 S,3R)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclo pentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0226]
[0227] Prepared similar to example 10 using intermediate 10. White solid 0.045 g,. Melting point: 142-144 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.87(s, 3H), 0.98(s, 3H), 1,07(s, 3H), 1.46-1,52(m, 1H), 1.56-1,66(m, 2H), 1.68-1,72(m, 1H), 2.25- 2.41(m, 1H), 2.52-2.55(m, 1H), 2.64-2.68(m, 1H), 3.30-3.34(d, 1H), 3.45-3.49(m, 1H), 3.56-3.6(m, 0.5H), 3.68-3.71(m, 0.5H), 3.79-3.92(m, 1H), 4.36-4.42(m, 1H), 4.5-4.53(m, 1H), 4.95(d, J=9.3 Hz, 0.8H), 5.20(d. J=9.3 Hz, 0.2H), 5.34(d, J=51.2 Hz, 0.2H), 5.45(m, J=51.2 Hz, 0.8H), 7.57(s, 2H). m/z(M+H): 363.2.
Example 13: (2S,4S)-1-(2-((1S,3R)-3-((1H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrilemethane sulfonate [0228]
[0229] Prepared similar to example 11 using intermediate 10.The product (0.026 g, 0.071 mmol) obtained was dissolved in ethyl acetate. To this was added methanesulfonic acid (0.0062 g, 0.06 mmol) in ethyl acetate and stirred for 2 h. The solid that separated was decanted washed with ethyl acetate and dried to obtain the title 0.02 g compound as off-white hygroscopic solid. 1H NMR (400MHz, CDCI3) δ ppm: 1,05(s, 3H), 1.16(s, 3H), 1,35(s, 3H), 1.62-1,76(m. 2H), 1.8-1,87(m, 1H), 2.08-2.15(m, 1H), 2.45-2.55(m, 2H), 2.6-2.7(m, 1H), 2.81(s, 3H), 3.91-3.94(m, 1H), 4.02-4.07(m, 1H), 4.13-4.15(m, 1H), 4.2-4.24(m. 1H), 4.38-4.44(m, 1H), 4.61-4.66(m, 1 H), 5.08(d, J=9.4 Hz, 0.8H), 5.22(d, J=9.4 Hz, 0.2H), 5.5(d, J=50.5 Hz, 0.2H), 5.51 (d, J=50.5 Hz, 0.8H), 7.81(s, 1H), 8.02(s, 1H). m/z(M+H): 363.2.
Example 14: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl) cyclo pentylami-no)acetyl)pyrrolidine-2-carbonitrile [0230]
Step-1: ((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)(piperidin-1-yl)methanone hydrochloride) [0231]
[0232] A mixture of intermediate 6 (0.27 g. 1.0 mmol), 1 ,T-Carbonyldiimidazole (0.19 g, 1.2 mmol) and piperidine (0.10 g, 1 mmol) in dichloromethane was stirred at room temperature for 8 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SO4 and concentrated. Crude material was purified by column chromatography to obtain tert-butyl (1R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl)cyclopentylcarbamate. To the solution of tert-butyl (1 R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl) cyclopentylcarbamate in ethyl acetate was added hydrochloride solution in ethylacetate and stirred for 2 h to afford ((1S,3R)-3-amino-2,2,3-trimethylcyclopentyl)(pip-eridin-1-yl)methanone hydrochloride.1 H NMR (400MHz, D2O) δ ppm: 0.98(s, 3H), 1.11 (s, 3H), 1.31 (s, 3H), 1.54-1,60(m, 6H), 1.94-2.20(m, 4H), 3.47-3.48(m, 1H), 3.54-3.57(m, 2H), 3.65-3.66(m,2H). m/z(M+H): 239.2.
Step 2: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl) cyclopentylamino)acetyl)pyrro-lidine-2-carbonitrile [0233]
[0234] Intermediate 20 (0.040 g, 0.21 mmol) was added to a stirred suspension of step-1 intermediate (0.050 g, 0.21 mmol), K2CO3, (0.15 g, 1.05 mmol), Kl (0.034 g, 0.21 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using methanol in dichloromethane to obtain 0.01 g of desired compound as semi-solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 1.04(s, 6H), 1.53-1,72(m, 8H), 1.92-1,94(m, 1H), 2.15-2.4(m, 2H), 2.63-2.75(m, 1H), 3.01-3.05(m, 1H), 3.46-3.61(m, 8H), 4.2-4.3(m, 1H), 4.97(d, J=9.2 Hz, 0.8H), 5.30(d, J=51.2 Hz, 0.2H), 5.32(d, J=51.2 Hz, 0.8), 5.7(d, J=9.2 Hz, 0.2H). m/z(M+H): 393.3.
Example 15: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethyl-cyclopentylamino)acetyl)pyrrolidine-2-carbon itrile [0235]
Step 1 : tert-Butyl (1 R,3S)-3-((4-(hydroxymethyl)-1 H-1,2,3-triazol-1 -yl)methyl)-1,2,2-trimethylcyclopentylcar-bamate [0236]
[0237] A suspension of intermediate 4 (0.25 g, 0.88 mmol), Cul (0.19 g, 0.88 mmol) in diisopropylethylamine(3.65 mL), was added propargyl alcohol (0.051 mL, 0.88 mmol) and stirred for 48 h at room temperature. The excess diiso-propylethylamine was decanted and dried. The residue was purified by silica column using methanol in dichloromethane. 1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 0.92(s, 3H), 1.22(s, 3H), 1.37(s, 9H), 1.45(d,2H), 1.71(m, 1H), 1.95(m, 1H), 2.24(m, 2H), 4.15(t, 1H), 4.39(m, 1H), 4.5(s, 2H), 5.13(bs, 1H), 6.36(s, 1H), 7.98(s, 1H). m/z(M+H): 339.1.
Step 2: (1-(((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-1H-1,2,3-triazol-4-yl)methanol hydrochloride [0238]
[0239] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of the step-1 intermediate (0.25 g, 0.7 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid separated was washed with ethyl acetate to afford desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.93(s, 3H), 1.03(s, 3H), 1.32(s, 3H), 1.64(m, 1H), 1.74(m, 1H), 1.83(m, 1H), 2.05(m, 1H), 2.48(m, 1H), 4.36(t, 1H), 4.59(m, 1H), 4.70(s, 2H). m/z(M+H): 239.2.
Step 3: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-3-((4-(hydroxymethyl)-1 H-1,2,3-triazol-1 -yl) methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0240]
[0241] Intermediate 20 (0.062 g, 0.33 mmol) was added to a stirred suspension of step-2 intermediate (0.10 g, 0.36 mmol), K2CO3 (0.20 g, 1.46 mmol), Kl (0.03 g, 0.18 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using methanol in dichloromethane to yield 0.02 g title compound as off white solid. Melting point: 240-279 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.93(s, 3H), 0.98(s, 3H), 1.04(s, 3H), 1.41-1.73(m, 4H), 2.35-2.38(m, 2H), 2.65-2.73(m, 1H), 3.34-3.51(m, 2H), 3.63-3.77(m, 2H), 3.88-3.94(m, 1H), 4.21-4.49(m, 2H), 4.79(s, 2H), 4.94(d, J=9.2 Hz, 0.8H), 5.02(d, J=9.2 Hz, 0.2H), 5.35(d, J=51 Hz, 0.2H), 5.4(d, J=51 Hz, 0.8H), 7.52(s, 1H). m/z(M+H): 393.2.
Example 16: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-((4-(hydroxymethyl)-1 H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethyl-cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile [0242]
[0243] Prepared according to procedure described in Example 15 using intermediate 11.0.14 g; Melting point: 76-78 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.93 (s, 3H), 0.96(s, 3H), 1.06(s, 3H), 1.41-1.70(m, 4H), 2.35-2.38(m, 2H), 2.69-2.73(m, 1H), 3.29-3.96(m, 5H), 4.29-4.45(m, 2H), 4.79(s, 2H) 4.94(d, J=9.2 Hz, 0.8H), 5.02(d, J=9.2 Hz, 0.2H), 5.32(d, J=51 Hz, 0.2H), 5.4(d, J=51 Hz, 0.8H), 7.52(s, 1H). m/z(M+H): 393.2.
Example 17: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)methanesulfonamide [0244]
Step-1 :_A/-{[(1S,3R)-3-tert-Butoxycarbonylamino-2,2,3-trimethylcyclopentyl] methyl)methanesulfonamide [0245]
[0246] To a solution of intermediate 5 (0.22 g, 0.85 mmol) in dichloromethane, triethylamine (0.11 g, 1.06 mmol) was added followed by methane sulfonyl chloride (0.2 g, 0.91 mmol) maintaining the temperature at 0 °C. The reaction mixture was stirred for another 30 minutes. After adding 20 mL water, the reaction mixture was extracted with dichloromethane. Organic layerwas separated, dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 20% ethyl acetate in hexane. 1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 1.03(s, 3H), 1.31(s, 3H), 1.4(s, 9H), 1.96(m, 4H), 2.96(s, 3H), 3.23(d, 1H), 4.13(m, 1H), 4.48(bs, 1H).
Step 2: N-(((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)methane sulfonamidehydrochloride [0247]
[0248] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of the step 1 intermediate (0.09 g, 0.27 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid that separated out was washed with ethyl acetate to afford 60 mg of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.81(s,3H),0.99(s,3H), 1.81(s,3H), 1.71(m, 1H), 1.88(m,3H),2.71(m, 1H),2.88(s,3H),3.1(m, 1H),6.9(bs, 1H),7.76(bs, 3H).
Step 3: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)methanesulfonamide [0249]
[0250] To a stirred suspension of the step-2 intermediate (0.06 g, 0.22 mmol), K2CO3 (0.11g, 0.8 mmol) and Kl (0.003 g, 0.02 mmol) in 1mL of DMSO, intermediate 20 (0.038 g, 0.22 mmol) was added. The reaction mixture was stirred for 24 hours under nitrogen atmosphere. After completion of the reaction; it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield 0.018 g product as off White solid. Melting point: 157-160 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.8(s, 3H), 0.9(s, 3H), 1.07(s, 3H), 1.63-1.77(m, 2H), 1.89-1.93(m, 1H), 2.03-2.05(m, 1H), 2.2-2.28(m, 1H), 2.3-2.45(m, 1H), 2.62-2.63(m, 1H), 2.79(s, 3H), 2.88-3.01 (m, 2H), 3.3-3.5(m, 2H), 3.65-3.75(m, 2H), 3.92-4.01(m, 1H), 4.93(d, J=8.8, 0.2H), 5.02(d, J=8.8, 0.8H), 5.3(d, J=51.2, 0.8H), 5.35(d, J=51.2, 0.2H) m/z (M+H): 469.2.
Example 18: N-(((1R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methyl)methanesulfonamide [0251] Prepared using intermediate 12 according to procedure described in Example 17
[0252] 0.047g, off-white solid. Melting point: 154-157 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.95(s, 6H), 1.2(s, 3H), 1.63-1.69(m, 4H), 1.86-1.88(m, 1H), 2.03-2.05(m, 1H), 2.35-2.45(m, 1H), 2.57-2.65(m, 1H), 2.82(s, 3H), 2.92-3.05(m, 2H), 3.21-3.33(m, 2H), 3.79-3.9(m, 2H), 4.99(d, J=9.4, 1H), 5.4(dd, 54.4, 1H). m/z (M+H): 389.2.
Example 19: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-4-fluorobenzenesulfonamide [0253]
Step-1 : tert-Butyl (1 R,3S)-3-((4-fluorophenylsulfonamido)methyl)-1,2,2-trimethyl cyclopentylcarbamate [0254]
[0255] To a solution of intermediate 5 (0.2 g, 0.78 mmol) in dichloromethane and triethylamine (0.26 g, 2.57 mmol), 4-fluorobenzenesulfonylchloride (0.13 g. 0.65 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with 50 mL dichloromethane; the organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography using ethyl acetate and hexane. 1H NMR (400MHz, CDCI3) δ ppm: 0.73(s, 6H), 0.95(s, 3H), 1.41(s, 9H), 1.82(m, 2H), 1.91(m, 2H), 2.76(m, 1H), 3.05(d, 1H), 4.31(d, 1H), 4.43(bs, 1H), 7.21(m, 2H), 7.87(d, 2H). m/z(M+H): 415.1.
Step 2: N-(((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-4-fluorobenzene sulfonamide hydrochloride [0256]
[0257] Asolution of saturated HCI in ethyl acetate (2 mL) was added to a solution of the step-1 intermediate (0.13 g, 0.31 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid that formed was decanted and washed twice with ethyl acetate. 1H NMR (400MHz, d6DMSO) δ ppm: 0.74(s, 3H), 0.92(s, 3H), 1.13(s, 3H), 1.27(s, 1H), 1.62(m, 1H), 1.84(m, 3H), 2.58(m, 1H), 2.84(m, 1H), 7.45(d, 2H), 7.65(bs, 1H), 7.85(d, 2H), 7.95(bs, 3H). m/z(M+H): 315.2.
Step 3: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-4-fluorobenzenesulfonamide [0258]
[0259] To a stirred suspension of the step-2 intermediate (0.06 g, 0.17 mmol), K2CO3 (0.070 g, 0.5 mmol) and Kl (0.028 g, 0.17 mmol) in 1 mL of DMSO, intermediate 20 (0.032 g, 0.17 mmol) was added. The reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield 0.017g of product. 1H NMR (400MHz, CDCI3) δ ppm: 0.58(s, 3H), 0.85(s, 3H), 1,07(s, 3H), 1.14-1,23(m, 1H), 1.51-1,52(m, 2H), 1.64-1,79(m, 2H), 2.55-2.71(m, 2H), 2.89-2.96(m, 1H), 3.38-3.99(m, 5H), 4.5(d, J=8.2 Hz, 0.2H), 4.95(d, J=8.2 Hz, 0.8H), 5.41(d, J=52 Hz, 0.2H), 5.55(d, J=52 Hz, 0.8H), 7.12-7.16(m, 2H), 7.76-7.87(m, 2H). m/z(M+H): 469.2.
Example 20: N-(((1R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-4-fluorobenzenesulfonamide [0260]
[0261] Prepared using intermediate 12 according to procedure described in Example 19. 0.027 g, Off-White solid. Melting point: 75-78 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.68(s, 3H), 0.88(s, 3H), 0.99(s, 3H), 1.62-1.73(m, 2H), 1.88-2.18(m, 2H), 2.42-2.65(m, 3H), 2.92(m, 1H), 3.25-3.39(m, 2H), 3.86-3.97(m, 2H), 5.03(d, J=12 Hz, 0.2H), 5.04(d, J=12 Hz, 0.8H), 5.32(d, J=53.9 Hz, 0.2H), 5.36(d, J=53.9 Hz, 0.8H), 7.13-7.18(m, 2H), 7.79-7.83(m, 2H). m/z(M+H): 469.2.
Example 21 : N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-2-fluorobenzamide [0262]
Step 1: tert-Butyl (1R,3S)-3-((2-fluorobenzamido)methyl)-1,2,2-trimethylcyclo pentylcarbamate [0263]
[0264] To a solution of intermediate 5 (0.1 g, 0.39 mmol) in dichloromethane and triethylamine (0.13 g, 12.8 mmol), 2-fluorobenzoylchloride (0.05 g. 0.32 mmol) was added and stirred overnight at room temperature. The reaction mixture was diluted with 50 mL dichloromethane; the organic layerwas washed with water, dried and concentrated. 1H NMR (400MHz, CDCI3) δ ppm: 0.89(s, 3H), 1.07(s, 3H), 1.28(s, 3H), 1.44(s, 9H), 2.02(m, 2H), 3.31(m, 1H), 3.51(m, 3H), 3.62(m, 1H), 7.71(m, 1H), 7.27(m, 1H), 7.56(d, 1H), 8.03(d, 1H). m/z(M+H-100): 279.2.
Step 2: N-(((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-2-fluoro benzamidehydrochloride [0265]
A solution of saturated HCI in ethyl acetate (2mL) was added to a solution of the step-1 intermediate (0.11 g, 2.9 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid that separated out was washed with ethyl acetate to afford 50 mg of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.98(s, 3H), 0.99(s, 3H), 1.01(s, 3H), 1.2(m, 1H), 1.46(m, 1H), 1.68(m, 1H), 1.9(m, 1H), 3.33(m, 2H), 7.27(m, 2H), 7.54(m, 2H), 8.33(bs, 3H). m/z(M+H): 279.2.
Step 3: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-2-fluorobenzamide [0266]
[0267] To a stirred suspension of the step-2 intermediate (0.05 g, 0.15 mmol), K2CO3 (0.088 g, 0.64 mmol) and Kl (0.013 g, 0.07 mmol) in 2 mL of DMSO, intermediate-20 (0.03 g, 0.15 mmol) was added. The reaction mixture was stirred for 24 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product as 0.010 g, Off White solid. Melting point 123-127 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.96(s.3H), 0.99(s, 3H), 1.02(s, 3H), 1.08(m, 1H), 1,25(m, 1H), 1,86(m, 1H), 2.41(m, 2H), 2.69(m, 1 H), 3.32(m, 2.5H), 3.73(m, 2.5H), 3.89(m, 1 H), 4.93(d, J=9.3 Hz, 0.8H), 5.08(d, J=9.3 Hz, 0.2H), 5.3(d, J=51.4 Hz, 0.2H) 5.45(d, J=51.4 Hz, 0.8H), 7.15(m, 1H), 7.24(d, 1H), 7.43(m, 1H), 7.81 (bs, 1H), 8.01(m, 1H). m/z(M+H): 433.2.
Example 22: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxo ethylamino)-2,2,3-trimethylcy-clopentyl)methyl)-4,4-difluorocyclohexane carboxamide [0268]
Step-1: tert-Butyl (1R,3S)-3-((4,4-difluorocyclohexanecarboxamido)methyl)-1,2,2-trimethylcyclopentylcar-bamate [0269]
[0270] A solution of intermediate 5 (0.47 g, 1.8 mmol), 4,4-difluorocyclohexane carboxylic acid (0.2 g, 1.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.47 g, 2.4 mmol), N-hydroxybenzotriazole(0.066 g, 0.48 mmol) and diisopropylethylamine(0.47 g, 3.6 mmol) in DMF was stirred for 4 h. The reaction was diluted with water and extracted with ethyl acetate. The separated ethyl acetate layer washed with brine and dried over anhydrous Na2SO4 and concentrated. 1H NMR (400MHz, CDCI3) δ ppm: 0.82(s.3H), 0.93(s, 3H), 1.12(s, 3H), 1.43(s, 9H), 1.69-1,73(m, 2H), 1.8-1.87(m, 5H), 1.88-1.98(m, 4H), 2.15(d, 2H), 2.67(bs, 1H),3.11(m, 1H), 3.36-3.39(m, 1H),4.49(s, 1H), 5.38(bs, 1H). m/z(M-1H): 401.2.
Step-2: N-(((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-4,4-difluorocyclo hexanecarboxamidehydro-chloride [0271]
[0272] A solution of saturated HCI in ethyl acetate (3 mL) was added to a solution of the stepl intermediate (0.3 g, 0.7 mmol) in ethyl acetate and reaction mixture was stirred at room temperature for 2 h. The solid separated out was washed with ethyl acetate to afford 0.2 g of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.82(s, 3H), 0.96(s, 3H), 1.17(s, 3H), 1.31-1.4(m, 1H), 1.6(m, 3H), 1.74(m, 3H), 1.89(d, 2H), 2.03(d, 2H), 2.23(m, 1H), 2.75(d, 1H), 3.1(m, 2H), 3.19-3.21(m, 1H). m/z(M+H): 303.2.
Step 3: N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methyl)-4,4-difluorocyclohexanecarboxamide [0273]
[0274] To a stirred suspension of the step-2 intermediate (0.08 g, 0.238 mmol), K2CO3 (0.098 g, 0.71 mmol) and Kl (0.039 g, 0.071 mmol) in 2 mL of DMSO, intermediate 20 (0.045 g, 0.238 mmol) was added. The reaction mixture was stirred for 12 hours. After completion of the reaction, itwas diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by column chromatography to yield 0.03 g product as off-white solid. Melting point: 193-195 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.92(s, 3H), 0.95(s, 3H), 1.04(s, 3H), 1.36-1.41(m, 1H), 1.59-1.70(m, 6H), 1.76-1.85(m, 3H), 2.21-2.06(m, 3H), 2.15-2.17(m, 2H), 2.66-2.71(m, 1H), 3.05-3.09(m, 1H), 3.26-3.32(m, 1H), 3.39-3.47(m, 2H), 3.51-3.64(m, 1H), 3.73-3.84(m, 1H), 3.87-3.93(m, 1 H),4.9(d, J=9.2, 0.2H)4.91(d, J=9.2, 0.8H), 5.37(d, J=52, 0.2H), 5.45(d, J=52, 0.8H). m/z(M+H): 457.2.
Example 23: N-(((1R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methyl)-4,4-difluorocyclohexane carboxamide [0275]
[0276] Prepared similar to Example 22 using intermediate 12. 0.055 g, off-white solid. MP.: 189-194 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.93(s, 3H), 0.95(s, 3H), 1.04(s, 3H), 1.39-1.42(m, 1H), 1.59-1.7(m, 6H), 1.78-1.85(m, 3H), 2.0-2.17(s,5H), 2.21-3.12(m, 1H), 2.66-2.74(m, 1H), 3.05-3.1(m, 1H), 3.26-3.51 (m, 3H), 3.61-3.93(m, 2H), 4.87(d, J=9.2 Hz, 0.2H) 4.90(d, J= 9.2Hz, 0.8H), 5.37(d, J=52, 0.2H), 5.40(d, J=52, 0.8H); m/z(M+H): 457.2.
Example 24: 6-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile [0277]
Step 1: 6-(((1 S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methylamino)nicotino nitrile hydrochloride [0278]
[0279] To a suspension of intermediate 5 (0.2 g, 0.78 mmol), and K2CO3 in DMF, 6-chloro nicotinonitrile (0.107 g, 0.8 mmol) was added. The reaction mixture heated at 80 °C for 7 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x100 mL). Combined organic layer was dried over Na2SO4 and concentrated to afford tert-butyl (1 R,3S)-3-((5-cyanopyridin-2-ylamino)methyl)-1,2,2-trimethylcyclopentylcarbamate product. m/z(M+H): 359.1. A solution of saturated HCI in ethyl acetate (3 mL) was added to the stirred solution of tertbutyl (1 R,3S)-3-((5-cyanopyridin-2-ylamino)methyl)-1,2,2-trimethylcyclopentyl carbamate (0.15 g, 0.4 mmol) in ethyl acetate at room temperature. The reaction mixture was further stirred at room temperature for two hours. The solid separated was washed with ethyl acetate to afford 0.057 g of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.83(s, 3H), 1.0(s, 3H), 1.19(m, 3H), 1.20-1.23(m, 1H), 1.37-1.44(m, 1H), 1.64-1.69(m, 1H), 1.85-2.04(m, 3H), 3.16-3.18(m, 1H), 3.35-3.42(m, 1H), 7.68(bs, 1H), 7.84(bs, 1H), 8.03(m, 3H). 8.40(s, 1H).
Step 2: 6-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl amino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile [0280]
[0281] To a stirred suspension of the step-1 intermediate (0.08 g, 0.257 mmol), K2CO3 (0.149 g, 1.08 mmol) and Kl (0.042 g, 0.257 mmol) in 2 mL of DMSO, intermediate 20 (0.048 g, 0.257 mmol) was added. The reaction mixture was stirred for 24 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give 0.02 g product as offwhite solid. 1H NMR (400MHz,CDCI3) δ ppm: 0.85(s,6H),1.0(s,3H), 1.5-1.7(m,4H), 1.85-1.87(m,1H), 2.12-2.17(m, 1H), 2.3-2.5(m, 1H), 2.7-2.78(m, 1H), 3.14-3.18(m, 1H), 3.49-3.45(m, 2H), 3.66-3.67(m, 1H), 3.91-3.96(m, 1H), 4.9(d, J=9.1 Hz, 0.2H), 4.99(d, J=9.1 Hz, 0.8H), 5.37(d, J=52.2 Hz, 0.2H), 5.52(d, J=52.2 Hz, 0.8H), 6.41-6.43(m, 1H), 7.47-7.49(m, 1H), 8.31(s, 1H). m/z(M+H): 413.2.
Example 25: 6-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxo ethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile [0282]
[0283] Prepared similar to Example 24 using intermediate 12. 0.05 g, OffWhite solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.88(s, 3H), 0.96(s, 3H), 0.99(s, 3H), 1.50-1.67(m, 4H), 1.84-1.92(m, 1H), 2.13(m, 1H), 2.42-2.73(m, 1H), 3.18-3.97(m, 7H), 4.97(d, J=9.2, 0.2H), 4.99(d, J=9.2, 0.8H), 5.01(m, 1H), 5.37(d, J=52, 0.2H), 5.39(d, J=52, 0.8), 6.4(m, 1H), 7.46(m, 1H), 8.2(m, 1H). m/z(M+H): 413.2.
Example 26: 2-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxo ethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile [0284]
Step 1: 2-(((1 S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)methylamino)nicotino nitrilehydrochloride [0285]
[0286] Prepared similar to procedure described in example 24 step 1 using intermediate 5 (0.2 g, 0.78 mmol), and K2CO3 (0.32 g, 2.34 mmol) in DMF, 2-chloropyridine-3-carbonitrile (0.107 g, 0.78 mmol) to afford 0.057 g of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.8(s, 3H), 1.06(s, 3H), 1.23(s, 3H), 1.46(m, 1H), 1.65(m, 1H), 1.77(m, 1H), 2.09(m, 1H), 2.19(m, 1H), 3.33(m, 1H), 3.42-3.45(m, 1H), 6.61-6.65(m, 1H), 7.0(s, 1H), 7.88-7.92(m, 2H), 8.26-8.28(s, 3H), m/z(M+H): 259.2.
Step 2: 2-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1 -yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile [0287]
[0288] To a stirred suspension of the stepl intermediate (0.08 g, 0.257 mmol), K2CO3 (0.149 g, 1.08 mmol) and Kl (0.042 g, 0.257 mmol) in 2 mL of DMSO, intermediate 20 (0.048 g, 0.257 mmol) was added. The reaction mixture was stirred for 24 h under nitrogen atmosphere. After completion of reaction, itwas diluted with ethyl acetate and water. The separated aqueous layer was washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product. 0.015 g, Off-white solid. M.p.: 96-99 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.9(s, 6H), 1.04(s, 3H), 1.65-1,76(m, 4H), 1.86-1,9(m, 1H), 2.18-2.25(m, 1H), 2.3-2.5(m, 1H), 2.64-2.72(m, 1H), 3.33-3.53(m, 3H), 3.64-3.72(m, 2H), 3.77-4.0(m, 1H), 4.93-4.95(d, 1H), 5.27(d, J=51.3, 0.8H), 5.39(d, J=51.3, 0.2H), 6.45-6.53(m, 1H), 7.49-7.6(dd, 1H), 8.25(d, 1H). m/z(M+H): 413.2.
Example 27: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-((5-(trifluoro methyl)pyridin-2-ylamino)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0289]
[0290] Prepared according to procedure described in example 24 using 2-chloro-4-(trifluoromethyl) pyridine in step 1. 0.01g, Off-white solid. Melting point: 52-58 °C. 1H NMR(400MHz, CDCI3) δ ppm: 0.98(s, 6H), 1.04(s, 3H), 1.41-1,59(m, 3H), 1.66-1.69(m, 2H), 1.88(m, 1H), 2.12-2.18(m, 1H), 2.29-2.39(m, 1H), 2.63-2.76(m, 1H), 3.14-3.19(m, 1H), 3.42-3.65(m, 2H), 3.69-3.99(m, 2H), 4.98(d, J=9.2, 0.8H), 5.0(d, J=9.2, 0.2H), 5.31 (d, J=52, 0.2H), 5.38(d, J=52, 0.8H), 6.35-6.43(m, 1H), 7.51-7.53(d, 1H), 8.25-8.28(d, 1H). m/z(M+H): 455.2.
Example 28: (28,48)-1-(2-((1 R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclo pentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0291]
Step 1: (1R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl] N-tert-butoxy carbonyl-1,2,2-trimethyl cyclopentan-amine [0292]
[0293] To a stirred solution of intermediate 5 (0.2 g, 0.7 mmol) and triethylamine (0.12 mL, 0.85 mmol) in dichloromethane maintained at 0-5 °C, chloropropane sulfonyl chloride (0.09 mL, 0.7 mmol) was added. After 6 h the reaction mixture was diluted with dichloromethane, washed with water, dried with Na2SO4 and concentrated. The crude material purified by silica column using ethyl acetate and hexane. The obtained product (0.24 g, 0.6 mmol) was dissolved in methanol. To this NaOMe (0.063 g, 1.3 mmol) was added and refluxed under N2 atmosphere. After 24 hours, reaction mixture was concentrated, residue dissolved in ethyl acetate. Ethyl acetate layer washed with water, brine, dried over Na2SO4 and concentrated. Crude material purified by silica column using ethyl acetate and hexane. 1H NMR (400MHz, CDCI3) δ ppm: 0.76(s, 3H), 0.96(s, 3H), 1.18(s, 3H), 1.36(s, 9H), 1.79-1.96(m, 2H), 2.22-2.28(m, 2H), 2.80(t, 1H), 2.90(m, 1H), 3.10(m, 2H), 3.20(m, 2H), 4.43(s, 1H). m/z(M+H): 261.2.
Step 2: (1R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclo pentanamine hydrochloride [0294]
[0295] A solution of saturated HCI in ethyl acetate (3 mL) was added to a solution of the step-1 intermediate (0.36 g, 0.1 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid that separated out was washed with ethyl acetate to afford 0.28 g of desired product. 1H NMR (400MHz, CDCI3) δ ppm: 0.9(s, 3H), 1.0(s, 3H), 1.32(s,3H), 1.87-1.89(m, 1H), 1.92-1,98(m, 3H), 2.04(m, 1H), 3.16(m, 1H), 3.45(m, 1H),4.5(s, 1H),4.96(bs, 1H), 6.36(d, 1H), 7.55-7.58(d, 1H), 8.35(s, 1H). m/z(M+H): 261.2.
Step 3: (2S,4S)-1-(2-((1R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0296]
[0297] To a stirred suspension of the step-2 intermediate (0.120 g, 0.405 mmol), K2CO3 (0.167 g, 1.21 mmol) and Kl (0.067 g, 0.405 mmol) in 2 mL of DMSO, intermediate 20 (0.076 g, 0.405 mmol) was added. The reaction mixture was stirred for 24 h under N2 atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The separated aqueous layer was washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product as 0.012g, Off-White solid. M.P.: 126-128 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.88(s, 3H), 0.96(s, 3H), 1.06(s, 3H), 1.42-1.44(m, 1H), 1.66-1.68(m, 2H), 1.70-1.80(m, 1H), 1.83-1.85(m, 1H), 1.98-2.04(m, 1H), 2.29-2.36(m, 2H), 2.52-2.53(m, 1H), 2.76-2.79(m, 1H), 3.04-3.17(m, 3H), 3.3-3.6(m, 1.5H), 3.4-3.5.(m, 1.5H), 3.6-3.9(m, 2H), -4.9(d, J=9.2 Hz, 0.8H), 5.12(d, J=9.2 Hz, 0.2H), 5.36(d, J=52 Hz, 0.8H), 5.4(d, J=52 Hz, 0.2H). m/z(M+H): 415.2.
Example 29: (2S,4S)-1 -(2-((1 S,3R)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclo pentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0298]
[0299] Prepared similar to example 28 using intermediate 12. 0.015 g, off-white solid. M.P: 171-174 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.86(s, 3H), 0.88(s, 3H), 1.06(s, 3H), 1.43-1,44(m,1 H), 1.66-1.68(m, 1H), 1.70-1.80(m, 1H), 1.83-1,85(m, 1H), 1.98-2.04(m, 1 H), 2.29-2.36(m, 3H), 2.52-2.53(m, 1H), 2.76-4.2(m, 10H), 4.8(d, J=9.2, 0.8H), 5.12(d, J=9.2, 0.2H), 5. 25(d, J=51.2, 0.2H), 5.35(d, J=51.2, 0.8H), m/z(M+H): 415.2.
Example 30: (2S,4S)-1-(2-((1 S,3R)- 3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethylcyclo pentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0300]
)
Step 1: (1S,3R)-3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethylcyclo pentanamine [0301]
[0302] To a solution of intermediate 12 (0.375 g, 1.5 mmol) in acetonitrile, 1,4-butanesultone (0.2 g, 1.5 mmol) was added and stirred over night. To this phosphrous oxychloride (0.46 mL, 3 mmol) was added and stirred for another 6 hours. The reaction mixture was concentrated and to this was added 50 mL ethyl acetate. The ethyl acetate layer was washed with 20% NaOH, water, brine, dried with anhydrous Na2SO4 and concentrated. The crude material purified by alumina column chormatography using 2% methanol in dichloromethane.1 H NMR (400MHz, DMSO) δ ppm: 0.86(s, 3H), 0.95(m, 3H), 1.1(s, 3H), 1.3-1.66(m, 6H), 1.83-1.9(m, 1H), 1.94-2.01(m, 1H), 2.18-2.2(m, 1H), 2.94-3.15(m, 4H), 3.18-3.2(m, 2H). m/z(M+H): 275.1.
Step 2: (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethyl cyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0303]
[0304] To a stirred suspension of the stepl intermediate (0.13 g, 0.5 mmol), K2CO3 (0.138 g, 1mmol) and Kl catalytic amount in 2 mL of DMSO, intermediate 4 (0.085 g, 0.45 mmol) was added. The reaction mixture was stirred for 8 h under N2 atmosphere. After completion of reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by chromatography using 2 % methanol in DCM to yield the product; white solid (0.02 g).M.P.: 186-190 °C. 1H NMR(400MHz, d6-DMSO) δ ppm: 0.86(s, 3H), 0.95(m, 3H), 1.1(s, 3H), 1.4-1.66(m, 6H), 1.83-1.98(m, 2H), 2.04-2.18(m, 2H), 2.2-2.4(m, 1H), 2.62-2.70(m, 1H), 2.94-3.05(m, 3H), 3.18-3.92(m, 6H), 4.94(d, J=9.0, 0.8H), 5.12(d, J=9.0, 0.2H), 5.3(d, J=52.1, 0.2H), 5.4(d, J=52.1,0.8H). m/z(M+H): 429.1.
Example 31 : (2S,4S)-1 -(2-((1 R,3S)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino) acetyl)-4-fluor-opyrrolidine-2-carbonitrile methanesulfonate [0305]
Step 1: tert-Butyl (1R,3S)-3-((1H-tetrazol-1-yl)methyl)-1,2,2-trimethyl cyclopentyl carbamate [0306]
[0307] To a solution of intermediate 5 in acetic acid (1 mL), NaN3 and triethylorthoformate (0.25 mL) was added and the reaction mixture refluxed for 6 h. The reaction was cooled to room temperature and ice-cold water (20 mL) was added, extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated NaHCO3 solution, water, brine, dried with anhydrous Na2SO4 and concentrated. The crude product was purified by column using 50% ethyl acetate in hexane. 1H NMR (400MHz, CDCI3) δ ppm: 0.95(s, 3H), 1.12(s, 3H), 1.27(s, 3H), 1.48(s, 9H), 1.69(m, 2H), 2.35(m, 2H), 4.24(m, 1H), 4.54(m, 2H), 8.58(s, 1H). m/z(M+H): 310.2.
Step 2: (1R,3S)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentanamine hydrochloride [0308]
[0309] A solution of saturated HCI in ethyl acetate (3.5 mL) was added to a solution of the step-1 intermediate (0.15 g, 0.48 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for two hours. The solid that separated out was washed with ethyl acetate to afford 60 mg of desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.81(s, 3H), 0.99(s, 3H), 1.25(s, 3H), 1.55(m, 2H), 1.66(m, 1H), 2.0(m, 1H), 2.36(m, 1H), 4.4(m, 1H), 4.57(m, 1H), 8.15(bs, 3H), 9.47(s, 1H). m/z(M+H): 210.2.
Step 3: (2S,4S)-1-(2-((1 R,3S)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyr-rolidine-2-carbonitrile methanesulfonate [0310]
[0311] To a stirred suspension of the step-2 intermediate (0.09 g, 0.47 mmol), K2CO3 (0.25 g, 1.8 mmol) and Kl (0.078 g, 0.47 mmol) in 2 mL of DMSO, intermediate 20 (0.088 g, 0.47 mmol) was added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography using 2% methanol in dichloromethane to yield the product. The product that obtained (0.04 g, 0.11 mmol) was dissolved in ethyl acetate, to this was added methanesulfonic acid (0.0105 g, 0.11 mmol) diluted in ethyl acetate and stirred for 2 h. The solid that separated out was decanted washed with ethyl acetate and dried. Yield: 0.041g; Melting point: 210-214 °C; 1H NMR (400MHz, D2O) δ ppm: 1.1(s,3H), 1.17(s,3H),1.38(s,3H), 1.76(m,2H), 1.89(m, 1H),2.12(m, 1H),2.57(m,2H),2.7(m, 1H), 2.8(s, 3H), 3.8-3.9(m, 1H), 4.01-4.15(m, 2H), 4.48-4.54(m, 1H), 4.70-4.75(m, 1H), 4.81-4.87(m, 1H), 5.08(d, J=9.2 Hz, 0.8H), 5.12(d, J=9.2 Hz, 0.2H), 5.53(d, J=52.2 Hz, 0.2H), 5.6(d, J=52.2 Hz, 0.8H), 9.2(s, 1H). m/z(M+H): 364.2.
Example 32: (2S,4S)-1 -(2-((1 S,3R)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluor-opyrrolidine-2-carbonitrile [0312]
[0313] Prepared similar to example 31 using intermediate 12. 0.03 g Off-white solid. Melting point: 151-154 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.95(s, 6H), 1,2(s, 3H), 1.39-1,42(m, 1H), 1.59-1,74(m, 4H), 2.33-2.4(m, 2H), 2.66-2.74(m, 1H), 3.28-3.32(d, 1H), 3.43-3.47(d, 1H), 3.69-3.93(m, 2H), 4.49-4.53(m, 2H), 4.94-4.96(m, 1H), 5.32(d, J=54 Hz, 0.2H), 5.4(d, J=54 Hz, 0.8H), 8.62(s, 1H). m/z(M+H): 364.2.
Example 33: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-(morpholinomethyl) cyclopentylamino)acetyl)pyr-rol id i ne-2-carbon itri le [0314]
Step 1: tert-Butyl(1R,3S)-1,2,2-trimethyl-3-(morpholinomethyl)cyclopentyl carbamate [0315]
[0316] Intermediate-3 was heated in morpholine at 80 °C over night. The reaction mixture was poured into water, extracted with ethyl acetate, organic layer separated, washed with water, dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography using dichloromethane and methanol. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 3H), 1.01 (s, 3H), 1,35(s, 3H), 1.43 (s, 9H), 1.65-1,68(m, 1H), 1.83-1,88(m, 2H), 1.91-1,95(m, 2H), 2.18-2.22(m, 1H), 2.35-2.38(m, 1H), 2.42-2.49(m, 4H), 3.68-3.71(m, 4H), 4.51(s, 1H), m/z(M+1): 327.3.
Step 2: (1R,3S)-1,2,2-Trimethyl-3-(morpholinomethyl)cyclopentanamine hydrochloride [0317]
[0318] To a solution of Step 1 intermediate in ethyl acetate, 3 mL of saturated dry HCI in ethyl acetate was added and stirred for 2 hours. The solid that separated out was decanted and washed with ethyl acetate and dried. 1H NMR (400MHz, D2O) δ ppm: 0.90(s, 3H), 1.06(s, 3H), 1.35(s, 3H), 1.72-1.74(m, 1H), 1.93-1.95(m, 1H), 2.08-2.13(m, 2H), 2.25-2.27(m, 1H), 3.16-3.25(m, 4H), 3.51-3.61(m, 2H), 3.82-3.87(m, 2H), 4.09-4.12(m, 2H), m/z(M+1): 227.3.
Step 3: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-(morpholinomethyl)cyclo pentylamino)acetyl)pyrrolid-ine-2-carbonitrile [0319]
[0320] Coupling of the step-2 intermediate (0.097 g, 0.42 mmol), K2CO3 (0.138 g, 1.0 mmol) and Kl (0.033 g, 0.2 mmol) in 1 mL of DMSO with intermediate 20 (0.079 g, 0.42 mmol) was carried out similar to step-3 of example-1 to afford off-white hygroscopic solid (0.032 g). 1HNMR (400MHz, CDCI3) δ ppm: 0.86(s, 3H), 0.96(s, 3H), 1.06(s, 3H), 1.33-1.38(m, 2H), 1.81-1.86-(m, 1H), 2.0-2.03(m, 1.5H), 2.22-2.28(m, 1.5H), 2.37-2.43(m, 5H), 2.64-2.72(q, 1H), 3.35-3055(m, 2H), 3.66-3.79(m, 6H), 3.88-3.97(m, 1 H), 4.95(d, J=9.2 Hz, 0.8H), 5.35(d, J=9.2 Hz, 0.2H), 5.40(d, J=52.2 Hz. 0.2H), 5.45(d, J=52.2 Hz, 0.8H). m/z(M+H): 381.3.
Example 34: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-1,2,2-trimethyl-3-(morpholino methyl)cyclopentylamino)acetyl)pyr-rol id i ne-2-carbon itri le [0321]
[0322] Prepared similar to example 33 starting from intermediate 10 and mopholine in Step-1. 0.01gm, Off-white hygroscopic solid. Melting point: 163-166 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.82(s, 3H), 0.96(s, 3H), 1.08(s, 3H), 1.33-1.38(m, 2H), 1.80-1.85-(m, 1H), 1.99-2.03(m, 1H), 2.17-2.23(m, 1H), 2.35-2.41(m, 5H), 2.64-2.72(q, 1H), 3.31-3.35(d, 1H), 3.35-3.62(m, 1H), 3.66-3.70(m, 6H), 3.75-3.79(m, 1H), 3.89-3.98(m, 1H), 4.95(d, J=9.2 Hz, 0.8H), 5.25(d, J=9.2 Hz, 0.2H), 5.38(d, J=51.1 Hz, 0.2H), 5.5(d, J=51.1 Hz, 0.8H). m/z(M+H): 381.3.
Example 35: (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholino methyl)cyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile dimethanesulfonate [0323]
[0324] Example 34 (70 mg, 0.184 mmol) was dissolved in ethyl acetate, to this was added (34 mg, 0.36 mmol) methanesulfonic acid diluted in ethyl acetate and stirred for 2 h. The solid that separated out was decanted washed with ethyl acetate and dried. 0.055 g, White solid. Melting point: 220-225 °C. 1H NMR (400MHz, D2O) δ ppm: 1.01 (s, 3H), 1.14(s, 3H), 1.36(s, 3H), 1.7-1.74(m, 1H), 1.90-1.93(m, 1H), 2.1-2.17(m, 1H), 2.26-2.28(m, 1H), 2.5-2.71(m, 1H), 2.71-2.75(m, 1H), 2.81(s, 6H), 3.15-3.18(m, 2H), 3.25-3.28(m, 3H), 3.3-3.4(m, 2H), 3.77-4.14(m, 9H) 5.05(d, J=9.2 Hz, 0.8H), 5.52(d, J=9.2 Hz, 0.2H), 5.4(d, J=52.0 Hz, 0.2H), 5.5(d, J=52.0 Hz, 0.8H). m/z(M+H): 381.2.
Example 36: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-(pyrrolidin-1-yl methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0325]
[0326] Prepared according to example 33 off-white solid (0.045 g). mp: 108-112 °C; IR(KBr): 2244 &1670 cm-1; 1H NMR (CDCI3): 400 MHz δ 0.81(s, 3H), 0.93(s, 3H), 1.10(s, 3H), 1.63-1.70 (m, 5H), 1.95(m, 2H), 2.30-2.71(m, 8H), 3.35-3.97 (m, 5H), 4.94 (dd, dd, J=4.4 &13.6 Hz, 1H), 5.25 (d, J=9.2 Hz, 0.2H), 5.35 (d, J=9.2 Hz, 0.8H), 5.42(d, J=48 Hz, 0.2H), 5.48(d, J=48 Hz, 0.8H); m/z (M+1): 365.3.
Example 37: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-1,2,2-trimethyl-3-(pyrrolidin-1-yl methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0327]
[0328] Prepared similar to example 33 starting from from intermediate 10 and pyrrolidine. 0.036 g, White solid. Melting point: 123-126 °C. 1H NMR (400MHz, D2O) δ ppm: 0.79(s, 3H), 0.95(s, 3H), 1.08(s, 3H), 1.40-1,44(m, 1H), 1.60-1,63(m, 2H), 1.76(s, 4H), 1.95(m, 2H), 2.2-2.33(m, 2H), 2.48-2.5(m, 5H), 2.64-2.68(m, 1H), 3.3-3.34(d, 1H), 3.49-3.53(m, 1H), 3.61- 3.79(m, 1H), 3.88-3.97(m, 1H), 4.94-4.96(m, 1H), 5.22-5.48(m, 1H). m/z(M+H): 365.2.
Example 38: (2S,4S)-4-fluoro-1-(2-((1 R,3S)-3-(((R)-3-hydroxypyrrolidin-1-yl) methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0329]
[0330] Prepared similar to example 33 starting from intermediate 3 and 3-hydroxypyrrolidine. 0.01g, Offwhite solid; Melting point: 130-135 °C; 1H NMR (400MHz, CDCI3) δ ppm: 0.83(s, 3H), 0.93(s, 3H), 1.06(s, 3H), 1.35-1.42(m, 1H), 1.64- 1.73(m, 6H), 1.85-1.98(m, 3H), 2.15-2.51(m, 5H), 2.64-2.68(m, 2H), 2.87-2.88(m, 1H), 3.35-3.48(m, 1H), 3.65- 3.69(m, 1H), 3.89-3.98(m, 1H), 4.3(bs, 1 H), 4.94(d, J=8 Hz, 0.8H), 5.35(d, J=8.0 Hz, 0.2H), 5.4(d, J=51.2 Hz, 0.2H), 5.45(d, J=51.2 Hz, 0.8H). m/z(M+H): 381.2.
Example 39: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidin-1-yl methyl)cyclopentylami- no)acetyl)pyrrolidine-2-carbonitrile [0331]
[0332] Prepared similar to example 33 using intermediate 3 and piperidine. 0.04gm, Creamy white solid. Melting point: 100-103 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.81 (s, 3H), 0.9(s, 3H), 1.06(s, 3H), 1.39-1.41 (m, 2H), 1.55-1.57(m, 4H), 1.62- 1.65(m, 4H), 1.85-1.87(m, 1H), 1.99-2.01(s, 1H), 2.14-2.16(m, 1H), 2.33-2.36(m, 4H), 2.64-2.72(m, 1H), 3.35-3.53(m, 2H), 3.66-3.75(m, 1H), 3.88-3.98(m, 1H), 4.94(d, J=9.2 Hz, 1H), 5.28(d, J=52.2 Hz, 0.2H), 5.4(d, J=52.2 Hz, 0.8H). m/z(M+H): 379.3.
Example 40: (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-tremethyl-3-(piperidin-1-yl methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0333]
[0334] Prepared similar to example 35 using intermediate 10 and piperidine 0.09 g, Pale green solid. Melting point: 135-137 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.93(s, 3H), 0.95(s, 3H), 1.04(s, 3H), 1.39-1.42(m, 1H), 1.61-1.88(m, 7H), 1.98-2.01 (m, 3H), 2.25-2.34(s, 6H), 2.63-2.71 (m, 1H), 3.3-3.34(d, 1H), 3.49-3.53(m, 1H), 3.55-3.97(m, 3H), 4.95(d, J=9.2 Hz, 0.8H), 5.33(d, J=9.2 Hz, 0.2H), 5.4(d, J=52.2 Hz, 0.2H), 5.45(d, J=52.2 Hz, 0.8H). m/z(M+H): 457.2.
Example 41 : (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-((4-hydroxypiperidin-1-yl) methyl)1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0335] Prepared similar to example 33 using intermediate 3 and 4-hydroxy piperidine
[0336] 0.007 g Off white solid. 1H NMR(400MHz, CDCI3) δ ppm: 0.83(s, 3H), 0.93(s, 3H), 1.06(s, 3H), 1.55-1.64(m, 5H), 1.86-1.94(m, 3H), 2.0-2.19(m, 3H), 2.2-2.35(m, 1H), 2.38-2.45(m, 2H), 2.64-2.74(m, 3H), 3.38-3.47(m, 2H), 3.66-3.78(m, 2H), 3.88-3.94(m, 1H), 4.93-4.95(d, J=9.4 Hz, 1H), 5.36(d, J=51.0 Hz, 0.2H), 5.48(d, J=51.0 Hz, 0.8H). m/z(M+H): 395.3.
Example 42: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenyl sulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0337]
Step 1: tert-Butyl (1R,3S)-1,2,2-trimethyl-3-((4-(methylthio)phenylthio)methyl) cyclopentylcarbamate [0338]
[0339] To a suspension of Intermediate-3 (0.40 g, 1.19 mmol) and cesium carbonate (0.972 g, 2.98 mmol) in DMF, 4-(methylsulfanyl)thiophenol (0.16 g, 2.98 mmol) was added and the reaction heated at 80 °C over night. The reaction mixture poured into water, extracted with ethyl acetate, washed with water, dried with Na2SO4 and concentrated. The residue was purified by column using ethyl acetate and hexane. 0.295 g, Off- white solid, 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 0.94(s, 3H), 1.30(s, 3H), 1.43 (s, 9H), 1.79-2.04(m, 5H), 2.14(s, 3H), 2.63-2.70(m, 1H),3.03- 3.06(m, 1H),4.48(s, 1H), 7.16-7.19(m, 2H), 7.24-7.26(m, 2H). m/z(M-100)+H: 296.2.
Step 2: (1/?,3S)N-ferf-Butoxycarbonyl-1,2,2-trimethyl-3-({[4-(methylsulfonyl) phenyl]sulfonyl}methyl)cyclopen-tanamine [0340]
[0341] To a dichloromethane solution of step 1 intermediate (0.274 g, 0.69 mmol), mCPBA (mefa-chloroperbenzoic acid) (1.2 g, 4.17 mmol) was added and stirred at room temperature for 4 hours. Reaction mixture was diluted and extracted with dichloromethane, washed with NaHCO3 solution and dried with anhydrous Na2SO4 and concentrated. The compound obtained was purified by silica column chromatography. 0.250 g, Off white solid, Melting point 200-203 °C, 1H NMR (400MHz, CDCI3) δ ppm: 0.78(s, 3H), 0.95(s, 3H), 1,35(s, 3H), 1.45 (s, 9H), 1.46-1,49(m, 1H), 1,85-2.08(m, 3H), 2.25-2.35(m, 1H), 2.95-3.14(m, 2H), 3.14(s, 3H), 4.45(s, 1H),8.13-8.18(m, 4H), m/z(M-56)+ H: 404.
Step-3: (1R,3S)-1,2,2-Trimethyl-3-((4-(methylsulfonyl)phenylsulfonyl)methyl) cyclopentanaminehydrochloride [0342]
[0343] To a solution of Step 2 intermediate (0.200 g, 0.0043 mol) in ethyl acetate, 3 mL of saturated dry HCI in ethyl acetate was added and stirred for 2 hours. The separated solid out was decanted and washed with ethyl acetate and dried. 1H NMR (400MHz, DMSO-d6) δ ppm: 0.74(s, 3H), 0.86(s, 3H), 1.15(s, 3H), 1.50-1,55(m, 1H), 1,67(m, 1H), 1.81 (m, 2H), 2.08-2.10(m, 1H), 2.47(s, 3H), 3.42-3.52(m, 2H), 7.8(bs, 3H), 8.2(m, 4H). m/z(M+H): 360.1.
Step 4: (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0344]
[0345] The Step 3 intermediate (0.080 g, 0.22 mmol) was added to a stirred suspension of intermediate 20 (0.018 g, 0.11 mmol), K2CO3, (0.038g, 0.20 mmol), Kl (0.013 g, 0.08 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 0.5% methanol in dichloromethane. 0.01g, White solid. Melting point: 220-224 °C. 1H NMR(400MHz, CDCI3) δ ppm: 0.79(s, 3H), 0.88(s, 3H), 1.04(s, 3H), 1.46-1,53(m, 1H), 1.60-1,70(m, 2H), 2.0-2.05(m, 2H), 2.29-2.39(m, 2H), 2.65-2.73(m, 1H), 3.11 (s, 3H), 3.13-3.15(m, 2H), 3.32-3.49(m, 2H), 3.3-3.75(m, 1H), 3.87-3.96(m, 1H), 4.92(d, J=9.2 Hz, 0.8H),5.1(d, J=9.2 Hz, 0.2H), 5.4 ((d, J=54 Hz, 0.2H), 5.5 (d, J=54 Hz, 0.8H), 8.15-8.19 (s, 4H). m/z(M+H): 514.1.
Example 43:(2S,4R)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0346]
[0347] Step 3 intermediate of example 42 (0.097 g, 0.244 mmol), K2CO3 (0.14 g, 1.0 mmol) and Kl (0.02 g, 0.12 mmol) in 1 mL of DMSO was coupled with intermediate 22 (0.046 g, 0.244 mmol), similar to step-4 of example 42 to afford 0.02 g of title compound as white solid. Melting point 163-166 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 6H), 0.88(s, 3H), 1.08(s, 3H), 1.45-1.51(m, 1H), 1.98-2.03(m, 1H), 2.32-2.37(m, 1H), 2.61-2.63(m, 1H), 2.76-2.78(m, 1H), 3.11(s, 3H), 3.13-3.18(m, 2H), 3.26-3.87(m, 4H), 4.75(d, J=9.2 Hz, 0.8H), 5.1 (d, J=9.2 Hz, 0.2H), 5.3 (d, J=52 Hz, 0.2H), 5.4(d, J=52 Hz, 0.8H), 8.15-8.18(m, 4H). m/z(M+H): 514.2.
Example 44: (S)-1 -(2-((1 R,3S)-1,2,2-Trimethyl-3-((4-(methylsulfonyl)phenyl sulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0348]
[0349] Step 3 intermediate of example 42 (0.097 g, 0.255 mmol), K2CO3 (0.138 g, 1 mmol) and Kl (0.019 g, 0.12 mmol) in 1 mL of DMSO is coupled with intermediate 21 (0.042 g, 0.25 mmol) similar to step-4 of example 40 afforded 0.025 g of title compound as white solid. Melting point: 162-166 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 3H), 0.88(s, 3H), 1.03(s, 3H), 1.48-1.51(m, 1H), 1.58-1.69(m, 3H), 1.98-2.03(m, 1H), 2.14-2.19(m, 2H), 2.22-2.35(m, 3H), 3.11(s, 3H), 3.14-3.15(m, 2H), 3.29-3.59(m, 3H), 3.62-3.73(m,1 H), 4.73-4.75(m,1H) 8.18(s, 4H). m/z(M+H): 496.1.
Example 45: (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0350]
[0351] Prepared similar to example 42 replacing intermediate 3 with intermediate 10; 0.03 g, white solid. M.P.: 211-216 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 3H), 0.88(s, 3H), 1.06(s, 3H), 1.45-1.70(m, 4H), 1.98-2.04(m; 1H), 2.26-2.37(m, 2H), 2.65-2.72(m, 1H), 3.11(s, 3H), 3.15-3.30(m, 3H), 3.47-3.91(m, 3H), 4.92(d, J=9.3 Hz, 1H),5.37(d, J=53 Hz, 0.2H), 5.49(d, J=53 Hz, 0.8H) 8.12(s, 4H). m/z(M+H): 514.1. m/z(M+H): 514.1.
Example 46: (S)-1-(2-((1S,3R)-1,2,2-Trimethyl-3-((4-(methylsulfonyl) phenyl sulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0352]
[0353] Prepared similar to example 44 replacing intermediate 3 with intermediate 10. 0.03 g, White solid. Melting point: 158-160 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s„ 3H), 0.88(s, 3H), 1.05(s, 3H), 1.47-1.71(m, 4H), 1.98-2.02(m, 1H),. 2.15-2.33(m, 5H), 3.11(s, 3H), 3.12-3.61(m, 5H), 4.74-4.75(m, 1H), 8.17(s, 4H). m/z(M+H): 496.1.
Example 47: (2S,4R)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methyl sulfonyl)phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0354]
[0355] Prepared similar to example 43 starting from intermediate 10. 0.02 g OffWhite solid, Melting point 172-175 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 3H), 0.88(m, 3H), 1,04(s, 3H), 1.45-1,75(m, 4H), 1.98-2.03(m, 1H), 2.32-2.37(m, 1H), 2.4-2.53(m, 1H), 2.72-2.79(m, 1H), 3.11(s, 3H), 3.13-3.18(m, 2H), 3.38-3.39(m, 2H), 3.65-3.95(m, 2H), 4.75 (d, J=8.4 Hz, 0.8H), 4.82 (d, J=8.4 Hz, 0.2H), 5.25(d, J= 52 Hz, 0.2H), 5.4(d, J=52 Hz,0.8H), 8.13-8.18(m, 4H). m/z(M+H): 514.1.
Example 48: (2S,4S)-4-Fluoro-1 -(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol -5-yl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0356]
Step 1: ferf-Butyl [(1R,3S)-1,2,2-trimethyl-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)cyclopentyl]carbamate [0357]
[0358] A solution of intermediate 6 (0.5 g, 1.84 mmol), carbonyldiimidazole (0.59g, 3.68 mmol) and 4-fluoro-/V’-hy-droxybenzenecarboximidamide (0.284 g, 1.84 mmol) in dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was concentrated; toluene was added and refluxed of another 24 hours. Toluene was removed under reduced pressure, crude mixture purified by column using ethyl acetate 5% in hexane.1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 1.21(m, 3H), 1.44(s, 9H), 1.57(s, 3H), 2.08-2.2(m, 4H), 3.3-3.37(m, 1H), 7.13-7.26(m, 2H), 8.09-8.12(m, 2H. m/z(M+H-100): 290.1.
Step 2: (1R,3S)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclo pentanamine hydrochloride [0359]
[0360] Asaturated solution of dry HCI in ethyl acetate (2 mL) was added to ethyl acetate solution of step-1 intermediate and stirred for 2 h. Ethyl acetate was removed under reduced pressure; the residue was triturated with ether, separated solid was washed with ether and dried. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.76(s, 3H), 1,20(m, 3H), 1(s, 3H), 1.9(m, 1H), 2.18(m, 2H), 2.8(m, 1H), 3.62(m, 1H), 7.4-7.44(m, 2H), 8.05-8.09(m, 2H), 8.14(bs, 3H). m/z(M+H): 290.1.
Step-3: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0361]
[0362] To a stirred suspension of the step-2 intermediate (0.1 g, 0.30 mmol), K2CO3 (0.17 g, 1.22 mmol) and Kl (0.02 g, 0.12 mmol) in 1 mL of DMSO were added a DMSO solution of intermediate 20 (0.058 g, 0.30 mmol) and the reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the prod-uct.0.025g, White solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.82(s, 3H), 1.18(s, 3H), 1.19(s, 3H), 1.22(m, 1H), 1.59(m, 1H), 1.88(m, 1H), 1.97(m, 1H), 2.61(m, 1H), 2.69(m, 1H),2.89(m, 1H), 3.41(m, 1H), 3.45(m, 1H), 3.69(m, 1H), 3.98(m, 1H), 4.95(d, J=9.2, 0.8H), 5.34(d, J=9.2, 0.2H), 5.35(d, J=51, 0.2H), 5.5(d, J=51,0.8H), 7.14-7.19(m, 2H), 8.09-8.12(m, 2H). m/z(M+H): 442.1.
Example 49: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0363]
[0364] Prepared similar to example 48 using intermediate 13, carbonyldiimidazole and 4-fluoro-/V’-hydroxybenzene-carboximidamide.0.065 g, Off white solid. MP 160-163 °C. 1H NMR (400 MHz, CDCI3) δ ppm: 0.82(s, 3H), 1.18(s, 3H),1.22(s,3H),1.77-1,80(m,1H),1.93-1,98(m,1H), 2.09-2.13(m,1H),2.46-2.49(m,2H),2.65-2.73(m,1H), 3.35-3.41 (m, 2H), 3.41-3.78(m, 3H), 3.9-3.99(m, 1H), 4.96(d, J=9.2 Hz, 0.8H), 5.2(d, J=9.2 Hz, 0.2H), 5.35(d, J=51 Hz, 0.2H), 5.45 (d, J=51.1 Hz, 0.8H), 7.14-7.19(m, 2H), 8.08-8.11(m, 2H). m/z(M+H): 444.1.
Example 50: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0365]
Step 1: ferf-Butyl [(1R,3S)-1,2,2-trimethyl-3-(5-methyl-1,2,4-oxadiazol-3-yl) cyclopentylcarbamate [0366]
[0367] A solution of intermediate 6, carbonyldiimidazole and N’-hydroxyacetimidamide in dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was concentrated. Toluene was added and refluxed of another 24 h. Toluene was removed under reduced pressure and crude mixture was purified by column chromatography using ethyl acetate 5% in hexane. m/z(M+H): 310.2.
Step 2: (1R,3S)-1,2,2-Trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentan aminehydrochloride [0368]
[0369] Asaturated solution of dry HCI in ethyl acetate (2 mL) was added to ethyl acetate solution of step-1 intermediate and stirred for 2 hours. Ethyl acetate was removed under reduced pressure; the residue was triturated with ether and solid separated was washed with ether and dried. 1H NMR (400MHz, CDCI3) 6 ppm: 0.85(s, 3H), 1,19(s, 3H), 1.45(s, 3H), 2.07(m, 1H), 2.22-2.37(m, 3H), 2.4(s, 3H), 3.58(t, 1H).
Step: 3: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0370]
[0371] To a stirred suspension of the step-2 intermediate (0.1 g, 0.40 mmol), K2CO3 (0.225 g, 1.62 mmol) and Kl (0.033 g, 0.2 mmol)) in 1 mL of DMSO was added a DMSO solution of intermediate 20 (0.069 g, 0.36 mmol) and the reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product as an off-white solid. 0.050 g, White solid. Melting point: 147-151 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s,
3H), 1.11(s, 3H), 1.2(s, 3H), 1.86-1.88(m, 1H), 1.90-1.93(m, 1H), 2.05-2.07(m, 1H), 2.29-2.37(m, 1H), 2.39(s, 3H), 2.61-2.75(m, 1H), 3.27-3.32(m, 1H), 3.39-3.50(m, 2H), 3.67-3.75(m, 2H), 3.90-3.99(m, 1H), 4.94 (d, J=9.2, 0.8H), 5.31 (d, J=9.2, 0.2H), 5.35(d, J=52, 0.2H)5.45(d, J=52, 0.8H). m/z(M+H): 364.2.
Example 51 : (2S,4S)-4-Fluoro-1-(2-((1S,3R)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0372] Prepared similar to example 50 starting from intermediate 13 and N’-hydroxyacetimidamide
[0373] 0.024 g, Off white solid. Melting point: 160-163 °C. 1H NMR (400MHz, CDCI3)ôppm: 0.77(s, 3H), 1.13(s, 3H), 1.17(s, 3H), 1.7-1.73(m, 1H), 1.86-1.89(m, 2H), 2.04-2.05(m, 1H), 2.2-2.3(m, 1H), 2.39(s, 3H), 2.65-2.8(m, 1H), 3.28-3.39(m, 2H), 3.51-3.55(m, 1H), 3.61-3.68(m, 1H), 3.89-3.95(m, 1H), 4.95 (d, J=9.2 Hz, 0.8H), 5.20(d, J=9.20 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H); m/z(M+H): 364.2.
Example 52: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0374]
[0375] Prepared similarto example 50 using intermediate 6 and N’-hydroxy-2-methyl propanimidamide in step 1.0.015 g, Off-white hygroscopic solid. Melting point: 91-94 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.75(s, 3H), 1.09(s, 3H), 1.16(s, 3H), 1.32-1.35(d, J=6.9, 6H), 1.79-1.83(m, 1H), 1.92-1.93(m, 1H), 2.05-2.07(m, 1H), 2.35-2.39(m, 2H), 2.65-2.73(m, 1H), 3.06-3.09(m, 1H), 3.29-3.80(m, 4H), 3.95-4.0(m, 1H), 4.95 (d, J=9.2 Hz, 0.8H), 5.20(d, J=9.2 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H); m/z(M+H): 392.2.
Example 53: (2S,4S)-1-(2-((1 R,3R)-3-(Cyanomethyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoropyrrolid-ine-2-carbonitrile [0376]
[0377] To a solution of intermediate 7 (0.2 g, 0.75 mmole) in Acetonitrile was added p-toluenesulphonic acid (0.28 g, 1.50 mmol) and the reaction mixture was stirred at room temperature for five hours. The volatiles were removed under reduced pressure and triturated with diethyl ether to afford the desired product. The product thus obtained was dissolved in 1 mL of DMSO and K2CO3 (0.202 g, 1.47 mmol), Kl (0.081 g, 0.49 mmol) and intermediate-20 (0.142 g, 0.75 mmol) were added. The reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layerwas dried over anhydrous Na2SO4, concentrated and purified by chromatog
raphy to yield the product as an off-white solid. 0.08 g, Off white solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.89(s, 3H), 0.95(s, 3H), 1.2(s, 3H), 1.59-1.61(m, 1H), 2.01-2.05(m, 2H), 2.11-2.15(m, 2H), 2.25-2.42(m, 3H), 2.62-2.73(m, 1H), 3.34-3.50(m, 2H), 3.65-3.76(m, 1H), 3.88-3.97(m, 1H), 4.94 (d, J=9.2 Hz, 0.8H), 5.08(d, J=9.2 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H); m/z(M+H): 321.2.
Example 54: (2S,4S)-4-Fluoro-1-(2-((1R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0378]
Step 1: ferf-Butyl {(1R,3R)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethyl cyclopentylcarbamate: [0379]
[0380] To a solution intermediate 7 (0.80 g, 0.003 mol) in ethanol, 50% of hydroxylamine aqueous solution (6 mL) is added and heated to 80-85 °C for five hours. After completion of reaction, ethanol was removed and diluted with water and ethyl acetate. The layers are separated and the organic layer is dried over Na2SO4, and concentrated on a rotavapor. It gave 0.85 g, off-white solid, m/z (M+1): 300.2.
Step 2: tert-Butyl (1R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl) methyl) cyclopentylcarbamate [0381]
[0382] To a solution of Step-1 intermediate (0.42 g, 0.0014 mol) in trimethylorthoacetate (5 mL), (1 R)-(-)-camphorsul-phonicacid (10 mg) is added and heated to 100-105 “Cforfive hours. After completion of reaction, trimethylorthoacetate was removed under reduced pressure and diluted with water and ethyl acetate. The layers were separated and the organic layerwas dried over anhydrous Na2SO4, and concentrated on a rotavapor. The crude material was purified, by column chromatography. 0.270 g, Off-white sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 1.10(s, 3H), 1.35(s, 3H),1.43 (s,9H), 1.74-1.78(m, 1H), 1.88-1.89(m, 2H), 2.15-2.20(m, 2H), 2.50-2.52(m, 1 H),2.53(s,3H), 2.82-2.86(m, 1H), 4.52(s, 1 H),. m/z(M-100)+ H: 224.2.
Step 3: (1R,3R)-1,2,2-Trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl) cyclopentanaminehydrochloride [0383]
[0384] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of intermediate step-1 (0.26 g, 0.0008 moles)) in ethyl acetate at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and triturated with diethyl ether to afford the desired product. 0.180 g, Offwhite sticky mass, 1H NMR (400MHz, DMSO) δ ppm: 0.85(s, 3H), 0.95(s, 3H), 1.12(s, 3H),.1.65-1,74(m, 2H), 1.90-1,95(m, 1H), 2.16-2.16(m, 2H), 2.57-2.63(m, 1 H),2.64(s,3H),2.80-2.85(m, 1H), 7.42(BS, 3H). m/z(M+1): 224.2.
Step-4: (2S,4S)-4-Fluoro-1-(2-((1R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0385]
[0386] To a stirred suspension of the step-3 intermediate (0.07g, 0.269mmol), K2CO3 (0.148 g, 1.07 mmol) and Kl (0.020 g, 0.12 mmol) in 1 mL of DMSO was added a DMSO solution of intermediate 20 (0.051 g, 0.269 mmol) and the reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product as 0.03 g, off-white solid. Melting point: 121-123°C. 1H NMR (400MHz, CDCI3) δ ppm: 0.98(s, 6H), 1,04(s, 3H), 1.3-1.42(m, 1H), 1.84-1.9(m, 3H), 2.17-2.4(m, 2H), 2.58(s, 3H), 2.62-2.88(m, 2H), 3.41-4.02(m, 4H), 4.96 (d, J=9.2, 0.8H), 5.25(d, J=9.2, 0.2H), 5.37(d, J=52, 0.2H), 5.45(d, J=51,0.8H); m/z(M+H): 378.2.
Example 55: (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0387]
[0388] Prepared similar to example 54 using intermediate 14 as starting material. 0.024 g, White solid. Melting point: 131-133 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.90(s, 3H), 0.94(s, 3H), 1.09(s, 3H), 1.34-1.37(m, 1H), 1.57-1.76(m, 4H), 2.2-2.4(m, 2H), 2.56(s, 3H), 2.58-2.77(m, 2H), 3.3-3.93(m, 4H), 4.95 (d, J=9.2 Hz, 0.8H), 5.16(d, J=9.2 Hz, 0.2H), 5.36(d, J=52 Hz, 0.2H), 5.45(d, J=51.6 Hz, 0.8H);. m/z(M+H): 378.2.
Example 56: (2S,4S)-4-Fluoro-1 -(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl) -1,2,4-oxadiazol-3-yl)methyl) cyclopentylamino) acetyl)pyrrolidine-2-carbonitrile [0389]
Step-1: tert-Butyl (1S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)cyclopentylcar-bamate [0390]
[0391] To a solution of ferf-butyl {(1 S,3S)-3-[(2Z-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}car-bamate (prepared by reacting intermediate 14 and 50% hydroxylamine solution as described in example 54 step 1) in THF, trifluoroacetic anhydride was added and stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, saturated NaHCO3 solution was added and extracted with ethyl acetate (2x50 mL), and organic layers are combined, washed with water and brine, dried with anhydrous Na2SO4 and concentrated. Crude material purified by column chromatography. 1H NMR (400MHz, CDCI3) δ ppm: 0.79(s, 3H), 0.94(s, 3H), 1.39-1,40(m, 1H), 1,43(s, 3H), 1,5(s, 9H), 1.75-1,83(m, 1H), 1.95-2.0(m, 2H), 2.22-2.27(m, 1H), 2.64-2.70(dd, 1H), 2.85-2.9(dd, 1H), 4.52(s, 1H).
Step-2: (1S,3S)-1,2,2-Trimethyl-3-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl] methyl}cyclopentanamine hydrochloride [0392]
[0393] A solution of saturated HC1 in ethyl acetate (2 mL) was added to a solution of intermediate step-1 (0.26 g, 0.83 mol) in ethyl acetate and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.89(s, 3H), 0.98(s, 3H), 1.21 (s, 3H), 1.33-1.49(s, 1H), 1.65-1.83(m, 2H), 1.9-1.96(m, 1H), 1,21-2.22(m, 1H), 2.68-2.74(dd, 1H), 2.92-2.97(dd, 1H), 8.0(bs, 3H). m/z(M+H): 278.1.
Step-3: (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-trifluoromethyl-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0394]
[0395] To a stirred suspension of the step-2 intermediate (0.095 g, 0.50 mmol), K2CO3 (0.138 g, 1.0 mmol) and Kl (0.033 g, 0.2 mmol) in 1 mL of DMSO was added a DMSO solution of intermediate-20 (0.095 g, 0.5 mmol) and the reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product 0.02 g, White solid. Melting Point 130-131 °C. 1H NMR (400MHz, DMSO) δ ppm: 0.92(s, 6H), 1.12(m, 3H), 1.3-1.45(m, 1H), 1.6(m, 1H), 1.7-1.75(m, 2H), 1.27-2.29(m, 2H), 2.69-2.78(m, 2H), 2.86-2.91(d, 1H), 3.3-3.99(m, 4H), 4.94 (d, J=9.2, 0.8H), 5.15(d, J=9.2, 0.2H), 5.35(d, J=51.2, 0.2H), 5.44(d, J=51,0.8H); m/z(M+H): 432.1.
Example 57: (2S,4S)-4-Fluoro-1 -(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl) -1,2,4-oxadiazol-3-yl)me-thyl)cyclopentylamino) acetyl) pyrrolidine-2-carbonitrile methanesulfonate [0396]
[0397] Example 56 (20 mg, 0.046 mmol) was dissolved in ethyl acetate, to this added (4.4 mg, 0.046 mmol) methanesulfonic acid diluted in ethyl acetate and stirred for 2 h. The solid separated out was decanted, washed with ethyl acetate and dried. 0.02 g, White solid. Melting Point 130-131 °C. 1H NMR (400MHz, D2O) δ ppm: 1.11(s, 6H), 1.39(m, 3H), 1.52-1.61(m, 1H), 1.83-1.9(m, 2H), 2.06-2.11(m, 1H), 2.38-2.4(m, 1H), 2.49-2.5(m, 1H), 2.61-2.63(m, 1H), 2.75(s, 3H), 2.79-2.81(m, 1H), 2.82-2.85(m, 1H), 3.76-3.95(m, 2H), 4.02-4.24(m, 1H), 4.74-4.79(m, 1H), 5.10 (d, J=9.2 Hz, 0.8H), 5.28(d, J=9.2 Hz, 0.2H), 5.50(d, J=51.2 Hz, 0.2H), 5.55(d, J=52 Hz, 0.8H);m/z(M+H): 432.1.
Example 58: (2S,4S)-1-(2-((1S,3S)-3-((5-tert-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0398]
Step 1 : tert-butyl(1 S,3S)-3-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylcarbamate [0399]
[0400] To a solution of trimethylacetic acid (0.150 g, 0.0014 mol) in DCM, CDI (0.356 g, 0.0021 moles) was added and stirred for2 h. ferf-butyl{(1 S,3S)-3-[(2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate prepared in Step-1 example 56) (0.483 g, 0.00161 mol) was added and continued the stirring. After completion of reaction, it is diluted with water. The layerwas separated and the organic layerwas dried over anhydrous Na2SO4, and concentrated on a rotavapor. The crude material wass dissolved in toluene (20 mL) and heated to 120-125 °C for ten hours. After completion of reaction, toluene was removed under reduced pressure and diluted with ethyl acetate and water. The layerwas separated. The organic layer is dried over Na2SO4 and concentrated on a rotavapor. The crude material is purified by column. 0.321 g, Off white sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 1.10(s, 3H), 1.35(s, 3H), 1.40(s, 9H), 1.43 (s, 9H), 1.74-1.78(m, 1H), 1.88-1.89(m, 2H), 2.15-2.20(m, 2H), 2.50-2.52(m, 1H), 2.82-2.86(m, 1H), 4.52(s, 1H). m/z(M-100)+ H: 266.2.
Step 2: (1S,3S)-3-((5-tert-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethyl cyclopentanamine hydrochloride [0401]
[0402] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of intermediate step-1 (0.315 g, 0.86 mmol) in ethyl acetate and the reaction mixture was stirred at room temperature for2 h. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 0.250 g, White solid, 1H NMR (400MHz, d6 DMSO) ppm: 0.80(s, 3H), 1.11(s, 3H), 1.35(s, 3H), 1.40(s, 9H), 1.74-1.78(m, 1H), 1.88-1.89(m, 2H), 2.15-2.20(m, 2H), 2.50-2.52(m, 1H), 2.82-2.86(m, 1H), 8.04(bs, 3H). m/z(M+1): 266.2.
Step 3: (2S,4S)-1-(2-((1S,3S)-3-((5-tert-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0403]
[0404] To a stirred suspension of the step-2 intermediate (0.3 g, 1.01 mmol), K2CO3 (0.540g, 4.05 mmol) and Kl (0.084 g, 0.5 mmol) in 1 mL of DMSO was added a DMSO solution of intermediate 20 (0.182 g, 0.96 mmol) and the reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product 0.13 g Off White solid, melting point: 152-154°C. 1H NMR (400MHz, CDC13) ppm: 0. 89(s, 3H), 0.91(s, 3H), 1.09(s, 3H), 1.42(s, 9H), 1.58-1.79(m, 4H), 2.27-2.36(m, 2H), 2.56-2.79(m, 3H), 3.30-3.60(m, 2H), 3.75-3.77(m, 1H), 3.90-3.93(m, 1H), 4.95(d, J=9.2 Hz, 0.8H,), 5.15(d, J=9.20 Hz, 0.2H,), 5.35(d, J=51 Hz, 0.2H,), 5.5(d, J=51 Hz, 0.8H); m/z(M+1): 420.2.
Example 59: (2S,4S)-1-(2-((1S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0405]
Step 1: (1 S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethyl cyclopentanamine [0406]
[0407] To a solution of ferf-butyl{(1 S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}car-bamate (prepared in Step-1 example 56)(0.3 g, 1mmol) in toluene, pyridine (0.079 g, 1 mmol) and cyclohexanecarbo-
nylchloride was added and stirred for 3 hours. The reaction mixture was refluxed for another 12 h. The reaction mixture diluted with ethyl acetate, washed with 0.1N HCI. Ethyl acetate layerwas separated, dried and concentrated, residue purified by silica column chromatography using 20% ethyl acetate in hexane, m/z (M+1 )-100: 292.1. The product that obtained was dissolved in ethyl acetate. To this a solution of saturated HCI in ethyl acetate (2mL) was added and reaction mixture was stirred at room temperature fortwo hours. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 1H NMR (400MHz, d6-DMSO) δ ppm: 0.8(s, 3H), 0.9(s, 3H), 1.2(s, 3H), 1.42-1.50(m, 3H), 1.52-1.72 (m,2H), 1.89-1.92(m, 5H), 1.95-1.98(m, 3H), 2.13-2.15(m, 1H), 2.51-2.54(m, 1H), 2.74(m, 1H), 3.02(m, 1H), 7.95(bs, 3H).
Step 2: (2S,4S)-1-(2-((1S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0408]
[0409] To a stirred suspension of the step-2 intermediate (0.15 g, 0.50 mmol), K2CO3 (0.138 g, 1 mmol) and Kl catalytic amount in 1 mL of DMSO was added a DMSO solution of intermediate 20 (0.95 g, 0.5 mmol) and the reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product. 0.050 g, Off white solid. Melting point:152-153°C. 1H NMR (400MHz, CDCI3) δ ppm: 0.9(s, 6H), 1.2(s, 3H), 1.3-1.45(m, 2H), 1.40-1.85(m, 11H), 2.04-2.07(m, 2H), 2.26-2.29(m, 2H), 2.56-2.68(m, 1H), 2.74-2.78(m, 2H), 2.90-2.92(m, 1H), 3.30-3.34(m, 1H), 3.48-3.53(m, 1H), 3.60-3.8(m, 1H), 3.85-3.95(m, 1H), 4.95(d, J=9.2, 0.8H,), 5.25(d, J=9.2, 0.2H), 5.35(d, J=51,0.2H,), 5.5(d, J=51,0.8H);). m/z(M+ H): 446.2.
Example 60: (2S,4S)-4-Fluoro-1 -(2-((1 S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol -3-yl)methyl)-1,2,2-trimethyl-cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile [0410]
Step 1: Ethyl 3-(((1 S,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclo pentyl)methyl)-1,2,4-oxadiazole-5-carboxylate [0411]
[0412] To a solution of ferf-butyl {(1 S,3S)-3-[(2Z-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}car-bamate (prepared in Step-1 example 56) (0.40 g, 1.3 mmoles) in toluene (10 mL), pyridine (0.317mL, 4.0 moles) and ethyloxalyl chloride (0.233 g, 2.0 mmoles) were added at 0-5 °C, and stirred for two hours. After two hours reaction mixture was heated to 120-125 °C for 12 hours in an oil bath. After completion of reaction, toluene was removed under reduced pressure and diluted with water and ethyl acetate. The organic layerwas dried over Na2SO4 and concentrated
on a rotavapor. It gave brown colour sticky mass, which is purified by column chromatography. 0.25 g, Off white sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.85(s, 3H), 0.97(s, 3H), 1.32(s, 3H), 1.43(s, 9H), 1.46 (s, 3H), 1.72-1,78(m, 1H), 1.88-1.89(m, 2H), 1.97-2.00(m, 2H), 2.40-2.42(m, 1H), 2.64-2.68(m, 1H), 2.84-2.88(m, 1H). 4.50(s, 1H), 4.52-4.56(m, 2H), m/z (M-56)+ H: 326.1.
Step 2: tert-Butyl (1S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylcar-bamate [0413]
[0414] To a solution of step-1 intermediate (0.26 g, 0.6 mmol) in THF (10mL), NaBH4 (0.051 g, 1.36mmole) is added and stirred for two hours at 0-5 °C. After completion of reaction, THF was removed under reduced pressure and diluted with water and ethyl acetate. The layerwas separated and the organic layer dried over Na2SO4, and concentrated on a rotavapor. The crude material was purified by column chromatography. 0.090 g, Off white sticky mass, m/z (M+1 )-100: 240.2.
Step 3: (3-(((1S,3S)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-1,2,4-oxadiazol-5-yl)methanol hydrochloride [0415]
[0416] A solution of saturated HCI in ethyl acetate (2 mL) was added to a solution of intermediate step-1 (0.085 g, 0.2 mmoles) in ethyl acetate and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product 0.055 g, White solid, 1H NMR (400MHz, d6 DMSO) δ ppm: 0.85(s, 3H), 0.95(s, 3H), 1.27(s, 3H), 1.45-1.47(m, 1H), 1.69-1.75(m, 2H), 1.95-2.00(m, 1H), 2.12-2.15(m, 1H), 2.53-2.57(dd, 1H), 2.75-2.78(dd, 1H), 4.68(s, 2H), 5.97(bs, 1H). 8.03(bs, 3H), m/z (M+1): 240.1.
Step 4: (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl) methyl)-1,2,2-trimethyley-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0417]
[0418] To a stirred suspension of the step-3 intermediate (0.15 g, 0.54 mmol), K2CO3 (0.138 g, 1 mmol) and Kl catalytic amount in 1 mL of DMSO were added a DMSO solution of intermediate 20 (0.95 g, 0.5 mmol) and the reaction mixture was stirred for 12 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product. 0.016g, Off white solid. Melting point-147-149 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.94(s, 3H), 0.97(s, 3H), 1.10(s, 3H), 1.40-1.42(m, 1H), 1.55-1.80(m, 3H), 2.20-2.40(m, 2H), 2.55-2.70(m, 2H), 2.81-2.87(m, 1H), 3.30-3.34(m, 2H), 3.40(s, 2H), 3.50-3.55(m, 1H), 3.61-3.69(m, 1H), 3.90-3.99(m, 1H), 4.95(d, J=9.16 Hz, 0.8H),5.15(d, J=9.16 Hz, 0.2H), 5.37(d, J=50.8 Hz, 0.2H), 5.44(d, J=50.8 Hz, 0.8H), m/z(M+ H): 394.2.
Example 61 : (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile methanesulfonate [0419]
Step 1: tert-Butyl (1S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylcarbamate [0420]
[0421] To a solution of ferf-butyl {(1 S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}car-bamate (prepared in Step-1 example 56) (0.300 g, 1.0 mmoles) in isobutyronitrile (7mL), ZnCI2 (0.0410 g, 3.0 mmol), PTSA (0.057g, 3.0 mmol) were added under N2 atmosphere. It was heated to 90-95 °C for six hours. After completion of reaction, isopropyl cyanide was removed under reduced pressure and diluted with water and ethyl acetate. The layers are separated and the organic layer was dried over Na2SO4, and concentrated on a rotavapor. The crude material is purified by column. 0.120 g, Offwhite sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.81(s, 3H), 0.97(s, 3H), 1.21(s, 3H), 1,34(d,6H), 1,43(s,9H), 1.70-1,73(m, 1H), 1,95-2.00(m, 2H), 2.22-2.25(m, 2H), 2.55-2.59(m, 1 H), 2.79-2.83(m,1 H), 3.17-3.19(m, 1H), 4.51(s, 1H),. m/z(M-100)+H: 252.2.
Step 2: (1S,3S)-3-((5-lsopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclo pentanamine hydrochloride [0422]
[0423] A solution of saturated HCI in ethyl acetate (2mL) was added to a solution of intermediate step-2 (0.11g, 0.3mmole) in ethyl acetate and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 0.070 g, Off-white sticky mass, 1H NMR (400MHz, CDCI3) δ ppm: 0.87(s, 3H), 0.98(s, 3H), 1,22(s, 3H), 1.34 (d, 6H), 1.69-1,73(m, 1H), 1.95-2.00(m„ 2H), 2.10-2.15(m, 2H), 2.55-2.59(m, 1H), 2.80-2.82(m, 1H), 3.22-3.24(m, 1H), 8.04(bs, 3H). m/z(M+1): 252.2.
Step 3: (2S,4S)-4-Fluoro-1 -(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl) methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile methanesulfonate [0424]
[0425] To a stirred suspension of the step-2 intermediate (0.15 g, 0.52 mmol), K2CO3 (0.138 g, 1 mmol) and Kl catalytic
amount in 1 mL of DMSO was added a DMSO solution of intermediate 20 (0.98 g, 0.5 mmol) and the reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield (2S,4S)-4-fluoro-1-(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl) pyrrolidine-2-car-bonitrile. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile (0.032 g, 0.08 mmole) was dissolved in ethyl acetate and solution of methanesulphonic acid (7.9 mg, 0.08mmole) in 1 mL ethyl acetate was added and stirred for one hour. Then ethyl acetate was concentrated and washed with diethyl ether to obtain the title compound. 0.03 g, Off white hygroscopic solid. 1H NMR (400MHz, D2O δ ppm: 1,02(s, 3H), 1,09(s, 3H), 1,35(s, 3H), 1,37(d, 6H), 1.49-1,57(m, 1H), 1.84-1,89(m, 2H), 2.04-2.08(m, 1H), 2.35-2.38(m, 1H), 2.40-2.75(m, 3H), 2.80(s, 3H), 2.9-2.94(m, 1H), 3.26-3.29(m, 1H), 3.77-3.80(m, 1H), 3.90-3.95(m, 1H), 4.01-4.15(m, 1H), 4.20-4.35(m, 1H), 5.10, d, J=9.36 Hz, 0.8H), 5.25(d, J=9.36 Hz, 0.2H), 5.55(d, J=51 Hz, 0.2H),5.56(d, J=51 Hz, 0.8H). m/z(M+ H): 406.2.
Example 62: (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-3-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethyl-cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile [0426]
Step 1 : (1S,3S)-3-((5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentanamine hydrochloride [0427] Prepared similar to example 58 using intermediate ferf-butyl {(1S 3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate (prepared in Step-1 example 56, carbonyldiimidazole and 4-fluorobenzoic acid.
[0428] 1H NMR (400MHz, d6-DMSO) δ ppm: 0.9(s, 3H), 1.0(s, 3H), 1.21(s, 3H), 1.43-1.48(m, 1H), 1.65-1.69(m, 1H), 1.71-1.8(m, 1H), 1.91=1.96(m, 1H), 2.20-2.23(m, 1H), 2.59-2.63(m, 1H), 2.66-2.88(m, 1H), 7.45-7.5(m, 2H), 8.0(bs, 3H), 8.14-8.18(m, 2H). m/z(M+H); 303.2.
Step 2: (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl) methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0429]
[0430] To a stirred suspension of the step-2 intermediate (0.2 g, 0.58 mmol), K2CO3 (0:138g, 1mmol) and Kl catalytic amount in 1 mL of DMSO were added a DMSO solution of intermediate 20 (0.112 g, 0.58 mmol) and the reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic
layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product. 0.12 g, Off white solid. Melting Point 158-16 0°C. 1H NMR (400MHz, DMSO) δ ppm: 0.96(s, 6H), 1.11(m, 3H), 1.41-1.71(m, 6H), 2.32-2.37(m, 2H), 2.61-2.88(m, 3H), 3.32-3.54(m, 2H), 4.95(d, J=9.2 Hz, 0.8H), 5.25(d, J=9.2 Hz, 0.2H), 5.35(d, J=51 Hz, 0.2H), 5.45(d, J= 51 Hz, 0.8H), 7.19-7.23(m, 2H), 8.13-8.15(m, 2H); m/z(M+H): 458.1.1.
Example 63: (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0431] Prepared similar to example 62 ferf-butyl {(1 S,3S)-3-[(2Z-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcy-clopentyljcarbamate (prepared in Step-1 example 56, carbonyldiimidazole and pyridine-4-caboxylic acid.
[0432] 0.025 g, Off-White solid. Melting Point 180-184 °C. 1H NMR (400MHz, DMSO) δ ppm: 0.96(s, 6H), 1.11(m, 3H), 1.41-1.71(m, 6H), 2.32-2.37(m, 2H), 2.65-2.75(m, 2H), 2.86-2.90(m, 1H), 3.32-3.54(m, 2H), 4.94-4.97(d, 0.8H), 5.12-5.15(d, 0.2H) 5.28-5.4(m, 1H), 7.96-7.97(m, 2H), 8.84-8.85(m, 2H). m/z(M+H): 441.2.
Example 64: (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0433]
Step 1: (1R,3S)-Methyl 3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethyl cyclopentanecarboxylate [0434]
[0435] To a solution of (1S,3R)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (1 g, 9.35 mmol) in dichloromethane, carbonyldiimidazole(1.51 g, 9.34 mmol), 4-fluoroN’-hydroxybenzene carboximidamide(0.791 g, 5.14 mmol) were added and stirred for 12 h. After the completion of the reaction an aqueous NH4CI and dichloromethane was added. The organic layer separated, dried and concentrated. The residue obtained was dissolved in toluene and refluxed for 24 hours. The volatiles were removed under high vaccum, crude compound purified by column. Yield: 0.8 g; 1H NMR (400MHz, CDCI3) δ ppm: 0.64(s, 3H), 1.28(s, 3H), 1.36(s, 3H), 1.58-1.60(m, 1H), 1.95-2.09(m, 1H), 2.35-2.49(m, 1H), 2.85-3.00(m, 2H), 3.75(s; 3H), 7.14-7.26(m, 2H), 8.07-8.11(m, 2H). m/z(M+H): 333.1.
Step 2: (1R,3S)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclo pentanecarboxylic acid [0436]
[0437] To a solution of step-1 intermediate (0.8 g, 2.4 mmole) in THF, lithium hydroxide (0.11 g, 4.8 mmole) dissolved in water was added and stirred for 48 h. The reaction was concentrated under reduced pressure, diluted with water and washed with diethyl ether. Aqueous layer was acidified with con HCI and extracted with ethyl acetate, dried and concentrated. Yield: 0.5g; 1H NMR (400MHz, CDCI3) δ ppm: 0.72(s, 3H), 1.41(s, 3H), 1.44(s, 3H), 1.88(m. 1H), 2.04(m, 1H), 2.37(m, 1H), 2.92(m, 2H), 7.14-7.26(m, 2H), 8.07-8.11(m, 2H). m/z(M-H): 317.1.
Step 3: (1R,3S)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclo pentanecarboxamide [0438]
[0439] To a solution of intermediate 2(0.5 g, 1.6mmol) in dichloromethane maintained at - 10°C, one drop of DMF followed by oxalyl chloride (0.16 mL, 1.73mmol) was added and stirred for 2 h. The volatiles were removed by passing N2 gas. The residue was dissolved in diethyl ether, aqueous ammonia (10 ml) was added and stirred for 0.5 h. The organic layer was separated, aqueous layer washed with dichloromethane (2x50 mL). Organic layer were combined, dried and concentrated. 1H NMR (400MHz, CDCI3) δ ppm: 0.71(s, 3H), 1.39(s, 3H), 1.45(s, 3H), 1.84-1.90(m. 1H), 1.96-1.99(m, 1H), 2.35-2.38(m, 1H), 2.81-2.93(m, 1H), 2.96-2.99(m, 1H), 5.39(s, 1H), 5.56(s, 1H), 7.14-7.18(m, 2H), 8.08-8.11(m, 2H). m/z(M+H): 318.2.
Step 4: (1R,3S)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclo pentanamine hydrochloride [0440]
[0441] Step 3 intermediate (0.4 g, 1.26 mmol) was dissolved in a 3 mL solvent mixture of ethyl acetate, acetonitrile and water in the ratio 1:1:0.5 respectively. To this PIFA (0.76g, 1.76mmol) was added and stirred, maintaining the temperature at 45 °C for 5 h. The reaction was further stirred at room temperature for 8 h. Excess PI FA was decomposed by heating at 70 °C for 10 minutes. Reaction mixture was concentrated under reduced pressure, acidified with dilute HCI, washed with diethyl ether. Aqueous layer was separated, basified with NaHCO3 solution and extracted with dichloromethane, washed with water, brine, dried and concentrated. The residue was dissolved in ethyl acetate and HCI in
ethyl acetate was added and stirred. The separated solid was filtered and washed with ethyl acetate. 1H NMR (400MHz, D2O δ ppm: 0.65(s, 3H), 1.23(s, 3H), 1.40(s, 3H), 1.77-1.90(m, 2H), 2.21-2.26(m, 1H),2.77-2.80(m, 1H), 3.54-3.58(m, 1H), 7.39-7.44(m, 2H), 8.04-8.08(m, 2H). m/z(M+H): 290.2.
Step 5: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0442]
[0443] To a stirred suspension of the step-4 intermediate (0.07 g, 0.21 mmol), K2CO3 (0.116 g, 0.84 mmol) and Kl catalytic amount in 1mL of DMSO were added a DMSO solution of intermediate 20 (0.0.37 g, 0.19 mmol) and the reaction mixture was stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by chromatography to yield the product. 0.04g, White solid. 1H NMR(400MHz, CDCI3)Ô ppm: 0.68(s, 3H), 1,23(s, 3H), 1.41 (s, 3H), 1.59-1,62(m.2H), 1.65-1,83(m, 1H),2.23-2.29(m,2H),2.61-2.73(m, 1H),2.9-2.93(m, 1H),3.02-3.06(m, 1H), 3.41-3.78(m, 3H), 3.92-4.01(m, 1H),4.95(d, J=9.2, 0.8H), 5.12(d, J=9.2, 0.2H), 5.20(d, J=52, 0.2H), 5.35(d, J=52, 0.8H) 7.14-7.26(m, 2H), 8.08-8.11(m, 2H). m/z(M+H): 444.2.
Example 65: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0444] Prepared similarto example 64 starting form (1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarbox-ylic acid..035 g, White solid.: M.P:127-131 °C.
[0445] m/z(M+H): 444.2. 1H NMR (400MHz, CDCI3) δ ppm: 0.66(s, 3H), 1.21(s, 3H), 1.42(s, 3H),1.42-1,62(m, 2H) 1.75-1,82(m, 1H), 2.18-2.40(m, 2H), 2.66-3.08(m, 3H), 3.60-3.97(m, 4H), 4.95-4.97(d, J=9.2 Hz, 0.8H), 5.1 (d, J=9.2 Hz, 0.2H), 5.25(d,J=51 Hz, 0.2H), 5.44(d, J=51 Hz, 0.8H), 7.14-7.18(m, 2H), 8.07-8.11(m, 2H).
Fxample 66: (S)-1-(2-((1S,3R)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclo pentylami-no)acetyl)pyrrolidine-2-carbonitrile methanesulfonate [0446] Prepared similar to example 64 starting using intermediate 21 in step 5.
[0447] 0.04 g, White solid. Melting point: 206-211 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.9(s, 3H), 1,4(s, 3H), 1,49(s, 3H), 2.03-2.04(m, 2H), 2.19-2.23(m, 2H), 2.34-2.36(m, 2H), 2.5-2:51 (m, 1H), 2.81 (s, 3H), 2.88-2.89(m, 1H), 3.52-3.54(m, 1H),3.62-3.65(m, 1H), 3.78-3.82(m, 1H), 4.1-4.2(m, 2H), 4.82-4.84(m, 1H), 7.3-7.34(m, 2H), 8.0-8.06(m, 2H). m/z(M+H): 426.1.2.
Example 67: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0448]
[0449] Prepared according to procedure described in example 64 starting form (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid and /V’-hydroxy-2-methylpropanimidamide. 0.045 g, White solid. Melting point: 82-85 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.60(s, 3H), 1.18(s, 3H), 1.32(s, 3H), 1.36(d, 6H), 1.50-1.8(m, 3H), 2.15-2.39(m, 2H), 2.61-2.86(m, 2H), 2.99-3.09(m, 2H), 3.44-3.78(m, 2H), 3.87-4.05(m, 2H), 4.95 (d, J=9.2, 0.8H), 5.20(d, J=9.2, 0.2H), 5.35(d, J=52, 0.2H), 5.45(d, J=52, 0.8H); m/z(M+H): 392.2.
Example 68: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0450] Prepared similarto example 64 starting form (1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarbox-ylic acid /V’-hydroxypyridine-3-carboximidamide.
[0451] 0.017g, Off White solid. Melting point: 126-130 °C. 1H NMR(400MHz, CDCI3) δ ppm: 0.68(s, 3H), 1.25(s, 3H), 1.44(s, 3H), 1.59-1.61(m, 1H), 1.80-1.82(m, 1H), 2.10-2.30(m, 2H), 2.65-2.75(m, 1H), 2.92-2.94(m, 2H), 3.04-3.08(m, 1H), 3.61-3.79(m, 2H), 3.88-3.97(m, 2H), 4.95(d, J=9.2 Hz, 0.8H), 5.11(d, J=9.2 Hz, 0.2H), 5.35(d, J= 52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H), 7.43(t, J=5.48 Hz,1H 8.37(d, J=8.16 Hz, 1H), 8.74(d, J=4.64 Hz, 1H), 9.32(s, 1H). m/z(M+H): 427.2.
Example 69: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0452] Prepared similarto example 64 using (1S,3R)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylicacid /V’-hydroxypyridine-3-carboximidamide
[0453] 0.031 g, Off white solid. Melting point: 70-75 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.63(s, 3H), 1.2(s, 3H), 1.4(s, 3H), 1.59-1.63(m, 1H), 1.77-1.84(m, 1H), 2.24-2.3(m, 2H), 2.66-2.74(s, 1H), 2.9-2.95(m, 1H), 3.02-3.06(m, 1H), 3.41-3.78(m, 3H), 3.93-4.02(m, 1H), 4.96(d, J=9.1 Hz, 0.8H), 5.25(d, J=9.1 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H), 7.42(t, J=4.92 Hz, 1H), 8.37 (d, J=7.96 Hz, 1H), 8.73(d, J=4.64 Hz, 1H), 9.31(s, 1H); m/z(M+H): 427.2.
Example 70: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0454] Prepared similarto example 64 using ((1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid and /\/’-hydroxypyridine-4-carboximidamide
[0455] 0.03 g. Off white solid. Melting point: 149-153 °C. m/z(M+H): 427.2 1H NMR (400MHz, CDCI3) δ ppm: 0.63(s, 3H), 1.2(s, 3H), 1:4(s, 3H), 1.51-1.56(m, 1H), 1.7-1.77(m, 1H), 2.12-2.22(m, 2H), 2.59-2.66(s, 1H), 2.83-2.87(m, 1H), 2.96-3.01(m,1H), 3.37-3.41(m, 1H), 3.53-3.9(m, 3H), 4.88(d, J=9.1 Hz, 0.8H), 4.98(d, J=9.1 Hz, 0.2H), 5.30(d, J=52 Hz, 0.2H), 5.45(d, J=51 Hz, 0.8H), 7.88(d, J=5.88 Hz, 2H), 8.68(d, J=4.72 Hz, 2H). m/z(M+H): 427.2.
Example 71: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0456] Prepared similarto example 63 using ((1 S,3R)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid and /\/’-hydroxypyridine-4-carboximidamide.
[0457] 0.020 g, Off white solid. Melting point: 167-171 °C. 1H NMR (400MHz, CDCI3)ôppm: 0.68(s, 3H), 1.23(s, 3H), 1.43(s, 3H), 1.60-1.62(m, 1H), 1.78-1.85(m, 1H), 2.24-2.31(m, 2H), 2.66-2.74(m, 1H), 2.90-2.93(m, 1H), 3.04-3.08(m, 1H), 3.43-3.54(m, 2H), 3.64-3.79(m, 1H), 3.93-4.02(m, 1H), 4.96(d, J=9.1 Hz, 0.8H), 5.15(d, J=9.1 Hz, 0.2H), 5.32(d, J=52 Hz, 0.2H), 5.45(d, J=51 Hz, 0.8H), 7.97(d, J=9.42 Hz, 2H), 8.77(d, J=4.88 Hz, 2H); m/z(M+H): 427.2.
Example 72: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-2,2,3-trimethyl-3-(3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile [0458] Prepared similarto example 64 ((1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid and using /\/’-hydroxypyrazine-2-carboximidamide.
0.04 g, White solid. Melting point: 65-70 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.7(s, 3H), 1.2(s, 3H), 1.46(s, 3H), 1.5-1.6(m, 2H), 1.8-1.87(m, 1H), 2.2-2.39(m, 2H), 2.66-2.77(m, 1H), 2.98-3.09(m, 2H), 3.44-3.88(m, 2H), 3.91-3.97(m, 1H), 4.95(d, J=9.1 Hz, 0.8H), 5.10(d, J=9.1 Hz, 0.2H), 5.29(d, J=52 Hz, 0.2H), 5.45(d, J=52.8 Hz, 0.8H), 8.72(d, J=2.32 Hz, 1H),8.77(d, J=1.68 Hz, 1H), 9.3(s, 1H). m/z(M+H): 428.2.
Example 73: (2S,4S)-4-Fluoro-1-(2-((1R,3S)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0459]
[0460] Prepared similarto example 64 using ((1S,3R)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid Λ/’-hydroxyethanimidamide. 0.04 g, Offwhite solid. M.P: 144-147 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.77(s, 3H), 1.13(s,3H), 1.17(s,3H), 1.58-1.61(m. 1H), 1.71-1.76(m, 1H), 2.2-2.25(m, 2H), 2.38(s, 3H), 2.65-2.73(m, 1H),2.8-2.82(m, 1H), 2.97-3.02(m, 1H), 3.38-3.42(m, 1 H), 3.48-3.52(m, 1H), 3.62-3.74(m, 1H), 3.91-4.0(m, 1H), 4.94(d, J=9.2 Hz, 0.8H), 5.18(d, J=9.2 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J= 52 Hz, 0.8H). m/z(M+H): 364.2.
Example 74: (2S,4S)-4-Fluoro-1-(2-((1S,3R)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile [0461]
[0462] Prepared similarto example 64 using ((1 R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid Λ/’-hydroxyethanimidamide. 0.06 g, Offwhite solid. Melting point: 137-141 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.63(s, 3H), 1.1(s, 3H), 1.19(s, 3H), 1.55-1.58(m. 1H), 1.69-1.77(m, 2H), 2.14-2.29(m, 1H), 2.38(s, 3H), 2.65-2.85(m, 2H), 2.97-3.02(m, 1H), 3.42-4.05(m, 4H), 4.95(d, J=9.2 Hz, 0.8H), 5.25(d, J=9.2 Hz, 0.2H), 5.36(d, J=52 Hz, 0.2H), 5.45(d, J= 52 Hz,0.8H). m/z(M+H): 364.2.
Example 75: (S)-1-(2-((1R,SR)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1] octan-1-ylamino)acetyl)pyrroli-dine-2-carbonitrile [0463]
[0464] To a stirred suspension of the intermediate 15 (0.13 g, 0.61 mmol), K2CO3 (0.17 g, 1.2 mmol) and Kl catalytic amount in 2 mL of DMSO, intermediate 21 (0.106g, 0.61 mmol) was added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by silica column using 2% methanol in dichloromethane to yield the product as 0.025 g, white solid. Melting point 141-144 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.8(s, 3H), 1.1 (s, 3H), 1,2(s, 3H), 1.80-1.88(m, 2H), 1.91-1.98(m, 3H), 2.09-2.21(m, 3H), 2.29-2.31(m, 2H), 3.08(s, 3H), 3.5(m, 1H), 3.54(m, 1H), 3.88-3.92(dd, 1H), 4.81(s, 1H). m/z(M+H): 347.1.
Example 76: (2S,4S)-4-Fluoro-1-(2-((1R,SR)-3,5,8,8-tetramethyl-3-azabicyclo [3.2.1] octan-1-ylamino)acetyl)pyr-rol id i ne-2-carbon itri le [0465]
[0466] To a stirred suspension of the intermediate 16 (0.12g, 0:66mmol), K2CO3 (0.27 g, 1.8 mmol) and Kl catalytic amount in 2 mL of DMSO, intermediate 20 (0.125 g, 0.66 mmol) were added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by silica column chromatography using 2% methanol in dichloromethane to yield the product as 0.055 g, Offwhite solid. Melting point 122-126 °C, 1H NMR (400MHz, CDCI3) δ ppm: 0.82-0:85(2s, 6H), 0.92(s, 3H), 1.57-1.68(m, 3H), 1.87-1.89(m, 2H), 1.91-1.98(m, 1H), 2.16-2.29(m, 1H), 2.3(s, 3H), 2.38(s, 2H), 2.52-2.55(m, 1H), 2.64-2.71(m, 1H), 3.37-3.96(m, 3H), 4.92(d, J= 9.2, 0.8H), 5.22(d, J= 9.2, 0.2H), 5.35(d, J=51, 0.2H), 5.45(d, J=51,0.8H); m/z(M+H): 337.
Example 77: (2S,4R)-4-Fluoro-1-(2-((1R,SR)-3,5,8,8-tetramethyl-3-azabicyclo [3.2.1] octan-1-ylamino)acetyl)pyr-rolidine-B-carbonitrile [0467] Prepared similarto example 75 by coupling intermediate 16 and intermediate 22.
[0468] 0.015 g, White solid. Melting point 74-79 °C. 1H NMR (400MHz, CDCI3) δ ppm: 0.8(s, 3H), 0.9(s, 3H), 1.0(s, 3H), 1.59-1.66(m, 2H), 1.85(m, 1H), 2.16-2.19(d, 1H), 2.29(s, 3H), 2.31-2.34(m, 3H), 2.5(m, 1H), 2.56-2.58(m, 1H), 2.75-2.77(m, 1H), 3.31-3.91(m, 4H), 4.75(t, J=8.2 Hz, 0.8H), 5.08(t, J=8.2 Hz, 0.2H), 5.25(d, J=51.2 Hz, 0.2H), 5.35 (d, J=51.2 Hz, 0.8H). m/z(M+H): 337.1.
Example 78: (S)-1-(2-((1R,SR)-3,5,8,8-Tetramethyl-3-azabicyclo[3.2.1]octan-1-yl amino)acetyl)pyrrolidine-2-car-bonitrile [0469]
[0470] Prepared similar to example 75, by coupling intermediate 16 and intermediate 21.0.03g, White solid. 1H NMR
(400MHz, CDCI3) δ ppm: 0.82(s, 3H), 0.86(s, 3H), 0.9(s, 3H), 1.25(s, 1H), 1.59-1.67(m, 3H), 1.86(m, 1H), 2.16-2.19(m, 3H), 2.23(s, 3H), 2.29-2.35(m, 4H), 2.53-2.56(dd, 1 H), 3.35-3.43(m, 2H), 3.59(bs, 1H), 4.74-4.76-4.96(m, 1H); m/z(M+H): 319.3.
Example 79: (S)-1 -(2-((1 R,SR)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile [0471]
[0472] To a stirred suspension of the intermediate 17 (0.05 g, 0.27 mmol), K2CO3 (0.11 g, 0.79 mmol) and Kl (0.049 g, 0.3 mmol) in 2 mL of DMSO, intermediate-21 (0.046 g, 0.27 mmol) was added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 concentrated and purified by silica column chromatogrpahy using methanol in dichloromethane to yield the product. 0.009 g, White solid. Melting point 174-177°C. 1H NMR (400MHz, CDCI3) δ ppm: 0.99(s, 3H), 1,04(s, 6H), 1.78-2.34(m, 8H), 3.39-3.60(m, 4H), 3.88(m, 2H), 4.06(d, J=10.6 Hz, 1H), 4.80(m, 1H); m/z(M+H): 319.3.
Example 80: (S)-1 -(2-((1 R,SR)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-yl amino)acetyl)pyrrolidine-2-carbon-itrile [0473]
[0474] To a stirred suspension of the intermediate 18 (0.1 g, 0.59 mmol), K2CO3 (0.16 g, 1.1 mmol) and Kl (0.049 g, 0.29 mmol) in 2 mL of DMSO, intermediate 21 (0.081 g, 0.47 mmol) was added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, concentrated and purified by silica column chromatography using methanol in dichloromethane to yield the product. 0.01g, Yellow sticky solid. 1H NMR(400MHz, CDCI3) δ ppm: 0.75(s, 3H), 0.94(s, 3H), 1.01(s, 3H), 1.57-1.68(m, 4H), 1.88-1.93(m, 1H), 2.18-2.21(m, 2H), 2.23-2.31(m, 2H), 3.04-3.07(d, J= 10.8 Hz, 1H), 3.34-3.38(m, 3H), 3.53-3.56(m, 1H), 3.69-3.72(d, J= 10.52 Hz, 2H), 4.74-4.75(d, J=6.0 Hz, 0.8H), 5.8-5.82(d, J=6.0 Hz, 0.2H); m/z(M+H): 306.2.
Example 81 : (2S,4S)-4-Fluoro-1 -(2-((1 R,5R)-5,8,8-trimethyl-3-oxabicyclo [3.2.1]octan-1-ylamino)acetyl)pyrrolid-ine-2-carbonitrile [0475]
[0476] To a stirred suspension of intermediate 18 (0.0.55 g, 0.325 mmol), K2CO3 (0.134 g, 0.97 mmol) and Kl (0.053 g, 0.33 mmol) in 2 mL of DMSO, intermediate 20 (0.61g, 0.325 mmol) was added. The reaction mixture was stirred for 8 h under nitrogen atmosphere. After completion of the reaction, it was diluted with ethyl acetate and water. The layers
were separated and the aqueous layerwas washed twice with ethyl acetate. The combined organic layerwas dried over anhydrous Na2SO4, concentrated and purified by silica column chromatography using methanol in dichloromethane to yield the product. 0.007g, White solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.75(s, 3H), 0.86(s, 3H), 0.94(s, 3H), 1.6-1,73(m, 4H), 1.89-1,95(m, 1H), 2.25-2.45(m, 1H), 2.64-2.72(m, 1H), 3.05-3.08(d, J=10.8 Hz, 1 H), 3.28-3.39(m, 2H), 3.49-3.58(m. 1H), 3.69-3.71 (d, J=9.6 Hz, 2H), 3.83-3.92(m, 1H), 4.93(d, J= 9.2 Hz, 0.8H), 5.12(d, J=9.2 Hz, 0.2H), 5.35(d, J=51 Hz, 0.2H), 5.45(d, J=51 Hz, 0.8H). m/z(M+H): 324.2.
Example 82: (2S,4S)-4-Fluoro-1 -(2-((1 S,5S)-5,8,8-trimethyl-3-oxabicyclo[3.2.1] octan-1-ylamino)acetyl)pyrrolid-ine-2-carbonitrile [0477] Prepared similarto example-80 by coupling intermediate 19 and intermediate 20
[0478] 0.005 g White solid. 1H NMR (400MHz, CDCI3) δ ppm: 0.75(s, 3H), 0.86(s, 3H), 0.94(s, 3H), 1.6-1,73(m, 4H), 1.89-1.95(m, 1H), 2.25-2.45(m, 1H), 2.64-2.72(m, 1H), 3.05-3.08(d, J=10.7 Hz, 1H), 3.28-3.39(m, 2H), 3.49-3.58(m. 1H), 3.70-3.71(d, J=9.9 Hz, 2H), 3.83-3.92(m, 1H), 4.96(d, J=9.2 Hz, 0.8H), 5.00(d, J=9.2 Hz, 0.2H), 5.35(d, J=52 Hz, 0.2H), 5.45(d, J=52 Hz, 0.8H); m/z(M+H): 324.2.
Example 83: (2S,4S)-1-(2-((1S,3R)-3-(3-(1H-1,2,4-Triazol-1-yl)propyl)-2,2,3-trimethylcyclopentyl amino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0479]
Step 1: (1S,3R)-Methyl 3-(hydroxymethyl)-2,2,3-trimethylcyclopentane carboxylate [0480]
[0481] To a solution of step I intermediate of Intermediate I (0.59 g, 2.7 mmol) in THF maintained under N2 atmosphere, borane-dimethylsulfidecomplex(0.28mL,6mmol)was added dropwise and stirred atroom temperature. After completion of the reaction, the reaction was quenched by oxone and water. Reaction mixture was extracted with ethyl acetate, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give 0.55 g of the desired product. 1H NMR (400MHz, CDCI3): δ 0.89(s, 3H), 1.01(s,3H), 1.19(s, 3H), 1.36-1.41 (m, 1H), 1.72-1.88(m, 2H), 2.09-2.19(m, 1H), 2.79-2.84(t, J=9.2 oxone, 1H), 3.52-3.60(q, J=10.8 oxone, 2H), 3.68(s, 3H); m/z(M+H): 201.2.
Step 2: Methyl (1S,3R)-3-formyl-2,2,3-trimethylcyclopentane carboxylate [0482]
[0483] To solution of step-1 intermediate (1.1 g, 1.016 mmol) in 30 mL of dichloromethane, pyridinium chlorochromate (2.96 g, 13.75 mmol), MgSO4 (1.72 g, 14.3 mmol) and 1.5 g of celite was added. The reaction mixture was stirred for 1.5 hours. After completion, reaction mixture was concentrated and the crude material was immediately purified by silica column chromatography (100% DCM.) to afford the desired product (0.8 g) as colorless liquid. 1H NMR (CDCI3) δ ppm: 0.89(s, 3H) 1.18(s, 3H), 1.29(s, 3H), 1.52-1.61(m, 1H), 1.89-1.98(m, 1H), 1.99-2.32(m, 1H), 2.39-2.52(m, 1H), 2.80-2.85(m, 1H), 3.68-3.69(s, 3H), 9.67(s, 1H). m/z (M+H): 199.
Step 3: Methyl(1S,3S)-3-[(3-terf-butoxy-3-oxoprop-1-en-1-yl]-2,2,3-trimethyl cyclopentanecarboxylate [0484]
[0485] To a suspension of sodium hydride (0.242 g, 10.08 mmol) in dry tetra hydrofuran (10 mL), t-butyldiethylphospho-noacetate (1.23 g; 5.24 mmol) was added at 0 °C under N2 atmosphere and stirred for 40 min. To this step-2 intermediate (0.3 g; 4.3 mmol) was added and stirred for 1.5 h. After completion, reaction mixture was acidified with KHSO4 solution and extracted with ethyl acetate. The extracted organic layer was dried over Na2SO4, concentrated under reduced pressure and dried under high vacuum. The compound was purified by silica column chromatography to afford desired product (0.95 g) as colorless liquid. 1H NMR (CDCI3) δ ppm: 0.72(s, 3H), 1,02(s, 3H), 1,07(s, 3H), 1,46(s, 9H), 1.52-1,54(m, 1H) 1.58-1,93(m, 1H), 1.94-2.04(m, 1H), 2.09-2.29(m, 1H), 2.83-2.87(m, 1 H), 3.66(s, 3H), 5.68(d, J=4, 1H), 6.93(d, J=8, 1H).
Step 4: tert-butyl 3-(1S,3S)-3-acetoxy-1,2,2-trimethylcyclopentyl)propanoate [0486]
[0487] To a solution of step-3 intermediate (0.95 g; 3.2 mmol) in methanol (30 mL), ammonium formate (1.21 g; 19.26 mmol) and of dry 10% Pd/C (0.225 g) was added and stirred at 60-65 °C for 20 min. After completion, the reaction mixture was filtered through celite bed and the filtrate obtained was concentrated on rotavapor, dried under high vacuum to afford the desired compound (0.865 g) as colorless sticky mass. 1H NMR (CDCI3) δ ppm: 0.71(s, 3H), 0.82(s, 3H), 1.01(s, 3H), 1.41(s, 9H), 1.45-1.80(m, 5H), 2.09-2.15(m, 2H), 2.22-2.29(m, 1H), 2.80-2.85(m, 1H), 3.68(s, 3H).
Step 5: 3-[(1S,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentyl] propanoic acid [0488]
[0489] To a stirred solution of step-4 intermediate (0.86 g, 2.88 mmol) in dichloromethane (15 mL) at room temperature, trifluoroaceticacid (6.14 mL) was added. After 1.5 hours, the reaction mixture was concentrated and dried under reduced pressure. The compound was purified by silica column chromatography to afford the desired product (0.664 g) as colorless sticky mass. 1H NMR (CDCI3) δ ppm: 0.71(s, 3H), 0.83(s, 3H), 1.02(s, 3H), 1.22-1.28(m, 1H), 1.41-1.48(m,
1H), 1.52-1.76(m, 3H), 1.79-1.88(m, 1H), 2.15-2.23(m, 1H), 2.25-2.41(m, 1H), 2.39-2.52(m, 1H), 2.81-2.86(m, 1H), 3.68(s, 3H). m/z (M-H): 241.
Step 6: Methyl (1S,3S)-3-(3-hydroxypropyl)-2,2,3-trimethylcyclopentane carboxylate [0490]
[0491] To a solution of step-5 intermediate (0.645 g, 2.66 mmol) in dry THF (10 mL) under N2 atmosphere, borane dimethylsulphide (0.328 mL, 3.46 mmol) was added slowly for 30 min through a septum and stirred for overnight. The reaction mixture was quenched with water, oxone then stirred for 30 mins. Then the reaction mixture was extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the desired product (0.565 g) as colorless liquid, m/z (M+18): 246.
Step-7: Synthesis of methyl (1S,3S)-2,2,3-trimethyl-3-{3-[(methylsulfonyl) oxy]propyl}cyclopentane carboxylate [0492]
[0493] To a solution of step-6 intermediate (0.565 g, 2.47 mmol) and triethylamine (1.036 mL, 7.43 mmol) in dichloromethane (15 mL), methanesulfonyl chloride (0.886 mL, 4.95 mmol) was added at 0 °C. After 1 hour, the reaction mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, concentrated under reduced pressure. The residue was purified by silica column chromatography to afford the desired product (0.695 g) as colorless sticky mass. 1H NMR (CDCI3) δ ppm: 0.73(s, 3H), 0.88(s, 3H), 1.02(s, 3H), 1.28-1.43(m, 2H), 1.44-1.48(m, 1H), 1.62-1.69(m, 2H), 1.73-1.86(m, 2H), 2.17-2.22(m, 1H), 2.81-2.86(m, 1H), 2.94 (s, 3H), 3.68(s, 3H), 4.22-4.23(t, 2H).
Step 8: Methyl (1S,3S)-2,2,3-trimethyl-3-[3-(1H-1,2,4-triazol-1-yl) propyl] cyclopentane carboxylate [0494]
[0495] To suspension of 1,2,4-triazole (0.108 g, 1.56 mmol) and K2CO3 (0.325 g, 2.3 mmol) in DMF (1 mL), between 60-65 °C, step-7 intermediate (0.48 g, 1.56 mmol) dissolved in DMF (0.5 mL) was added. The reaction mixture was stirred at 80 °C for 2.5 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layerwas dried over Na2SO4, concentrated under reduced pressure and dried under high vacuum to afford the desired product; (0.34 g) pale brown sticky mass. 1H NMR (CDCI3) δ ppm: 0.71(s, 3H), 0.85(s, 3H), 1.03(s, 3H), 1.27-1.32(m, 2H), 1.39-1.51(m, 1H), 1.52-1.66(m, 2H), 1.82 -1.88 (m, 2H), 2.79-2.84(m, 1H), 2.84-2.88 (m, 1H), 3.67 (s, 3H), 4.12-4.17(t, 2H), 7.94(s, 1H), 8.05(s, 1H), m/z (M+1) 279.
Step 9: (1S,3S)-2,2,3-trimethyl-3-[3-(1H-1,2,4-triazol-1-1)propyl]cyclopentane carboxylic acid [0496]
[0497] To solution of step-8 intermediate (0.51 g, 1.82 mmol) tetrahydrfuran (9 mL) and MeOH (5 mL), LiOH (0.52 g, 21.93 mmol) in 3 mL of water was added and stirred. The reaction mixture was heated at 70 - 75 °C for 7-8 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The aqueous layer was acidified with KHSO4 solution (pH 1) and extracted with ethyl acetate. The extracted organic layer was dried over Na2SO4, concentrated under reduced pressure to afford the desired product (0.3 g) as white solid. 1H NMR (CDCI3) δ ppm: 0.67(s, 3H), 0.79(s, 3H), 0.92 (s, 3H), 1.03-1.17(m, 2H), 1.26-1.39(m, 1H), 1.40-1.48(m, 1H), 1.56-1.64(m, 2H), 1.71-1.83(m, 1H), 1.84-1.89(m, 1H), 2.63-2.67(m, 1H), 4.07 (t, J=8, 2H), 7.87(s, 1H), 8.43(s, 1H), 11.90 (bs, 1H). m/z (M+H) 266.
Step-10: Synthesis of (1S,3S)-2,2,3-trimethyl-3-[3-(1H-1,2,4-triazol-1-yl)propyl cyclopentanecarboxamide [0498]
[0499] To solution of step-9 intermediate (0.3 g, 1.13 mmol) and triethylamine (0.173 g, 1.24 mmol) in THF (7 mL), ethyl chloroformate (0.118 mL, 1.24 mmol) was added at 0°C. The reaction mixture was stirred for 30 minutes at 0 °C. To this reaction mixture 23% aq. ammonia (9 mL) was added dropwise and stirred overnight. The reaction mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated under reduced pressure to afford the desired product (0.23 g) as off-white solid. 1H NMR (CDCI3) δ ppm: 0.63(s, 3H), 0.80(s, 3H), 0.90(s, 3H), 1.12-1,18(m, 3H), 1.27-1,38(m, 1H), 1.42-1,53(m, 2H), 1.58-1,75(m, 1H), 1.77-1,85(m, 1H), 1.87-1,97(m, 1H), 4.14(t, J=8 Hz, 2H), 6.73(bs, 1H), 6.97(bs, 1H), 7.95(s, 1H), 8.50(s, 1H). m/z (M+H) 265.
Step 11: (1S,3R)-2,2,3-trimethyl-3-[3-(1H-1,2,4-triazol-1-yl)propyl] cyclopentanamine [0500]
[0501] Step-10 intermediate (0.24 g, 1.016 mmol) was dissolved in a solvent mixture of acetonitrile (3 mL), ethyl acetate (3 mL), water (1.5 mL). To this PIFA (0.547 g, 1.272 mmol) was added and at stirred at 10 °C for 40 minutes. After that the temperature was maintained at 50°C for 7 h. The reaction stirred for another 8 h at room temperature. The reaction mixture was heated upto 70 °C for 10 mins and concentrated under reduced pressure, acidified with KHSO4 solution (pH 1) and extracted with dichloromethane. The aqueous layer was basified with NaOH solution and extracted with dichloromethane. The organic layer was concentrated and dried under high vacuum. The compound was purified by alumina column chromatography to afford desired product (0.1 g) as pale brown sticky mass, m/z (M+1): 237.
Step 12: (2S,4S)-1-(2-((1S,3R)-3-(3-(1H-1,2,4-triazol-1-yl)propyl)-2,2,3-trimethyl cyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile [0502]
[0503] To a suspension of step-11 intermediate (0.095 g, 0.40 mmol), K2CO3 (0.167 g, 1.207 mmol) and Kl (3 mg) in DMSO (1 mL) were stirred at room temperature. To this intermediate 20 (0.06 g, 0.32 mmol) was added and stirred for 3.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure and dried under vacuum. The compound was purified by silica column chromatography to afford the desired product (0.023 g) as pale brown solid. M.P 152-154 °C. 1H NMR (CDCI3) δ ppm: 0.77(s, 3H), 0.88(s, 3H), 0.88(s, 3H), 1.19-1.31(m, 3H), 1.39-1.47(m, 1H), 1.50-1.71(m, 1H), 1.72-1.89(m, 1H), 1.90-2.16(m, 2H), 2.30-2.43(m, 1H), 2.68-2.89(m, 1H), 2.91-2.97(m, 1H), 3.37-3.55(m, 1H), 3.62-3.77(m, 2H), 3.89-4.02(m, 1H), 4.14(t, J=8 Hz, 2H), 4.95(d, J=11.2 Hz. 0.8H), 5.11(d, J=11.2 Hz, 0.2H), 5.35(d, J=51.2 Hz, 0.2H), 5.48(d, J=51.2 Hz, 0.8H), 7.94(s, 1H), 8.05(s, 1H). m/z (M+1) 391.2.
Demonstration of in vitro efficacy of test compounds Protocol For DPP IV Assay: [0504] DPP IV measurement in vitro: DPP IV activity was determined by the cleavage rate of 7-amino 4-methylcou-marin (AMC) from the substrate H-Gly-Pro-AMC. In brief, the assay was conducted by adding 3 ng of human recombinant Dipeptidyl peptidase IV enzyme (hrDPP IV, available commercially from R&D systems) in 70 μι of the assay buffer (25 mM HEPES, 140 mM NaCI and 1 % BSA, pH 7.8) to a 96 well black flat bottom microtitre plate. Test compounds were added as 10 μι additions to all wells except blank and total activity wells. After incubation of test substance with enzyme for 60 minutes at room temperature, 10 μι of 100 μΜ substrate H-Gly-Pro-AMC was added. After mixing, the plate was left for 20 minutes at room temperature Then the reaction was terminated by addition of 10 μι of 25% glacial acetic acid. Fluorescence was measured using Spectra Max Gemini XS (Molecular Devices., USA) at an excitation filter of 360 nm and emission filter of 460 nm.
[0505] Test for IC50 Studies: Test compounds dissolved in DMSO were diluted with assay buffer at different concentrations and tested in duplicates. Percentage inhibition was calculated with respect to total activity. IC50 value was calculated using Prism Software.
Protocol for DPP 8 Assay: [0506] DPP 8 measurement in vitro: DPP 8 activity was determined by the cleavage rate of 7-amino, 4-fluorometh-ylcoumarin (AFC) from the substrate H-Ala-Pro-AFC. In brief, the assay was conducted by adding 30 ng of human recombinant Dipeptidyl peptidase 8 enzyme (hrDPP 8, available commercially from R&D systems) in 70 μι of the assay buffer (50 mM TRIS and 5 mM EDTA, pH 7.7) to a 96 well black flat bottom microtitre plate. Test compound was added as 10 μι additions to all wells except blank and total activity wells. After incubation of test substance with enzyme for 30 minutes at room temperature, 10 μι of 100 μΜ substrate H-Ala-Pro-AFC was added. After mixing, the plate was left for 30 minutes at room temperature. Then the reaction was terminated by addition of 10 μι of 25% Glacial Acetic Acid. Fluorescence was measured using Spectra Max Gemini XS (Molecular Devices, USA) at an excitation filter of 400 nm and emission filter of 505 nm.
[0507] Test for IC50 Studies: Test compound dissolved in DMSO were diluted with assay buffer at different concentrations and tested in duplicates. Percentage inhibition was calculated with respect to total activity. IC50 value was calculated using Prism Software.
Protocol for DPP 9 Assay: [0508] DPP 9 measurement in vitro: DPP 9 activity was determined by the cleavage rate of 7-amino 4-methylcoumarin (AMC) from the substrate H-Gly-Pro-AMC. In brief, the assay was conducted by adding 10 ng of human recombinant Dipeptidyl peptidase 9 enzyme (hrDPP 9, available commercially from R&D systems) in 70 μι of the assay buffer (50 mM TRIS and 5 mM EDTA, pH 7.7) to a 96 well black flat bottom microtitre plate. Test compound was added as 10 μι additions to all wells except blank and total activity wells. After incubation of test substance with enzyme for 30 minutes at room temperature, 10 μι of 100 μΜ substrate H-Gly-Pro-AMC was added. After mixing, the plate was left for 30 minutes at room temperature. Then the reaction was terminated by addition of 10 μι of 25% Glacial Acetic Acid. Fluorescence was measured using Spectra Max Gemini XS (Molecular Devices, USA) at an excitation filter of 360 nm and emission filter of 460 nm.
[0509] Test for IC50 studies: Test compound dissolved in DMSO were diluted with assay buffer at different concentrations and tested in duplicates. Percentage inhibition was calculated with respect to total activity. IC50 value was calculated by using Prism Software.
[0510] DPP IV inhibition data (expressed either as IC50 in nanomolaror percentage at 300 nM compound concentration) is presented in table 1.
Table 1 : DPP-IV inhibition using human recombinant DPP-IV enzyme and selectivity towards DPP 8 & 9
(continued)
(continued)
[0511] As Shown in table 1 compounds of formula (I) exerted potent DPP IV inhibition with good selectivity over DPP 8 and DPP 9 enzymes.
Demonstration of in vivo efficacy of test compounds
Protocol For Oral Glucose Tolerance Test: [0512] Effect of compound on glucose tolerance was examined in 7 week old C57BL/6 mice. Animals were kept for 18 h fasting and were challenged with glucose (2 g/kg) 30 min after compound (10 mg/kg) administration. Blood samples for glucose measurement were obtained by tail bleed pre dose and at serial time points after the glucose load (30, 60 and 120 minutes). Blood glucose estimation was done by using ContourTS active strips on glucometer (Bayer). To find the time response on glucose excursion, animals were challenged with glucose at different time point after compound administration (0.5, 2, 4, 6, 8, 12 or 24 hours) at blood glucose was measured at pre (0 minute) and post (30, 60 and 120 minutes) glucose load.
[0513] Results of blood glucose were expressed as area under curve (AUC) was calculated using Prism software.
Table-2: Antihyperglycemic activity of selected compounds in mice, as determined by oral glucose tolerance test.
[0514] As summarized in table 2, examples of present invention showed uptb 29.62% reduction in AUC (Area under curve) at 12 h post administration of compound.
Claims 1. Compound of formula (I),
their tautomeric forms, stereoisomers and pharmaceutically acceptable salts thereof; wherein Y represents -CH2-or -CHF-; m and n are 1 ; p is 0, 1 or 2; X represents a bond, C^Cg alkylene or -C(=O)-; R1 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -N3, -S(O)pR10, -NR10S(O)pR11, -CN, -COOR10, -CONR10R11, - OR10, -NR10R11 or -NR10COR11 or a group selected from:
R12 represents hydrogen or substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, hydroxylalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; R2 and R4 independently represent hydrogen or alkyl, or R2 and R4 can be combined together to form an optionally substituted 4-10 membered ring having 0-4 hetero atoms selected from N, O and S; R3 represents alkyl; R5 represents hydrogen; R6 represents hydrogen; R7 represents hydrogen; R8 is -CN; R10 and R11 independently represent hydrogen, nitro, hydroxy, cyano, formyl, acetyl, halogen or optionally substituted groups selected from amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl and heteroarylalkyl; when the groups R1, R2, R4, R10, R11 and R12 are substituted or when the term "substituted" is used, the substituents are one or more and are selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=O), thioxo (=S), thioalkyl, amino, hydrazino, formyl, alkyl, haloalkyl, alkoxy, haloalkoxy, arylalkoxy, cycloalkyl, cycloalkyloxy, aryl, heterocycloalkyl, heteroaryl, alkylamino, tolyl, -COORa, - C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb, -NRaC(O)NRbRc, -NRaC(S)NRbRc, - N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb, -NRaC(O)Rb, -NRaC(S)Rb, - SONRaRb, -SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb, -OC(O)Ra -RaNRbRc, -RaORb, -SRa, -SORa and -SO2Ra; the substituents are further optionally substituted by one or more substituents as defined above; wherein Ra, Rb and Rc independently represent hydrogen orsubstituted or unsubstituted groups selected from alkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl and cycloalkenyl; or Ra and Rb can be combined together to form a ring structure having 4-8 atoms. 2. The compound according to claim 1, wherein: when alkoxy group is present, the alkoxy group is selected from
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy; when aryloxy group is present, the aryloxy group is selected from phenoxy and naphthyloxy; when halogen is present, the halogen is fluorine, chlorine, bromine or iodine; when alkyl group is present, the alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, f-butyl, pentyl, hexyl, heptyl or octyl; when alkenyl group is present, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl; when the alkynyl group is present, the alkynyl group is ethynyl, propynyl or butynyl; when cycloalkyl group is present, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, perhydronaphthyl, adamantyl, bridged cyclic groups or spirobicyclic groups; when cycloalkenyl group is present, the cycloalkenyl group is selected from cyclopentenyl and cyclohexenyl; when heterocycloalkyl or heteroaryl group is present, the heterocycloalkyl or heteroaryl group is a heterocyclyl group selected from azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pterid-inyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, 2-ox-oazepinyl, azepinyl, pyrrolyl, piperonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, isothiazolyl, quinuclidinyl, isothiazolid-inyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimi-dazolyl, thiadiazolyl, benzo pyranyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, oxadiazolyl, benzindazolyl, indazolyl, phenylpiperidinyl, furyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomorpholinyl, piperidonyl, 2-oxopiperazi-nyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl, chromanyl, isochromanyl, oxabicyclo[3.2.1]octane, 3-oxabicyclo[3.2.1]octanone, 3-azabicyclo [3.2.1]octane-2,4-dione and 3-azabicyclo[3.2.1]octane; when aryl group is present, the aryl group is phenyl, naphthyl, anthracenyl, indanyl or biphenyl; when alkylene group is present, the alkylene group is methylene, ethylene, propylene or butylene; when hydroxyalkyl group is present, the hydroxyalkyl group is hydroxymethyl or hydroxyethyl; when haloalkyl group is present, the haloalkyl group is trifluoromethyl, tribromomethyl or trichloromethyl; when haloalkoxy group is present, the haloalkoxy group is selected from chlo-romethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy and trichloromethoxy; when heterocyclylalkyl group is present, the heterocyclylalkyl group is selected from oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, morpholi-nylmethyl, pyrrolidinylmethyl, piperidinylmethyl, 1,2-thiazinanel,1-dioxide-ylmethyl and isothiazolidinel,1-dioxide-yl-methy when heteroarylalkenyl group is present, the heteroarylalkenyl group is selected from pyridinylethenyl, thienylethenyl and triazolylethenyl; and when heteroarylalkynyl group is present, the heteroarylalkynyl group is selected from pyridinylethynyl and thienylethynyl. 3. A compound offormula (I), as claimed in claim 1, which is selected from: 1. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoro-pyrro I id i n e-2-carbo n itri I e ; 2. (2S,4R)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile methanesulfonate; 3. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoro-pyrro I id i n e-2-carbo n itri I e ; 4. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile methanesulfonate; 5. (2S,4R)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro-pyrrolidine-2-carbonitrile methanesulfonate; 6. (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino) acetyl)pyrrolidine-2-carbonitrile; 7. (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino) acetyl)pyrrolidine-2-carbonitrile methanesulfonate; 8. (S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)pyrrolidine-2-carbonitrile; 9. (S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)pyrrolidine-2-carbonitrile methanesulfonate; 10. (2S,4S)-1-(2-((1R,3S)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoro-pyrro I id i n e-2-carbo n itri I e ; 11. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoro-pyrro I id i n e-2-carbo n itri I e ; 12. (2S,4S)-1-(2-((1S,3R)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoro-pyrro I id i n e-2-carbo n itri I e ; 13. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoro- pyrrolidine-2-carbonitrile methanesulfonate; 14. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidine-1 -carbonyl) cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile; 15. (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 16. (2S,4S)-4-Fluoro-1-(2-((1S,3R)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 17. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methyl)methanesulfonamide; 18. N-(((1R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methyl)methanesulfonamide; 19. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino) -2,2,3-trimethylcy- clopentyl)methyl)-4-fluorobenzenesulfonamide; 20. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino) -2,2,3-trimethylcy- clopentyl)methyl)-4-fluorobenzenesulfonamide; 21. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methyl)-2-fluorobenzamide; 22. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino) -2,2,3-trimethylcy- clopentyl)methyl)-4,4-difluorocyclohexane carboxamide; 23. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino) -2,2,3-trimethylcy- clopentyl)methyl)-4,4-difluorocyclohexanecarboxamide; 24. 6-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile; 25. 6-(((1R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile; 26. 2-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcy-clopentyl)methylamino)nicotinonitrile; 27. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 28. (2S,4S)-1-(2-((1 R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 29. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 30. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 31. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-Tetrazol-1-yl)methyl)-1,2,2-trimethyl cyclopentylamino)acetyl)-4-fluoropyrro-lidine-2-carbonitrile methanesulfonate; 32. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluoropyrroli-dine-2-carbonitrile; 33. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(morpholinomethyl)cyclopentyl amino)acetyl)pyrrolidine-2-carbonitrile; 34. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholinomethyl)cyclopentylamino)acetyl)pyrrolidine-2-carbonitrile; 35. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholinomethyl)cyclo pentylamino)acetyl)pyrrolidine-2-carbonitrile dimethanesulfonate; 36. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclo pentylamino)acetyl)pyrrolid-ine-2-carbonitrile; 37. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile; 38. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 39. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile; 40. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolid-ine-2-carbonitrile; 41. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-((4-hydroxypiperidin-1-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 42. (2S,4S)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy- clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 43. (2S,4R)-4-Fluoro-1-(2-((1R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 44. (S)-1-(2-((1 R,3S)-1,2,2-Trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 45. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 46. (S)-1-(2-((1 S,3R)-1,2,2-Trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 47. (2S,4R)-4-Fluoro-1 -(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 48. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 49. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 50. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 51. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 52. (2S,4S)-4-Fluoro-1-(2-((1R,3S)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 53. (2S,4S)-1-(2-((1 R,3R)-3-(Cyanomethyl)-1,2,2-trimethylcyclopentyl amino)acetyl)-4-fluoropyrrolidine-2-car-bonitrile; 54. (2S,4S)-4-Fluoro-1-(2-((1 R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 55. (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 56. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl) pyrrolidine-2-carbonitrile; 57. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile methanesulfonate; 58. (2S,4S)-1-(2-((1 S,3S)-3-((5-ferf-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 59. (2S,4S)-1-(2-((1 S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)-4-fluoropyrrolidine-2-carbonitrile; 60. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 61. (2S,4S)-4-Fluoro-1-(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrilemethane sulfonate; 62. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-3-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 63. (2S,4S)-4-Fluoro-1-(2-((1S,3S)-1,2,2-trimethyl-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)methyl)cy-clopentylamino)acetyl)pyrrolidine-2-carbonitrile; 64. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 65. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 66. (S)-1-(2-((1 S,3R)-3-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylamino)acetyl)pyr-rolidine-2-carbonitrile methanesulfonate; 67. (2S,4S)-4-Fluoro-1-(2-((1 S,3R)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 68. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 69. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 70. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 71. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami- no)acetyl)pyrrolidine-2-carbonitrile; 72. (2S,4S)-4-Fluoro-1-(2-((1S,3R)-2,2,3-trimethyl-3-(3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 73. (2S,4S)-4-Fluoro-1-(2-((1 R,3S)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 74. (2S,4S)-4-Fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidine-2-carbonitrile; 75. (S)-1-(2-((1 R,5R)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 76. (2S,4S)-4-Fluoro-1-(2-((1R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 77. (2S,4R)-4-Fluoro-1-(2-((1R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; 78. (S)-1-(2-((1 R,5R)-3,5,8,8-Tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino) acetyl)pyrrolidine-2-carboni-trile; 79. (S)-1-(2-((1 R,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylamino) acetyl)pyrrolidine-2-carboni-trile; 80. (S)-1-(2-((1R,5R)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino) acetyl)pyrrolidine-2-carbonitrile; 81. (2S,4S)-4-Fluoro-1-(2-((1 R,5R)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino) acetyl)pyrrolidine-2-carbonitrile; 82. (2S,4S)-4-Fluoro-1-(2-((1S,5S)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidine-2-carbonitrile; and 83. (2S,4S)-1-(2-((1 S,3R)-3-(3-(1 H-1,2,4-Triazol-1-yl)propyl)-2,2,3-trimethylcyclopentyl amino)acetyl) -4-fluor-opyrrolidine-2-carbonitrile. 4. A process for the preparation of compound of formula (I), according to claim 1 by coupling of the compound of formula (II), which is in its free, salt or protected form, with a compound offormula (III)
wherein; L represents leaving groups selected from chloro, bromo, iodo, tosylates, mesylates and triflates; PG represents hydrogen or protecting groups comprising acetyl, trifluoroacetyl, arylsulphonyl, nosyl, tosyl, -Bocor-CBz; and n, R1, R2, R3, R4, R5, R6, R7, R8, X and Y are defined as in claim 1. 5. A compound offormula (II) according to claim 4 which is selected from compounds offormula (I I-2) and (I I-3)
wherein the group Y1 represents SO2 or CO; PG represents hydrogen or protecting group which is -Boc; n, R12 are as defined in claim 1. 6. A compound offormula (II) according to claim 4, which is selected from compounds offormula (II-4), (II-5), (II-6), (II-7), (II-8), (II-9) and (11-10)
wherein the groups R1, R12 are as defined in claim 1 and PG represents hydrogen or protecting group which is -Boc. 7. A compound offormula (II) according to claim 4, which is selected from: 1. tert-B uty l( 1 R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentylcarbamate; 2. ((1 S,3R)-3-(tert-Butoxycarbonylamino)-2,2,3-trimethylcyclopentyl)methyl methanesulfonate; 3. tert-B uty l( 1 R,3S)-3-(azidomethyl)-1,2,2-trimethylcyclopentylcarbamate; 4. tert-B uty l[(1 R,3S)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 5. (1S,3R)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentane carboxylic acid; 6. tert-B uty l[(1 S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 7. tert-Butyl [(1S,3R)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl]carbamate; 8. Methanesulfonic acid (1 R,3S)-3-t-butoxycarbonylamino-2,2,3-trimethyl-1-cyclopentylmethyl ester; 9. tert-Butyl [(1S,3R)-3-(azidomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 10. tert-Butyl [(1 S,3R)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 11. (1 R,3S)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentane carboxylic acid; 12. tert-Butyl [(1S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamate; 13. (1 R,5R)-1-Amino-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octane-2,4-dione; 14. (1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-amine; 15. (1 R,5R)-1 -Amino-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one; 16. (1 R,5R)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amine; 17. (1S,5S)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1 -amine; and 18. 3-(((1 S,3S)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-1,2,4-oxadiazol-5-yl)methanol hydrochloride. 8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate. 9. A pharmaceutical composition as claimed in claim 8, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension. 10. The compound according to any one of claims 1 to 3 for use in the treatment or prevention of diabetes or diabetic complications. 11. The compound according to anyone of claims 1 to 3 for use in the treatment of a metabolic disorder; Type II diabetes; impaired glucose tolerance; insulin resistance; food intake disorder; obesity; impaired fasting glucose; dyslipidemia; hypercholesterolemia or diabetic complications comprising stroke, coronary artery disease, hypertension, peripheral vascular disease, neuropathy, retinopathy, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis; neurodegenerative diseases; cognition disorders and anxiolytic diseases. 12. The compound according to any one of claims 1 to 3 for use in the (i) prevention or treatment of hyperglycemia (ii) reduction of body weight (iii) wound healing (iv) immuno modulation (v) reducing pain.
Patentansprüche 1. Verbindung von Formel (I),
ihre tautomeren Formen, Stereoisomere und pharmazeutisch annehmbares Salze davon; wobei Y -CH2- oder-CHF-darstellt; m und n 1 sind; p 0, 1 oder 2 ist; X eine Bindung, C^Cg-Alkylen oder-C(=O)- darstellt; R1 Folgendes darstellt: Wasserstoff, optional substituierte Gruppen die aus Folgendem ausgewählt werden: Alkyl, Cycloalkyl, Cycloalkylalkyl, Cycloalkenyl, Aryl, Arylalkyl, Arylalkenyl, Arylalkynyl, Heteroaryl, Heterocyclyl, Heterocyclylalkyl, Heteroarylalkyl, Heteroarylalkenyl, Heteroarylalkynyl, -N3, -S(O)pR10, -NR10S(O)pR11 ,-CN, -COOR10, -CONR10R11, -OR10, -NR10R11 oder-NR10COR11 odereine Gruppe die aus Folgendem ausgewählt wird:
R12 Folgendes darstellt: Wasserstoff oder substituierte oder nicht-substituierte Gruppen, die aus Folgendem ausgewählt werden: Alkyl, Alkoxy, Acyl, Hydroxylalkyl, Halogenalkyl, Alkenyl, Alkynyl, Cycloalkyl, Cycloalkylalkyl, Cycloalkenyl, Aryl, Arylalkyl, Heteroaryl, einem heterocyclischen Ring, Heterocyclylalkyl und Heteroarylalkyl; R2 und R4 unabhängig Wasserstoff oder Alkyl darstellen oder R2 und R4 kombiniert werden können, um einen optional substituierten 4-10 gliedrigen Ring mit 0 - 4 Heteroatomen zu bilden, die aus N, O und S ausgewählt werden; R3 Alkyl darstellt; R5 Wasserstoff darstellt; R6 Wasserstoff darstellt; R7 Wasserstoff darstellt; R8 -CN ist; R10 und R11 unabhängig Folgendes darstellen: Wasserstoff, Nitro, Hydroxy, Cyano, Formyl, Acetyl, Halogen oder optional substituierte Gruppen die aus Folgendem ausgewählt werden: Amino, Alkyl, Alkoxy, Alkenyl, Alkynyl, Cycloalkyl Cycloalkylalkyl, Cycloalkenyl, Aryl, Arylalkyl, Heteroaryl, Heterocyclyl, Heterocyclylalkyl und Heteroarylalkyl;
wenn die Gruppen R1, R2, R4, R10, R11 und R12 substituiert sind oder wenn der Begriff "substituiert" verwendet wird, die Substituenten einer oder mehrere sind und aus Folgendem ausgewählt werden: Halogenen, Hydroxy, Nitro, Cyano, Azido, Nitroso, Oxo (=O), Thioxo (=S), Thioalkyl, Amino, Hydrazino, Formyl, Alkyl, Halogenalkyl, Alkoxy, Haloalkoxy, Arylalkoxy, Cycloalkyl, Cycloalkyloxy, Aryl, Heterocycloalkyl, Heteroaryl, Alkylamino, Tolyl, -COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb,-NRaC(O)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb,-NRaC(O)Rb, -NRaC(S)Rb, -SONRaRb, -SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb,-OC(O)Ra, -RaNRbRc, -RaORb, -SRa, -SORa und -SO2Ra; wobei die Substituenten ferner optional durch einen oder mehrere Substituenten wie oben definiert substituiert sind; wobei Ra, Rb und Rc unabhängig Wasserstoff oder substituierte oder nicht-substituierte Gruppen darstellen, die aus Folgendem ausgewählt werden: Alkyl, Alkylen, Aryl, Arylalkyl, Heteroaryl, Heteroarylalkyl, Heterocycloalkyl, Cycloalkyl und Cylcoalkenyl; oder Ra und Rb kombiniert werden können, um Ringstrukturen mit 4 - 8 Atomen zu bilden. 2. Verbindung nach Anspruch 1, wobei: wenn die Alkoxy-Gruppe vorhanden ist, die Alkoxy-Gruppe aus Folgendem ausgewählt wird: Methoxy, Ethoxy, n-Propoxy, Isopropoxy, n-Butoxy, Isobutoxy und t-Butoxy; wenn die Aryloxy-Gruppe vorhanden ist, die Aryloxy-Gruppe aus Folgendem ausgewählt wird: Phenoxy und Naphthyloxy; wenn Halogen vorhanden ist, das Halogen Fluor, Chlor, Brom oder lod ist; wenn eine Alkyl-Gruppe vorhanden ist, die Alkyl-Gruppe Methyl, Ethyl, n-Propyl, Isopropyl, Butyl, Isobutyl, f-Butyl, Pentyl, Hexyl, Heptyl oder Octyl ist; wenn eine Alkenyl-Gruppe vorhanden ist, die Alkenyl-Gruppe Ethenyl, 1-Propenyl, 2-Propenyl, Iso-Propenyl, 2-Methyl-1-Pro-penyl, 1-Butenyl oder 2-Butenyl ist; wenn die Alkynyl-Gruppe vorhanden ist, die Alkynyl-Gruppe Ethynyl, Propynyl oder Butynyl ist; wenn eine Cycloalkyl-Gruppe vorhanden ist, die Cycloalkyl-Gruppe aus Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cyclooctyl, Cycloheptyl, Perhydronaphthyl, Adamantyl, überbrückten cyclischen Gruppen oder spirobicyclischen Gruppen besteht; wenn eine Cycloalkenyl-Gruppe vorhanden ist, die Cycloalkenyl-Gruppe aus Cyclopentenyl und Cyclohexenyl ausgewählt wird; wenn eine Heterocycloalkyl- oder Heteroaryl-Gruppe vorhanden ist, die Heterocycloalkyl- oder Heteroaryl-Gruppe eine Heterocyclyl-Gruppe ist, die aus Folgendem ausgewählt wird: Azetidinyl, Acridinyl, Benzodioxolyl, Benzodioxanyl, Benzofuranyl, Carbazolyl, Cinnolinyl, Dioxolanyl, Indolizinyl, Naphthyridinyl, Perhydroazepinyl, Phenazinyl, Phenothiazinyl, Phenoxazinyl, Phthalazinyl, Pyridyl, Pte-ridinyl, Purinyl, Ouinazolinyl, Ouinoxalinyl, Ouinolinyl, Isoquinolinyl, Tetrazolyl, Imidazolyl, Tetrahydroisoquinolinyl, 2-Oxoazepinyl, Azepinyl, Pyrrolyl, Piperonyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Pyrazolyl, Oxazolyl, Oxazolinyl, Triazolyl, Indanyl, Isoxazolyl, Isoxazolidinyl, Thiazolyl, Thiazolinyl, Thiazolidinyl, Thienyl, Isothiazolyl, Ouinuclidinyl, Isothiazolidinyl, Indolyl, Isoindolyl, Indolinyl, Isoindolinyl, Octahydroindolyl, Octahydroisoindolyl, Decahydroisoqui-nolyl, Benzimidazolyl, Thiadiazolyl, Benzopyranyl, Benzothiazolyl, Benzothiadiazolyl, Benzoxadiazolyl, Benzotria-zolyl, Benzothienyl, Benzoxazolyl, Oxadiazolyl, Benzindazolyl, Indazolyl, Phenylpiperidinyl, Furyl, Tetrahydrofuryl, Tetrahydropyranyl, Piperazinyl, Homopiperazinyl, Piperidyl, Piperidopiperidyl, Morpholinyl, Thiomorpholinyl, Pipe-ridonyl, 2-Oxopiperazinyl, 2- Oxopiperidinyl, Pyrrolidinyl, 2-Oxopyrrolidinyl, Oxazolidinyl, Chromanyl, Isochromanyl, Oxabicyclo[3.2.1]octan, 3-Oxabicyclo[3.2.1]octanon, 3-Azabicyclo[3.2.1]octan-2,4-dion und 3-Azabicyclo[3.2.1]oc-tan; wenn eine Aryl-Gruppe vorhanden ist, die Aryl-Gruppe Phenyl, Naphthyl, Anthracenyl, Indanyl oder Biphenyl ist; wenn eine Alkylen-Gruppe vorhanden ist, die Alkylen-Gruppe Methylen, Ethylen, Propylen oder Butylen ist; wenn eine Hydroxyalkyl-Gruppe vorhanden ist, die Hydroxyalkyl-Gruppe Hydroxymethyl oder Hydroxyethyl ist; wenn eine Halogenalkyl-Gruppe vorhanden ist, die Halogenalkyl-Gruppe Trifluormethyl, Tribrommethyl oderTrichlormethyl ist; wenn eine Halogenalkoxy-Gruppe vorhanden ist, Halogenalkoxy-Gruppe aus Chlormethoxy, Chlorethoxy, Trifluor-methoxy, Trifluorethoxy und Trichlormethoxy ausgewählt wird; wenn eine Heterocyclylalkyl-Gruppe vorhanden ist, die Heterocyclylalkyl-Gruppe aus Folgendem ausgewählt wird: Oxadiazolylmethyl, Triazolylmethyl, Tetrazolylme-thyl, Morpholinylmethyl, Pyrrolidinylmethyl, Piperidinylmethyl, 1,2-Thiazinanel,1-dioxid-ylmethyl und Isothiazoli-dinl,1-dioxid-ylmethyl; wenn eine Heteroarylalkenyl-Gruppe vorhanden ist, die Heteroarylalkenyl-Gruppe aus Pyri-dinylethenyl, Thienylethenyl und Triazolylethenyl ausgewählt wird; und wenn eine heteroarylalkynyl-Gruppe vorhanden ist, die Heteroarylalkynyl-Gruppe aus Pyridinylethynyl und Thienylethynyl ausgewählt wird. 3. Verbindung der Formel (I) nach Anspruch 1, die aus Folgendem ausgewählt wird: 1. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitril ; 2. (2S,4R)-1-(2-((1 R,3S)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitrilmethansulfonat; 3. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitril ; 4. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitrilmethansulfonat; 5. (2S,4R)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr- rolidin-2-carbonitrilmethansulfonat; 6. (S)-1-(2-((1 S, 3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolidin-2-car-bonitril; 7. (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolidin-2-car-bonitrilmethansulfonat; 8. (S)-1-(2-((1 R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolidin-2-car-bonitril; 9. (S)-1-(2-((1 R,3S)-3-((1H-1,2,4-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)pyrrolidin-2-car-bonitrilmethansulfonat; 10. (2S,4S)-1-(2-((1 R,3S)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitril ; 11. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitril ; 12. (2S,4S)-1-(2-((1 S,3R)-3-((2H-1,2,3-Triazol-2-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitril ; 13. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,3-Triazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyr-rolidin-2-carbonitrilmethansulfonat; 14. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidin-1 -carbonyl) cyclopentylamino)acetyl)pyrrolidin-2-carbonitril; 15. (2S,4S)-4-Fluor-1-(2-((1R,3S)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcyclopen- tylamino)acetyl)pyrrolidin-2-carbonitril; 16. (2S,4S)-4-Fluor-1-(2-((1S,3R)-3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-1,2,2-trimethylcyclopen- tylamino)acetyl)pyrrolidin-2-carbonitril; 17. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)methansulfonamid; 18. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)methansulfonamid; 19. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4-fluorbenzensulfonamid; 20. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4-fluorbenzensulfonamid; 21. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-2-fluorbenzamid; 22. N-(((1S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4,4-difluorcyclohexancarboxamid; 23. N-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thyl)-4,4-difluorcyclohexancarboxamid; 24. 6-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thylamino)nicotinnitril; 25. 6-(((1 R,3S)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thylamino)nicotinnitril; 26. 2-(((1 S,3R)-3-(2-((2S,4S)-2-Cyano-4-fluorpyrrolidin-1-yl)-2-oxoethylamino)-2,2,3-trimethylcyclopentyl)me-thylamino)nicotinnitril; 27. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((5-(trifluormethyl)pyridin-2-ylamino)methyl)cyclopentyla-mino)acetyl)pyrrolidin-2-carbonitril; 28. (2S,4S)-1-(2-((1 R,3S)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyrrolidin-2-carbonitril; 29. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxidoisothiazolidin-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyrrolidin-2-carbonitril; 30. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1,2,2-trimethylcyclopentylamino)acetyl)-4-fI uorpyrrol id in-2-carbon itri I ; 31. (2S,4S)-1-(2-((1 R,3S)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyrroli-din-2-carbonitrilmethansulfonat; 32. (2S,4S)-1 -(2-((1 S,3R)-3-((1H-Tetrazol-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyrroli-din-2-carbonitril; 33. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(morpholinmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbon itri I; 34. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(morpholinmethyl)cyclopentylamino)acetyl)pyrrolidin-2- carbon itri I; 35. (2S,4S)-4-Fluor-1-(2-((1 S, 3R)-1,2,2-trimethyl-3-(morpholinmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbonitrildimethansulfonat; 36. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbonitril; 37. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(pyrrolidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbonitril; 38. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 39. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbon itri I; 40. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-1,2,2-trimethyl-3-(piperidin-1-ylmethyl)cyclopentylamino)acetyl)pyrrolidin-2-carbon itri I; 41. (2S,4S)-4-Fluor-1 -(2-((1 R,3S)-3-((4-hydroxypiperidin-1-yl)methyl)-1,2,2-trimethylcyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 42. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 43. (2S,4R)-4-Fluor-1-(2-((1 R,3S)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 44. (S)-1-(2-((1 R,3S)-1,2,2-Trimethyl-3-((4-(methylsulfonyl)phenylsulfonyl)methyl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 45. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 46. (S)-1-(2-((1 S,3R)-1,2,2-Trimethyl-3-((4-(methylsulfonyl)phenylsulfonyl)methyl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 47. (2S,4R)-4-Fluor-1-(2-((1 S,3R)-1,2,2-trimethyl-3-((4-(methylsulfonyl) phenylsulfonyl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 48. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-3-(3-(4-fluorphenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 49. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-3-(3-(4-fluorphenyl)-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 50. (2S,4S)-4-Fluor-1-(2-((1R,3S)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 51. (2S,4S)-4-Fluor-1-(2-((1S,3R)-1,2,2-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 52. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,2,2-trimethylcyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 53. (2S,4S)-1-(2-((1 R,3R)-3-(Cyanomethyl)-1,2,2-trimethylcyclopentylamino)acetyl)-4-fluorpyrrolidin-2-carbo-nitril; 54. (2S,4S)-4-Fluor-1-(2-((1 R,3R)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 55. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 56. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(trifluormethyl)-1,2,4-oxadiazol-3-yl)methyl)cyclopen-tylamino)acetyl)pyrrolidin-2-carbonitril; 57. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(trifluormethyl)-1,2,4-oxadiazol-3-yl)methyl)cyclopen-tylamino)acetyl)pyrrolidin-2-carbonitrilmethansulfonat; 58. (2S,4S)-1-(2-((1 S,3S)-3-((5-tert-Butyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylamino)ace-tyl)-4-fluorpyrrolidin-2-carbonitril; 59. (2S,4S)-1-(2-((1 S,3S)-3-((5-Cyclohexyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylamino)ace-tyl)-4-fluorpyrrolidin-2-carbonitril; 60. (2S,4S)-4-Fluor-1 -(2-((1 S,3S)-3-((5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopen-tylamino)acetyl)pyrrolidin-2-carbonitril; 61. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitrilmethan sulfonat; 62. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-3-((5-(4-fluorphenyl)-1,2,4-oxadiazol-3-yl)methyl)-1,2,2-trimethylcyclopen-tylamino)acetyl)pyrrolidin-2-carbonitril; 63. (2S,4S)-4-Fluor-1-(2-((1 S,3S)-1,2,2-trimethyl-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)methyl)cyclopentyla- mino)acetyl)pyrrolidin-2-carbonitril ; 64. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-3-(3-(4-fluorphenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 65. (2S,4S)-4-Fluor-1-(2-((1 S,3R)-3-(3-(4-fluorphenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 66. (S)-1 -(2-((1 S,3R)-3-(3-(4-Fluorphenyl)-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylamino)acetyl)pyrro-lidin-2-carbonitrilmethansulfonat; 67. (2S,4S)-4-Fluor-1 -(2-((1 S,3R)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2,2,3-trimethylcyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 68. (2S,4S)-4-Fluor-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 69. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 70. (2S,4S)-4-Fluor-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 71. (2S,4S)-4-Fluor-1-(2-((1 R,3S)-2,2,3-trimethyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 72. (2S,4S)-4-Fluor-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acetyl)pyrrolidin-2-carbonitril; 73. (2S,4S)-4-Fluor-1 -(2-((1 R,3S)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 74. (2S,4S)-4-Fluor-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)ace-tyl)pyrrolidin-2-carbonitril ; 75. (S)-1-(2-((1 R,5R)-3,5,8,8-Tetramethyl-2,4-dioxo-3-azabicyclo[3.2.1 ]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 76. (2S,4S)-4-Fluor-1-(2-((1R,SR)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1 ]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 77. (2S,4R)-4-Fluor-1-(2-((1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1 ]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 78. (S)-1-(2-((1R,5R)-3,5,8,8-Tetramethyl-3-azabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 79. (S)-1-(2-((1R,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 80. (S)-1-(2-((1R,5R)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidin-2-carbonitril; 81. (2S,4S)-4-Fluor-1-(2-((1R,5R)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidin-2-car-bon itri I; 82. (2S,4S)-4-Fluor-1-(2-((1S,5S)-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acetyl)pyrrolidin-2-car-bonitril; and 83. (2S,4S)-1-(2-((1 S,3R)-3-(3-(1 H-1,2,4-Triazol-1-yl)propyl)-2,2,3-trimethylcyclopentylamino)acetyl)-4-fluor-pyrrolidin-2-carbonitril. 4. Verfahren zur Herstellung derVerbindung der Formel (I) nach Anspruch 1 durch Koppeln der Verbindung der Formel (II), die in ihrer freien, Salz- oder geschützten Form vorliegt, mit einer Verbindung der Formel (III)
wobei; L Abgangsgruppen darstellt, die aus Folgendem ausgewählt werden: Chlor, Brom, lod, Tosylaten, Mesylaten und Triflaten; PG Wasserstoff oder Schutzgruppen darstellt, die Folgendes umfassen: Acetyl, Trifluoracetyl, Arylsulphonyl, Nosyl, Tosyl, -Boc oder - CBz; und n, R1, R2, R3, R4, R5, R6, R7, R8, X und Y gemäß Anspruch 1 definiert sind. 5. Verbindung der Formel (II) nach Anspruch 4, die aus den Verbindungen der Formel (II-2) und (II-3) ausgewählt wird
wobei the Gruppe Y1 SO2 oder CO darstellt; PG Wasserstoff oder eine Schutzsgruppe darstellt, die -Boc ist; n, R12 gemäß Anspruch 1 definiert sind. 6. Verbindung der Formel (II) nach Anspruch 4, die aus Folgendem ausgewählt wird: Verbindungen der Formel (II-4), (II-5), (II-6), (II-7), (II-8), (II-9) und (11-10)
wobei die Gruppen R1, R12 wie in Anspruch 1 definiert sind und PG Wasserstoff oder eine Schutzgruppe darstellt, die -Boc ist. 7. Verbindung der Formel (II) nach Anspruch 4, die aus Folgendem ausgewählt wird:: 1. tert-Butyl( 1 R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentylcarbamat; 2. ((1S,3R)-3-(tert-Butoxycarbonylamino)-2,2,3-trimethylcyclopentyl)methylmethansulfonat; 3. tert-B uty l( 1 R,3S)-3-(azidomethyl)-1,2,2-trimethylcyclopentylcarbamat; 4. tert-B uty l[(1 R,3S)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamat; 5. (1 S,3R)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentancarboxylsäure; 6. tert-B uty l[(1 S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamat; 7. tert-B uty l[(1 S,3R)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl]carbamat; 8. Methansulfonsäure(1 R,3S)-3-t-butoxycarbonylamino-2,2,3-trimethyl-1-cyclopentylmethylester; 9. tert-B uty l[(1 S,3R)-3-(azidomethyl)-1,2,2-trimethylcyclopentyl]carbamat, 10. tert-Butyl[( 1 S,3R)-3-(aminomethyl)-1,2,2-trimethylcyclopentyl]carbamat; 11. (1 R,3S)-3-[(tert-Butoxycarbonyl)amino]-2,2,3-trimethylcyclopentancarboxylsäure; 12. tert-Butyl[(1S,3S)-3-(cyanomethyl)-1,2,2-trimethylcyclopentyl]carbamat; 13. (1 R,5R)-1-Amino-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-2,4-dion; 14. (1 R,5R)-3,5,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-1-amin; 15. (1 R,5R)-1-Amino-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-on; 16. (1 R,5R)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amin; 17. (1S,5S)-5,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-1-amin und 18. 3-(((1 S,3S)-3-Amino-2,2,3-trimethylcyclopentyl)methyl)-1,2,4-oxadiazol-5-yl)methanolhydrochlorid. 8. Pharmazeutische Zusammensetzung, die Folgendes umfasst: eine Verbindung der Formel (I) nach Anspruch 1 oder 3 oder ein pharmazeutisch annehmbares Salz davon als Wirkstoff zusammen mit einem pharmazeutisch annehmbaren Träger, Verdünnungsmittel, Trägerstoff oder Solvat.
9. Pharmazeutische Zusammensetzung nach Anspruch 8 in Form einer Tablette, einer Kapsel, eines Pulvers, eines Sirups, einer Lösung, eines Aerosols oder einer Suspension. 10. Verbindung nach Anspruch 1 oder 3 zur Verwendung bei der Behandlung oder Prävention von Diabetes oder diabetischen Komplikationen. 11. Verbindung nach Anspruch 1 oder3zurVerwendung beiderBehandlungvon Folgendem: einer Stoffwechselstörung; DiabetesTyp II; eingeschränkterGlukoseverträglichkeit; Insulinresistenz; Nahrungsaufnahmestörungen; Fettleibigkeit; beeinträchtigter Nüchternglukose; Dyslipidämie; Hypercholesterinämie oder diabetischen Komplikationen, die Folgendes umfassen: Schlaganfall, koronare Herzkrankheit, Bluthochdruck, periphere Gefäßerkrankung, Neuropathie, Retinopathie, nicht-alkoholische Fettleberkrankheit und nicht-alkoholische Steatohepatitis; neurodegenerative Erkrankungen; Kognitionsstörungen und anxiolytische Erkrankungen. 12. Verbindung nach Anspruch 1 oder 3 zur Verwendung bei der (i) Verhinderung oder Behandlung von Hyperglykämie, (ii) Reduktion des Körpergewichts, (iii) Wundheilung, (iv) Immunmodulation, (v) Schmerzlinderung.
Revendications 1. Composé de formule (I)
ses formes tautomères, ses stéréoisomères et sels pharmaceutiquement acceptables ; où Y représente -CH2- ou -CHF- ; m et n valent 1 ; p vaut 0, 1 ou 2 ; X représente une liaison, un groupe alkylène en C^Cg ou -C(=O)- ; R1 représente un atome d’hydrogène, des groupes éventuellement substitués choisis parmi alkyle, cycloalkyle, cycloalkylalkyle, cycloalcényle, aryle, arylalkyle, arylalcényle, arylalcynyle, hétéroaryle, hétérocyclyle, hétéro-cyclylalkyle, hétéroarylalkyle, hétéroarylalcényle, hétéroarylalcynyle, -N3, -S(O)pR10, -NR10S(O)pR11, -CN, -COOR1°,-CONR1°R11, - OR10, -NR10R11 ou -NR1°COR11 ou un groupe choisi parmi :
R12 représente un atome d’hydrogène ou des groupes substitués ou non substitués choisis parmi alkyle, alcoxy, acyle, hydroxylalkyle, halogénoalkyle, alcényle, alcynyle, cycloalkyle, cycloalkylalkyle, cycloalcényle, aryle,
arylalkyle, hétéroaryle, cycle hétérocyclique, hétérocyclylalkyle et hétéroarylalkyle ; R2 et R4 représentent indépendamment un atome d’hydrogène ou un groupe alkyle, ou R2 et R4 peuvent être combinés ensemble pourformerun cycle à4 à 10 chaînons éventuellement substitué ayantO à4 hétéroatomes choisis parmi N, O et S ; R3 représente un groupe alkyle ; R5 représente un atome d’hydrogène ; R6 représente un atome d’hydrogène ; R7 représente un atome d’hydrogène ; R8 est -CN ; R10 et R11 représentent indépendamment un atome d’hydrogène, un groupe nitro, hydroxy, cyano, formyle, acétyle, halogène ou des groupes éventuellement substitués choisis parmi amino, alkyle, alcoxy, alcényle, alcynyle, cycloalkyle, cycloalkylalkyle, cycloalcényle, aryle, arylalkyle, hétéroaryle, hétérocyclyle, hétérocyclylalkyle et hétéroarylalkyle ; lorsque les groupes R1, R2, R4, R10, R11 et R12 sont substitués ou lorsque le terme « substitué » est utilisé, les substituants sont au nombre d’un ou plus et sont choisis parmi les halogènes, les groupes hydroxy, nitro, cyano, azido, nitroso, oxo (=O), thioxo (=S), thioalkyle, amino, hydrazino, formyle, alkyle, halogénoalkyle, alcoxy, halogé-noalcoxy, arylalcoxy, cycloalkyle, cycloalkyloxy, aryle, hétérocycloalkyle, hétéroaryle, alkylamino, tolyle, -COORa, - C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb, -NRaC(O)NRbRc, -NRaC(S)NRbRc,-N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb, -NRaC(O)Rb, -NRaC(S)Rb, - SONRaRb,-SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb, -OC(O)Ra, -RaNRbRc, -RaORb, -SRa, -SORa et -SO2Ra ; les substituants sont en outre éventuellement substitués par un ou plusieurs substituants tels que définis ci-avant ; où Ra, Rb et Rc représentent indépendamment un atome d’hydrogène ou des groupes substitués ou non substitués choisis parmi alkyle, alkylène, aryle, arylalkyle, hétéroaryle, hétéroarylalkyle, hétérocycloalkyle, cycloalkyle et cycloalcényle ; ou Ra et Rb peuvent être combinés ensemble pourformer une structure cyclique ayant 4 à 8 atomes. 2. Composé selon la revendication 1, dans lequel : lorsqu’un groupe alcoxy est présent, le groups alcoxy est choisi parmi méthoxy, éthoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy ett-butoxy ; lorsqu’un groupe aryloxy est présent, le groupe aryloxy est choisi parmi phénoxy et naphtyloxy ; lorsqu’un halogène est présent, l’halogène est le fluor, le chlore, le brome ou l’iode ; lorsqu’un groupe alkyle est présent, le groupe alkyle est méthyle, éthyl, n-propyle, isopropyle, butyle, isobutyle, f-butyle, pentyle, hexyle, heptyle ou octyle ; lorsqu’un groupe alcényle est présent, le groupe alcényle est éthényle, 1-propényle, 2-propényle, iso-propényle, 2-méthyl-1-propényle, 1-butényle ou 2-butényle ; lorsque le groupe alcynyle est présent, le groupe alcynyle est éthynyle, propynyle ou butynyle ; lorsqu’un groupe cycloalkyle est présent, le groupe cycloalkyle est cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, cy-clooctyle, cycloheptyle, perhydronaphtyle, adamantyle, des groupes cycliques pontés ou des groupes spirobicycliques ; lorsqu’un groupe cycloalcényle est présent, le groupe cycloalcényle est choisi parmi cyclopenté-nyle et cyclohexényle ; lorsqu’un groupe hétérocycloalkyle ou hétéroaryle est présent, le groupe hétérocycloalkyle ou hétéroaryle est un groupe hétérocyclyle choisi parmi azétidinyle, acridinyle, benzodioxolyle, benzodioxanyle, benzofuranyle, carbazolyle, cinnolinyle, dioxolanyle, indolizinyle, naphtyridinyle, perhydroazépinyle, phénazinyle, phénothiazinyle, phénoxazinyle, phtalazinyle, pyridyle, ptéridinyle, purinyle, quinazolinyle, quinoxalinyle, quinolinyle, isoquinolinyle, tétrazolyle, imidazolyle, tétrahydroisoquinolinyle, 2-oxoazépinyle, azépinyle, pyrrolyle, pipéronyle, pyrazinyle, pyrimidinyle, pyridazinyle, pyrazolyle, oxazolyle, oxazolinyle, triazolyle, indanyle, isoxazolyle, isoxazo-lidinyle, thiazolyle, thiazolinyle, thiazolidinyle, thiényle, isothiazolyle, quinuclidinyle, isothiazolidinyle, indolyle, isoin-dolyle, indolinyle, isoindolinyle, octahydroindolyle, octahydroisoindolyle, décahydroisoquinolyle, benzimidazolyle, thiadiazolyle, benzopyranyle, benzothiazolyle, benzothiadiazolyle, benzoxadiazolyle, benzotriazolyle, benzothiény-le, benzoxazolyle, oxadiazolyle, benzindazolyle, indazolyle, phénylpipéridinyle, furyle, tétrahydrofuryle, tétrahydro-pyranyle, pipérazinyle, homopipérazinyle, pipéridyle, pipéridopipéridyle, morpholinyle, thiomorpholinyle, pipérido-nyle, 2-oxopipérazinyle, 2-oxopipéridinyle, pyrrolidinyle, 2-oxopyrrolidinyle, oxazolidinyle, chromanyle, isochroma-nyle, oxabicyclo[3.2.1]octane, 3-oxabicyclo[3.2.1]octanone, 3-azabicyclo[3.2.1]octane-2,4-dione et 3-azabicyclo[3.2.1]octane ; lorsqu’un groupe aryle est présent, le groupe aryle est phényle, naphtyle, anthracényle, indanyle ou biphényle ; lorsqu’un groupe alkylène est présent, le groupe alkylène est méthylène, éthylène, propylène ou butylène ; lorsqu’un groupe hydroxyalkyle est présent, le groupe hydroxyalkyle est hydroxyméthyle ou hydroxyéthyle ; le lorsqu’un groupe halogénoalkyle est présent, le groupe halogénoalkyle est trifluorométhyle, tri-bromométhyle ou trichlorométhyle ; lorsqu’un groupe halogénoalcoxy est présent, le groupe halogénoalcoxy est choisis parmi chlorométhoxy, chloroéthoxy, trifluorométhoxy, trifluoroéthoxy et trichlorométhoxy ; lorsqu’un groupe hétérocyclylalkyle est présent, le groupe hétérocyclylalkyle est choisi parmi oxadiazolylméthyle, triazolylméthyle, tétrazolylméthyle, morpholinylméthyle, pyrrolidinylméthyle, pipéridinylméthyle, 1,2-thiazinanel,1-dioxyde-ylméthyle et isothiazolidinel,1-dioxyde-ylméthyle; lorsqu’un groupe hétéroarylalcényle est présent, le groupe hétéroarylalcé- nyle est choisi parmi pyridinyléthényle, thiényléthényle et triazolyléthényle ; et lorsqu’un groupe hétéroarylalcynyle est présent, le groupe hétéroarylalcynyle est choisi parmi pyridinyléthynyle et thiényléthynyle. 3. Composé de formule (I), tel que revendiqué dans la revendication 1, qui est choisi parmi : 1. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyr-rolidine-2-carbonitrile ; 2. méthanesulfonate de (2S,4R)-1-(2-((1 R,3S)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 3. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyr-rolidine-2-carbonitrile ; 4. méthanesulfonate de (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 5. méthanesulfonate de (2S,4R)-1-(2-((1S,3R)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 6. (S)-1-(2-((1S,3R)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 7. méthanesulfonate de (S)-1-(2-((1 S,3R)-3-((1 H-1,2,4-triazol-1-yl)mtthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 8. (S)-1-(2-((1R,3S)-3-((1 H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 9. méthanesulfonate de (S)-1-(2-((1 R,3S)-3-((1H-1,2,4-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 10. (2S,4S)-1-(2-((1 R,3S)-3-((2H-1,2,3-triazol-2-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoro-pyrrolidine-2-carbonitrile ; 11. (2S,4S)-1-(2-((1 R,3S)-3-((1 H-1,2,3-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoro-pyrrolidine-2-carbonitrile ; 12. (2S,4S)-1-(2-((1 S,3R)-3-((2H-1,2,3-triazol-2-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoro-pyrrolidine-2-carbonitrile ; 13. méthanesulfonate de (2S,4S)-1-(2-((1 S,3R)-3-((1 H-1,2,3-triazol-1-yl)méthyl)-1,2,2-triméthylcyclopentyla-mino)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 14. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-(pipéridine-1-carbonyl)cyclopentylamino)acétyl)pyrrolidi-ne-2-carbonitrile ; 15. (2S,4S)-4-fluoro-1-(2-((1R,3S)-3-((4-(hydroxyméthyl)-1H-1,2,3-triazol-1-yl)méthyl)-1,2,2-triméthylcyclo-pentylamino)acétyl)pyrrolidine-2-carbonitrile ; 16. (2S,4S)-4-fluoro-1-(2-((1S,3R)-3-((4-(hydroxyméthyl)-1H-1,2,3-triazol-1-yl)méthyl)-1,2,2-triméthylcyclo-pentylamino)acétyl)pyrrolidine-2-carbonitrile ; 17. N-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopentyl)méthyl)méthanesulfonamide ; 18. N-(((1 R,3S)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopentyl)méthyl)méthanesulfonamide ; 19. N-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopen-tyl)méthyl)-4-fluorobenzènesulfonamide ; 20. N-(((1R,3S)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopen-tyl)méthyl)-4-fluorobenzènesulfonamide ; 21. N-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopen-tyl)méthyl)-2-fluorobenzamide ; 22. N-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopen-tyl)méthyl)-4,4-difluorocyclohexanecarboxamide ; 23. N-(((1R,3S)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopen-tyl)méthyl)-4,4-difluorocyclohexanecarboxamide ; 24. 6-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopentyl)méthylamino)nicotinonitrile ; 25. 6-(((1 R,3S)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopentyl)méthylamino)nicotinonitrile ; 26. 2-(((1S,3R)-3-(2-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoéthylamino)-2,2,3-triméthylcyclopentyl)méthylamino)nicotinonitrile ; 27. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-((5-(trifluorométhyl)pyridin-2-ylamino)méthyl)cyclopenty- lamino)acétyl)pyrrolidine-2-carbonitrile ; 28. (2S,4S)-1-(2-((1 R,3S)-3-[(1,1-dioxidoisothiazolidin-2-yl)méthyl]-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 29. (2S,4S)-1-(2-((1 S,3R)-3-[(1,1-dioxidoisothiazolidin-2-yl)méthyl]-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 30. (2S,4S)-1-(2-((1S,3R)-3-[(1,1-dioxido-1,2-thiazinan-2-yl)méthyl]-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 31. méthanesulfonate de (2S,4S)-1-(2-((1 R,3S)-3-((1 H-tétrazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 32. (2S,4S)-1-(2-((1 S,3R)-3-((1 H-tétrazol-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyrroli-dine-2-carbonitrile ; 33. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-(morpholinométhyl)cyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 34. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-(morpholinométhyl)cyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 35. diméthanesulfonate de (2S,4S)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-(morpholinométhyl)cyclopentyla-mino)acétyl)pyrrolidine-2-carbonitrile ; 36. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-(pyrrolidin-1-ylméthyl)cyclopentylamino)acétyl)pyrrolidi-ne-2-carbonitrile ; 37. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-(pyrrolidin-1-ylméthyl)cyclopentylamino)acétyl)pyrrolidi-ne-2-carbonitrile ; 38. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-3-(((R)-3-hydroxypyrrolidin-1-yl)méthyl)-1,2,2-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 39. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-(pipéridin-1-ylméthyl)cyclopentylamino)acétyl)pyrrolidine- 2-carbonitrile ; 40. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-(pipéridin-1-ylméthyl)cyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 41. (2S,4S)-4-fluoro-1 -(2-((1 R,3S)-3-((4-hydroxypipéridin-1-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 42. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 43. (2S,4R)-4-fluoro-1-(2-((1 R,3S)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 44. (S)-1-(2-((1R,3S)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylamino)acétyl)pyr-rolidine-2-carbonitrile ; 45. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 46. (S)-1-(2-((1 S,3R)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylamino)acétyl)pyr-rolidine-2-carbonitrile ; 47. (2S,4R)-4-fluoro-1-(2-((1 S,3R)-1,2,2-triméthyl-3-((4-(méthylsulfonyl)phénylsulfonyl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 48. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophényl)-1,2,4-oxadiazol-5-yl)-1,2,4-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 49. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophényl)-1,2,4-oxadiazol-5-yl)-1,2,4-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 50. (2S,4S)-4-fluoro-1-(2-((1R,3S)-1,2,2-triméthyl-3-(3-méthyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 51. (2S,4S)-4-fluoro-1-(2-((1S,3R)-1,2,2-triméthyl-3-(3-méthyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 52. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,2,2-triméthylcyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 53. (2S,4S)-1-(2-((1 R,3R)-3-(cyanométhyl)-1,2,2-triméthylcyclopentylamino)acétyl)-4-fluoropyrrolidine-2-carbonitrile ; 54. (2S,4S)-4-fluoro-1-(2-((1 R,3R)-1,2,2-triméthyl-3-((5-méthyl-1,2,4-oxadiazol-3-yl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 55. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-1,2,2-triméthyl-3-((5-méthyl-1,2,4-oxadiazol-3-yl)méthyl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 56. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-1,2,2-triméthyl-3-((5-(trifluorométhyl)-1,2,4-oxadiazol-3-yl)méthyl)cyclopen- tylamino)acétyl)pyrrolidine-2-carbonitrile ; 57. méthanesulfonate de (2S,4S)-4-fluoro-1-(2-((1 S,3S)-1,2,2-triméthyl-3-((5-(trifluorométhyl)-1,2,4-oxadiazol- 3-yl)méthyl)cyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 58. (2S,4S)-1-(2-((1 S,3S)-3-((5-ferf-butyl-1,2,4-oxadiazol-3-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acé-tyl)-4-fluoropyrrolidine-2-carbonitrile ; 59. (2S,4S)-1-(2-((1 S,3S)-3-((5-cyclohexyl-1,2,4-oxadiazol-3-yl)méthyl)-1,2,2-triméthylcyclopentylamino)acé-tyl)-4-fluoropyrrolidine-2-carbonitrile ; 60. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-3-((5-(hydroxyméthyl)-1,2,4-oxadiazol-3-yl)méthyl)-1,2,2-triméthylcyclo-pentylamino)acétyl)pyrrolidine-2-carbonitrile ; 61. méthanesulfonate de (2S,4S)-4-fluoro-1 -(2-((1 S,3S)-3-((5-isopropyl-1,2,4-oxadiazol-3-yl)méthyl)-1,2,4-tri-méthylcyclopentylamino)acétyl)pyrrolidine-2-carbonitrile ; 62. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-3-((5-(4-fluorophényl)-1,2,4-oxadiazol-3-yl)méthyl)-1,2,2-triméthylcyclopen-tylamino)acétyl)pyrrolidine-2-carbonitrile ; 63. (2S,4S)-4-fluoro-1-(2-((1 S,3S)-1,2,2-triméthyl-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)méthyl)cyclopenty-lamino)acétyl)pyrrolidine-2-carbonitrile ; 64. (2S,4S)-4-fluoro-1-(2-((1 R,3S)-3-(3-(4-fluorophényl)-1,2,4-oxadiazol-5-yl)-1,2,4-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 65. (2S,4S)-4-fluoro-1-(2-((1 S,3R)-3-(3-(4-fluorophényl)-1,2,4-oxadiazol-5-yl)-1,2,4-triméthylcyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 66. méthanesulfonate de (S)-1-(2-((1 S,3R)-3-(3-(4-fluorophényl)-1,2,4-oxadiazol-5-yl)-2,2,3-triméthylcyclopen-tylamino)acétyl)pyrrolidine-2-carbonitrile ; 67. (2S,4S)-4-fluoro-1 -(2-((1 S,3R)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2,2,3-triméthylcyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 68. (2S,4S)-4-fluoro-1 -(2-((1 S,3R)-2,2,3-trimethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 69. (2S,4S)-4-fluoro-1 -(2-((1 R,3S)-2,2,3-triméthyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 70. (2S,4S)-4-fluoro-1 -(2-((1 S,3R)-2,2,3-triméthyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 71. (2S,4S)-4-fluoro-1 -(2-((1 R,3S)-2,2,3-triméthyl-3-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 72. (2S,4S)-4-fluoro-1 -(2-((1 S,3R)-2,2,3-triméthyl-3-(3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)cyclopentylami-no)acétyl)pyrrolidine-2-carbonitrile ; 73. (2S,4S)-4-fluoro-1 -(2-((1 R,3S)-2,2,3-triméthyl-3-(3-méthyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 74. (2S,4S)-4-fluoro-1 -(2-((1 S,3R)-2,2,3-triméthyl-3-(3-méthyl-1,2,4-oxadiazol-5-yl)cyclopentylamino)acé-tyl)pyrrolidine-2-carbonitrile ; 75. (S)-1-(2-((1 R,5R)-3,5,8,8-tétraméthyl-2,4-dioxo-3-azabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 76. (2S,4S)-4-fluoro-1-(2-((1R,5R)-3,5,8,8-tétraméthyl-3-azabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 77. (2S,4R)-4-fluoro-1-(2-((1R,5R)-3,5,8,8-tétraméthyl-3-azabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 78. (S)-1-(2-((1 R,5R)-3,5,8,8-tétraméthyl-3-azabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 79. (S)-1-(2-((1 R,5R)-5,8,8-triméthyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 80. (S)-1-(2-((1R,5R)-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 81. (2S,4S)-4-fluoro-1-(2-((1 R,5R)-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; 82. (2S,4S)-4-fluoro-1-(2-((1S,5S)-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-1-ylamino)acétyl)pyrrolidine-2-carbonitrile ; et 83. (2S,4S)-1-(2-((1 S,3R)-3-(3-(1 H-1,2,4-triazol-1-yl)propyl)-2,2,3-triméthylcyclopentyl amino)acétyl)-4-fluoro-pyrrolidine-2-carbonitrile. 4. Procédé pour la préparation du composé de formule (I), selon la revendication 1 par couplage du composé de formule (II), sous sa forme libre, de sel ou protégée, avec un composé de formule (III)
où : L représente des groupes partants choisis parmi chloro, bromo, iodo, tosylates, mésylates et triflates ; PG représente un atome d’hydrogène ou des groupes protecteurs comprenant acétyle, trifluoroacétyle, arylsulfonyle, nosyle, tosyle, -Boc ou -CBz ; et n, R1, R2, R3, R4, R5, R6, R7, R8, X et Y sont tels que définis dans la revendication 1. 5. Composé de formule (II) selon la revendication 4, qui est choisi parmi les composés de formules (II-2) et (II-3)
où le groupe Y1 représente SO2 ou CO ; PG représente un atome d’hydrogène ou un groupe protecteur qui est -Boc ; n, R12 sont tels que définis dans la revendication 1. 6. Composé de formule (II) selon la revendication 4, qui est choisi parmi les composés de formules (II-4), (II-5), (II-6), (II-7), (II-8), (II-9) et (11-10)
où les groupes R1, R12 sont tels que définis dans la revendication 1 et PG représente un atome d’hydrogène ou un groupe protecteur qui est -Boc. 7. Composé de formule (II) selon la revendication 4, qui est choisi parmi : 1. tert-butyl( 1 R,3S)-3-(hydroxyméthyl)-1,2,2-triméthylcyclopentylcarbamate ; 2. méthanesulfonate de ((1S,3R)-3-(tert-butoxycarbonylamino)-2,2,3-triméthylcyclopentyl)méthyle ; 3. tert-butyl( 1 R,3S)-3-(azidométhyl)-1,2,2-triméthylcyclopentylcarbamate ; 4. tert-butyl[(1 R,3S)-3-(aminométhyl)-1,2,2-triméthylcyclopentyl]carbamate ; 5. acide (1 S,3R)-3-[(tert-butoxycarbonyl)amino]-2,2,3-triméthylcyclopentane carboxylique ; 6. tert-butyl[(1 S,3S)-3-(cyanométhyl)-1,2,2-triméthylcyclopentyl]carbamate ; 7. tert-butyl[(1 S,3R)-3-(hydroxyméthyl)-1,2,2-triméthylcyclopentyl]carbamate; 8. (1 R,3S)-3-t-butoxycarbonylamino-2,2,3-triméthyl-1-cyclopentylméthyl ester d’acide méthanesulfonique ; 9. tert-butyl[(1 S,3R)-3-(azidométhyl)-1,2,2-triméthylcyclopentyl]carbamate ; 10. tert-butyl[(1S,3R)-3-(aminométhyl)-1,2,2-triméthylcyclopentyl]carbamate; 11. acide (1R,3S)-3-[(tert-butoxycarbonyl)amino]-2,2,3-triméthylcyclopentane carboxylique ; 12. tert-butyl [(1S,3S)-3-(cyanométhyl)-1,2,2-triméthylcyclopentyl]carbamate ;
13. (1 R,5R)-1-amino-3,5,8,8-tétraméthyl-3-azabicyclo[3.2.1]octane-2,4-dione ; 14. (1 R,5R)-3,5,8,8-tétraméthyl-3-azabicyclo[3.2.1]octan-1-amine ; 15. (1 R,5R)-1-amino-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-2-one ; 16. (1 R,5R)-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-1-amine ; 17. (1S,5S)-5,8,8-triméthyl-3-oxabicyclo[3.2.1]octan-1-amine; et 18. chlorhydrate de 3-(((1S,3S)-3-amino-2,2,3-triméthylcyclopentyl)méthyl)-1,2,4-oxadiazol-5-yl)méthanol. 8. Composition pharmaceutique comprenant un composé de formule (I) tel que revendiqué dans la revendication 1 ou 3, ou sel pharmaceutiquement acceptable de celui-ci en tant qu’ingrédient actif accompagné d’un support, diluant, excipient ou solvate pharmaceutiquement acceptable. 9. Composition pharmaceutique telle que revendiquée dans la revendication 8, sous forme de comprimé, capsule, poudre, sirop, solution, aérosol ou suspension. 10. Composé selon la revendication 1 ou 3 à utiliser dans le traitement ou la prévention du diabète ou de complications diabétiques. 11. Composé selon la revendication 1 ou 3 à utiliser dans le traitement d’un trouble métabolique ; du diabète de type Il ; de l’intolérance au glucose, de la résistance à l’insuline ; d’un trouble de l’absorption alimentaire ; de l’obésité ; de troubles de la glycémie à jeun ; d’une dyslipidémie ; de l’hypercholestérolémie ou de complications diabétiques comprenant l’accident vasculaire cérébral, une coronaropathie, l’hypertension, une pathologie vasculaire périphérique, une neuropathie, une rétinopathie et la stéatose hépatique non alcoolique ; des maladies neurodégénératives ; des troubles cognitifs et des pathologies anxiolytiques. 12. Composé selon la revendication 1 ou 3 à utiliser dans (i) la prévention ou le traitement de l’hyperglycémie, (ii) la réduction du poids corporel, (iii) la cicatrisation de plaies, (iv) l’immuno-modulation, (v) la réduction de la douleur.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • WO 9819998 A [0009] [0080] · WO 2007113634 A [0009] [0080] [0179] [0183] • WO 0034241 A [0009] · WO 2005095339 A [0009] • WO 04064778 A [0009] · WO 2006011035 A [0009] • WO 03004498 A [0009] · US 20090017015 A [0014] • WO 03082817 A [0009] · US 7132104 B [0014] • WO 2005075426 A [0009] · WO 2003002553 A [0080] • WO 2006040625 A [0009] · US 20070112059 A [0179]
Non-patent literature cited in the description • Current Topics in Medicinal Chemistry. 2007, vol. 7, · Trends in Pharmacological Sciences. 2009, vol. 30, 579-595 [0008] [0009] 600-607 [0014] • G. LANKAS et al. Dipeptidyl Peptidase-IV Inhibition · Current Topics in Medicinal Chemistry. 2005, vol. 5, fortheTreatmentofType II Diabetes. Diabetes, 2005, 1623-1637 [0016] vol. 54, 2988-2994 [0010] · Journal of Medicinal Chemistry, 2003, vol. 46, • Scand. J. Immunol., 1999, vol. 50, 536-540 [0011] 2774-2789 [0080] [0181] • European Journal of Pharmacology, 2008, vol. 588, · Bioorganic Medicinal Chemistry, 2008, vol. 16, 325-332 [0012] 4093-4106 [0080] [0179] • European Journal of Pharmacology, 2000, vol. 404, · J. Org. Chem., 1975, vol. 40, 3554-3561 [0086] 239-245 [0012] · Liebigs Ann., 1996, 1941-1948 [0094] • Diabetes. Vase. Dis. Res., 2006, vol. 3,159-65 [0012] · Org. Lett., 2009, vol. 11 (2), 433-436 [0097] • Clin. Res. Cardiol., 2009, vol. 98, 75-79 [0012] · Liebigs Ann., 1996, 1941-1948 [0098] [0162] • Med. Sei. Mónit., 2009, vol. 15 (4), HY1-5 [0012] · Journal of Organic Chemistry, 1975, vol. 40, • Med Sei Mónit, 2009, vol. 15(4), HY1-5 [0012] 3554-3561 [0121] • Effects of Vildagliptin twice daily vs. Sitagliptin once · Tetrahedron letters, 1998, vol. 39, 1169-1172 [0183] daily on 24-hour acute glucose fluctuations. Journal of Diabetes and Its Complications, 2009 [0013]

Claims (4)

  1. Ä iNHiSÎTORÂâ SÎÂ&«ÂMt iÔêHYfWOk 1 Az (?) kèpieëe? jeileetet zegyaite,
    teutoer taá?, tetette és gyégysazetesg tetegaáhxié sói; âhol Y jeiesiéss -ÇRs zagy OHe-;:'- és a isisaiéss '?; p iaisetesé 0,1 zagy 2. X ieisaiése agy Ä, Ctete-aite?se zssy -C(«OX: k? jelsnte teteegte·, sasé esete «tetesziitesii asasörtek sz teéitetek feüi zéissztes: tes??, tetestek??. tekteaikk'tekA okteteksz·?. g?», Stesses, ste?s?xetei, tektetete?, heíereeri i'stetee?k???, ite?etec?k???~aitei. bstefése?-aik??. asiéteséi-sikeei?. êeisazsé?·· tekte??. -te, -teOíetete teR:íSO;;tete -Cte. -CÖÖX-« -Ctetete^* ORR -testetek” vagy AR*CO?te: zagy egy tetesse az teá?tetek keze? zteseziza;
    Rí? jeieete hitetegse zagy szztesztetete vagy szukztetea esögsXsk az sisétesk keze? záteszizx: tetei, teköte, esi?. ?:itesz??e?te?, ésietekk, tekete?, textes, eikiesäzi, ítektesikissiki?, tektea?kéeii; esi, etetete?, hetetek hefcerecSttes syete, hstesöteteteeite? és asiesteste-tekik Rf és R* fsierjte egymássá? ieggeiiseái hidrogén zagy sikk, vagy Rí és ste egyágassá eskethet sgy estei esetese szesezkiask
  2. 4-W tagé gystei, saeaek tex ivetsfesseeke zee te, 0 és $ kezű? zéiasztes; R· itessîÀss sikk; rte jteeeteee iiiéfsgtey R* itessteae izé? egén : R? iöiseféee hidrogén; Rtetesaiése -Cte; R* es :R?Î iteseiésa sgymésite iüggte?este hidrogén. tette, iiiémki, teaéö, fönte?, aste??, sstesgéa zagy esek esete szaesziiteá?? ssaesésk e kozsteszék késé? zéiesziza: stetes, a?k?i, tek« sieste?, aikisSS, aiXiatek??, tekies?kiite?X??, cteisteketei, se?, égitek??. itetsísaS?, heiexteikiii, SítessOsiiteXaikiS és eeisisaei-aikii:
    æiiiw az R·, rtç R*, R'ö R!- es Rv csoport- sznbsztitoé!;, vagy éniikb? § „ssuöszS&amp;áff küajezést haszcaljok, skkor s S2ubsz sietősek agy vagy toco csoportot jeientenex as ax eteobiak közöl választottak halogének, ftidroxi, nitro, cieno, azido, oüîozo, oxo {«0), tioxe («Sj, kceltel amido. bidtazlho, tenait, aikk, Imioaikk. elkoxl, halcaikaxi, ahbfkoxí,.-dfeloWI, cikicalkil-ox·. M helgrö-clkicalkl!, hoteroad!, sikliaráioo; tola. -COOR8, - OÍÖjRx -CtSjRg -CföjRRW, <·δ(§)ΗΗ^, -MRCföjiHRW; -NtWôjRRi’R8, - H(R»)SÖR“. -RíRASOíR8, NR5C(OjORR -NiteRR -RR^OfOlRR ., §ORRSRR -SOsRRaR-, -OR8. <· OR’CpJKïR8 -'OCfŰjNxrtR8. “OCiO-R8 -R-'IdRAFO. -RORR -SR8. -POP8 and -SOr-R8; g szahsztitocnsok adott esetben tovább tehetnék sxdbsxtiteàivsj égy vagy több sziJbsztiîocnsse! a leidlekbéb rr-egbatàrozoitak szaripf; tó R8, R* és P8 jMb egymástól iijggsfienôi hidrogén vagy sxdbsxíitosii vagy szobszhfcálstisn ssopctick az alábbiak közűi választva: aikii, éikitán, adi, ániaikii, heleroM beteroani-mikii, hsfe?omikioáiidk cRIcalki! ás crkloalkenll; vagy R8 és R*> egybttésen agy 4-8 atomból álló gyiirtlszerkozstei aJKothst,
    2. Az 1 Igénypöbt szerinti vegyülő?, ahol: ha jelen van: az aikexi csoport, akkor az aikoxi csoport fnetoxi, stoxi, mproccx-. zopropoxi, n-hntox?. tecbotoxi os l-ontoxt közút választott, ha joie?· vac az snloxl csoport, akkor az arvoxl csoport tenoxi és nathiox; közöl választott; ha jelén van a halogén, akkor a halogén fluor, kló?', brönt vagy löd; ha Jeten van az alki! csoport, akkor az allai csoport metil, etv fi-prop·· szegregé bats. »joo-it», y-hntii ps-ntth next?, hop?;· vagy aki:·, ha jelen vsán az aikecii csoport, akfcof az alkcml csoport éten?!, l-propenii, 2-propenii. szopfopen?!, S-íTset-s-l-propenil, t-ootensl vagy 2-00«, na jelen van az «sSsCi? csoport, akkor az s?xt?a· csoport et?n·!, propán vagy btivnü; hs jele?; van a ékioatkii csoport, akkor a otklo-aiktt csoport clkíogrcpíi, siklóból!!, oikiopsoiii, c-x-o?;ex!·, cikicokbi, GÍkionept!Í, perbiöronattik sdarnanttl, álbteslt cikltisos csoportek vagy spitc·· bsustcososs csoportok; fsa seien van a cikloaikec-i csoport, axkor a c?kioa?kersii csoport sikiopeníenl! és clidohexenü közöl választott, na jelen van a netOie-okiosAil vagy a heteroac! csoport, akkor g hgtens-ctidosiki! vagy beteroarn csoport egy ttetsrocikki csoport amely azetidimh aknák·!!, benxoöiswüi. benzodioxamk benzotoraoli. Karoazolii.. ctnnotinii. rHozolaml. Ináokzte·!. nafhridimí, perhidrcazeplcil, ténazinil, tecotiasinil, iénoxazteii, ftaiszlnii, pl;léik ptendínii, goriník ktnazoiinii, kinoxaläni, kteoiinii, laokineiinii, tstrazoiil. iisidazeki, téághidfo-ázekteoiicii, 2-oxoazep!s!!, azeplnü, pírról!!, piperenll, piraziall, plnnkdlnil, pifidazicit, pirazolü, ázazolli, oxáZöiicii, frlázölii, Indán!!, izexazolii. izozazolldln!!, bázeli!, tiazoiinit, iiazsitetcii, ttenii, izoliszoi!!, klnykltelcII, izöiiazoiidtei!, inooki, vzöinoo·:?, indokm·. izosnoohnsl. oktéhidro-indckl, oktahiöro'szok'dolli. dakahidro-izokinokl, benzimidazoiii, tiateazoH, benzopbaix, oeoxotiazeiil, bsczo-iteClazolii, Penzoxaptexoiii, benzsinazeiii, beazoitanii, benzoxszotit, oxsdlazoiii, henzlndazok!. ndazot::, mniipijjehöini!, feni, fetrabisrotehl; teiranidropiráP!!, ßlperazteli, hornoplperazteii, piperldlt, pipendc-pipendii. rnortelinii. ΡΟίΠοοο-ηϋ, ρ-peddcn··, Z-cxepipsnasc-i, 2-όχορ·οοί·ίΡη|!, pjrrcksinii, i-oxopirrotiiltei!, ox.azsiidinil, kiO-manjl, izokfOssanii, oxab;cikioj3 2.1loktan, 3-oxabiciktop..? Roktanot·, 3-azaP!c!k!oj3.2.-ljoktán-2A-d!orí ès 3-azabieikio[3.2.ijokiárs közöl választott; b« jéisn van as ani csoport, akkor az anresocorf tens, siaftii, antracen??, indánk vagy bilenil: na jelen van az arx-ón csepoíf, akkor az aikliéí? csoport mohién, áüléit, propilén vagy batílén: na leien van a hlötoxisikíhcsoport, ekkor a hldroxlsikil csoport bidroxlmall! vagy nidrex?et!!' ha jelen van a haíoeikk csoport, akkora haioaék csoportfrlkoomtehi, {nbíóm-mehi vagy Iriktormekh ha jelen van a haloalkoxi csoport, akkor a baloalkox.? csoport kiCnnrrtox!, kloretoxl, irifteermeíoxl. trteooretoxi sis trlkfórmstoxi közei választott, na jélérj van a héierdélkiteaikii csoport, ékkor a hsterociklihalkh csoport exadlazelihmeki, idazoüt-máí;!. tebazokt-meti!, mortdlink·· ;nst!l, pírrolid-nii-metll, pipe?ickoH-raet·!. 1,2-tiazirianoi. ?-öloxirhümeii! és Ixatiazolidine!. Vdioxld-iimc’ \oz d va Je, ' ’ ' c n ve ' a heterpanhaiksm! osepert, ékkor a 0®?θίορη!··ο!χδη!! csoport plddiniiefenk, fjenkatenii és toézöllléiénji közű! választott: és he jelé?? vsm a neteroarikalkin!! csoport, akkor é hateroarll'éiksnl! csoport ptedinkelsmi és íismkstink közöl választott 3 Rz t. igénypont szenna (!) krspleln vegyelek atnely a xövotkerok közei választott 1 (2SteS;-'0(te(t!P,,3Si'-3'(iiR-1.2,é-!nszok5-i(Î:î'Ætiij··: 2,2rtrknet!t-Cik:cpami!asájio}5oe?Z;'rt,Si;orpkfo!ig:ri-2-k?3rix,jyi)rti> < Giklopooisi-o/iKPoiOogOsi-O-fsoo/oif/okOiP-x-kg/boili/fO-iTÄns£ui;0h&amp;; j. (223,oH)- !-;· 8<·(ΐΐ3,3ΐ4·"ν5ΐ1(·ι-ΐ,2Λ4ο82ο(-1-:ίΐΐΐιθϊ(;)-ΐ,2,2'·ί:ΐϊΐ:8ί5!-ο(4(οροο/(58/ιΐ5πο)38θΐ55)-4-ϊ;ΐ5όίρ5ΐ/ο))3(5ΐ-:2,48ΐ53θίΐ5ί/(5; **’ 5,80,:10)-:-/8-5(10.354:-0-(11(-1-1,2,4-/55020(-1-55)5118((()-4,2,2-8(5081:5 0:4(Op05ÍÍ5!-3r5l58O)áC8?5í)-4-::0O/p5//Oíi058,-2-08100/551)5(- miPosKOífönáí: 3. (20;4R)-1-.(2-((10,3R)-3-(í1H-1í2,4-í5(82o(-1-5()5ií8Í5()-1,2,2-:01íií8í55 o(05opo5iii(-8íi:if;o)8O8((()-4-((í5orpi/íii((o5:i--2--0ó/öó/55(/í(- îîîstâïiszo/foïtô): 0.:43)042-í(1O:3í0-3-ÍílH'l:2,44í-:S20-1-55)íi-í355Í)-1.2,2-03i3t5Í-GÍ0ö5535:1í0/i1íoó) 8o«2i)p(l/055ps/:-2-4s/bo/55í)55; :- . (0:-1-(.2-((10,30)-3-((1)5-1:2.4-:/:423^-1-(5)31055:)-1,2,2-3Í52:€4:-OÍ4feóg3l/iS:115/íö) 8θ8ί(()Ρ(//Ο54ί(ϊ1-2-03:80/5((0(-511818888:/51051:34 0, (0)-1-(2-((10:33)-3-((154-1,2.4-1:1320)-1-/5):003:)-1,2:2-455-0315/-054(0550:4::0551::-50)300(55):555-5050551-2-43/00 : 5555-::5 50 -1 , (,! >· $5 ' 0 1 i 5 V ,0 1 , !i!'Y 1 \ V >51*- í ' ,10 ' η - V \ 1".....1....... :0, 5<;0,4oi-)-(2-(5 :R,OO)-3-l(8/í-1,2,3-l/5883;-2"(:)31Sí((;-1,2;2-í/::TÍ8!5(-C(05OpOíl(jíS;p:l;O)áOS((()-4-í(l58/pi//O!5íSÍST2'08/(jO51SÍÍi(: 11. < 20,-10)- 1-(2-(/ : R,305-3- (· 5 H-1,2.3-(08 805-1 -SÍÜHfeliS)-1,2 2-81 )5805 -Ci0(Op8:i458:il:5:O)OOOl(() 4-50Ofpií-5O50iít-2'kaíOO!l4í5(. < :40:-,: (2'(3'\κ ,"> ! '3 3’' ' 51, 3' !,' <.«(0,V 1 - 3 1 ·-' ,'-'151 0,-1 ; :<5. („,->, .0.1,, . ' ! '? (it 5(,1( ' ) ÍV “ , s ítííV 5 0)(ί)όρθίί(5(-Ο:Ϊ35::0)30ό(ί:)-4-:(:80!·ρ(ΐ'/Ο;505Γ:-2-43:'ΟΟ;ΐί(05- 52:81051825.5510/531; 14. (20,40)-4-(08--1 -(2--(( 1R,30)-1,2,2-(/i/:5o05-3-(p(po/5oi5i-l -0δ/Οθϊΐ(() O5k5Op8îiiî(-8m)oo)8CO0)p:r:o))c(s!i-2-548:0oo50(; 10. (2S,i'105'4-(S«Of'1'{2-({ (R.3S)-3-í(4-(h0:O0í51Ol:5)-10-1,2,3-4020(-1 -55)//:80(:-1.2,2-/5ίί1ιΟ155-0:4!θρθ8!5588)5;ΐθ)30Ο(5()ρί/50ϊίΟ:/5-2- ko/hosiíhK: 10. (20,40)-4- 5(5.505- 1-(2'-(t10,3R)'3-((4-(h0i8XÍf:l6S!()-1('i-1.2,3-08205-1--5()508--5)-1,2.2-0511015(-0:515^1:(5(0/:1588)0881:5)015-0(54(/:-2- kä/bo-oil/li; : .- 0-/000,085-3-(,8-((201.40:·2'·053!1Ο'4'1.:0055-.ίΐί.:’<..·((ί.(::5-· 1':í)-2-0x03(l5;3511!O0)-2.2,3-í!lf:iO5:5'O45OpO:5Í5;)rí:5l/s:l:i-!8(;5í:S?.:)SíO51,li81:O'' N i :1R , -s, 2 : : 0 ,5 , j , j> 11, 5 -1 5) 3 005 Pi\ 2, s ' < ~ v <<. 1 t(v ^"iínS:3R)-3-(2-((20,4S)-2-e)gí;ö-44(/5öfp:ooí(O0'1-)()-2-8XO8::5s:iiío3;-2:2:3-:5-)81o45-os0Op8f55(5):ii8í55)-4:4)o8í·- Oo/;30(szo;f&amp;:i-î8i;o; 2&amp; ^4(('R:3S)-342-((20,40)-2-ö(sífiO0-f(ooip5r/O55O)n-1-5()-2-0208(5(3/5-5085-2,2:3-tO5i:3í)5-cik(öp8ní0!8eí;5)-44)-:ö:' 08)s7o5$2y(fe?wl58: 21, N-((/ (S,30)-3-(2..((2:3,40)-2-51-3/50--4-15-,iO!'pií'/úÍÍ-á0--(-5Í)-2-O8O8(5(3íii(:ió)-2:2.3-5rÍíO8i55-ci4(oí>6;ií:5)ÍOoi;5Í-2-55-5Of(i8:i2-i3i;ö. 22, H4((10,3R)-3-(2-((20:40)-2-Oí3fio-4-f5i.io/p58ö((3:/f-1-5(!-2-ö4os(((s/r!(8O)-2:2.3-í/(ó58(;i-o5kS8S8!iti))5iieí55)i-4,4-45Í5oo/G?k(o(-:8Xóíi-teWsmsík 23, )4-(((1(2,30)-3-(2-((20:40)-2-05800-4-000/0(//0(53551--(-)()-2-0700155801500)-2,2,3415:11855(-0)4(0008((()810/5()-4,4-0(((0010(4(0:185/08-03/(50 23/5:58; 2-1 8-((( (0.3(0-3-(2-((20 40)'2-O:3fîO-4-î5OOfp5/5-CSl8:i:-1 -:5)-2-0408(((3055/:0--2,2.3-(fÍ!11O(!Í-O:k(opOil/:5)íllOÍ558/í:5í5O!51:><O(i!10:5l;í/:5 25. Ö-Í(i1R.30)-3-(2-(;2S:4S)-2-O!3í:O-4-f5yo/p5//o((3:8-1-5()-2-O4O8(((3íT:Í5:O)-2,2.3-lí!5/:O(i(-OÍk5Opi;5l8í)511O(iiaÍl5ÍÍÍó)íl5kO5!8O3!Í/:5; 2s. 2-5((10.,3R)-3-(2--;(2S..4$)-2-C555/:o-4-((/io/p5:-!-o(:ai/!-1-5()-.2-0200555351-:5:10)-2,2,3-l/55iio(!(-ol45op8!i//()5::ot(iaíi-íií:o)::ikoi(5:0/55(/i(; Zl. (/0.40)-4-(:005-1-(2-(: 1R.30}'· 2,2-ΐ/!ΐ::ί?ίί(-3·((5'((!'!((θΟ/:::8(!()θ:/:ΰ:/ΐ-2-;58ΐ'/1::·:θ)ΐ::8/ι::050051801::-3//15510)808(5()05:01:(8:/5-2-ko/oosiitiiS: 80 (80 40)-1-(2-((1 R,30)-50)( 1,1-8:0:4:80-(80/:380(50:5:-2-:5)//:85::)-1,2.2-(/:551Oí((-Ctk(Op3í;0(8O5(8O:3O8::5)'4-;5OOípí//O55O5/:-2-03/8O/551/:5. 20: (zo,40)-1-(2-((10,3R)-34(1,1-3:04580-(70((820((35/)-2-5))5158-:5)-1,2,2-(1)/88((5,0)4(0088(5:8//5:80)300)55),·48::50φ(//ο;5ί1(ΐ1:-2-48ίΟΟ/ϊ((/ί): 3o (20,0 5s)-1-(2-(( :0.0/))-3-5( 41-d:Ox:<(0- :.2-(5825/:8::.2-:5)5110(55)-:.2 2-(55508/:5-058(008515:58511:5:0)0001555-4-550Ο/ρ:5’θ(:Ο:0·2-03/00/::(/5(, 81. (23.45)-1-(2--(15,33)-3-((1 Hoet/azoM -(((«aiiii-l ,2,2ν8ΐ^$§! çikiopaoiiS-soKboiocoSil-X-lioô/ bi/íöiioio-S-ká/POOii/ií- /oatâoszoifesoOi; 42. (25,43)-1 -(3-((1 S(35)-3-((1 bi-iat/azoi-:-:1)//:8((()-1 .2,24b/ook(-öikiöp8/5((:8O)ioói3í?8íii)-4-(:4o/4Í(/8iic(i/5-2-ks?b6o(-:i(; S3. (23,431-4-((80/-1-(2-((15^5)-42040^8)::,3-(:30/(0:(0:))02()0((/(846/:0:3(0::)0)8085)4://0((3(:)-2-53/400((0:) Ά (23 43(-4-(8.:0/- s-(2-(( ?$.354:,2,2-S:)0:8!::-3-(0)oSo::n)))08:k!k(04öii((i3iois)o)pC8((ä)4://Oii>1äo-2'S3/PO/i:i/::. SS :23.434-0800/-:-(2-(( ?S, SS';- :,2,2-8):))8(::-S-(î:)0/(o::/!î))o::i)o:kSo46/:iii3/oî:)o)608iti)4:/foisî(io-2-^8/PO/!8:::-/(io:8(ào82:/i(ooô:. M {25,45)-4-4/:0/-1-(:2-((13.351-1,2,2-81//58(:(-3-(4://4(2((/:-18:0)8((()0(8(046/4::3/0::)8)8085)4(//0(:0(:)-2-48/40/)((0:: 2?. (25.43(-8-8(:0:-1 -(2-((1 $,3S(-1,2,2-8ï:/i8{;i-S-(4://o(i((!/i-1-i::8S’i{k:k(806iï{::gÎO:i)o)888(i()4Î//o;:8â:)-2-k3/8O/)it0:. 38. (25,83(-8--800.01-('2--((1F<3S4-3'(((S43'/5:(i/ox(pimoiid::':-1-(()0)0(((4-1,2.2'-(iio:8-::--8;kk)p85)ii(a5))teo}308t:s:pä//o;;i1s5-!-2--i(3:-(:o/:;is·!:; 18, (25.83(-8-(:00:--1 -(2-(( (5.35:-- î,2,2-8(0)8(:(-3-/4:400810-1 -((ovo·:;)ο:Κ:6480{:;6:οϊ:)ο)808{:()4·/:ο::8::)-2·83/pooit/::. -:0, (25.83(-8-(kior-1 -(2-(: (S,SS;-i S.S-ïmoote-S'-oipooëio-: -({o^oSlfOKiopiSfibiafoioolooteiäjp^ioiiiiio-Aka/POfüC'::. 81, i2S,8S1(-8-?1oo/-1-(2--((l5.3S53-((44):d/ox!p:4e/i4:;)-(--(i(:Ti8lii4 :.2,2-(0/'0S(si-c:k:8p0i:(:(8/0(00(ac0iii}4;/:0:kii0--2-><o:t:00:/fis; 82, (2S.8$;-4-i(0OÎ-':-(2--({':S.3S51,'2,2-;OfOei::-3--(:4-:O)8S:ÔZi.::(0!)::î;538;:0ZO(fc:)::1::)0(((kiX:Gp8O(::-3/0;OO(;sC8iii:8:î/Oi!d::)-2· ks/OGOif/i:: 83, (25.83;-44(00:--:-'(2--(-::S,S$)-1.2,2-i,0::):te('34(4-(:))at::SZ!;:(0;)::1:&amp;OiteZ5.:i(00::1:08(((}8iki0485)i:(-SfO:S)04oC8t:i:4i:/0:k1:0-2· ks/ôo-oit/i:; 88: (5)-1 -(2-((15,83)-1,2;2-sflp)68Í-3-{(4-(:O68Í324Í(p:)(()í8:;)(iS28:(ö0:;)/035)C;kiöpO/í(;::'6fO:oö)a083í4(//öS;p:;)-2-k3/4ó0Í{:1i) 45 Î2S,8S;-<V::00:'- A(2--(;133F-Î!-:.2,2-(OÍOOS-3--(i-8-(O)8?::820::0:)!Í)f&amp;OÍiS20:(OO::1l'O8-i::852(O480(:(-3/OíOO;SC8:::1pÍí/O::0:.:)-2· ko/beslätoi: 43. (341-:2-((15,35432.2-(:::06(((-3-((4-(:))3(::320((00::1:85)5(820:(00(()/06510:(/5040/0:(-80):00:308((()4(//8(:0(0--2-43/800((0(( 4:'· (25,45(-4-::06:- (-(2-(: (3.35)- :.2.24/!0)Oiii-3-(/4-4)!3(slS20iiO:)!()ie/Ôi020::8;)8)î8A(:iiOSS048î)(5:-3O:î0O;gC8:::)pi:/8iâ8:O'2- ks/boOitei;. 45. (23.83(-8-::00:-1-(2-((lS.3S)-3-(3-(4-(!0O/Í8Oli)' 1,2,4-0230:826(-5-(((-: .2,2-CÍ6i8?:: ·0:Χ(θ83/ί((:30200ΐ888(:()ρ;86((8:0'2- 40/0055)(()1() 45- i23.83;-4-::06:'-A(2-(ilS3F-()-3-;3-(4-ÍSoOi'(3S)!i)-1.2,4-o286ia20(-;5-ii;· Az.X-îiiOietii-c-kiôpeoSorf'looîsooXib-'/okoioS· 1(0/400((/(() SO; (25,43)-3^80/-1-(2-((15,33)-1,2,2-(/(0)6(((-3-(5-0:35-1,2,4-0230:320(-3-(()0(2(0460(((00):/58)85)3((()0://0(58(0-2-(/8/80/500:) 51 (23,45)-8-(1:./0/-1-(2-((13.35)-1.2,2-(0/))0(((-3-(3-0)8(((-1,2,4-o230:a26(-5-is)o(k(0400tiia,0:ioo)sce1?i)4(/f'0((d;o-2-k8:b30i8:5: 52, (23,45)-8-5/0/-1-(2-((15,33)-3-(38208/04(:-1,2,4-e2ad(82ö(-5-l()-1,2(2-(o?T:8íí(-c(k(öpS;)tiig{))ine)30O(:()p::/8((0i/í'2-k3fb4/!(5(() 53, (2Si45)-i-(2-((1S,3S43-i6Íso4fn8(í()-1,2,28/(?í)6((S-cikiop8i)t:i3/íi:oö)308((í)-3-((í/ö/pi//o(Í8:b-2-k8/booi(/ii; 54, (23,45)-8-530/-1-(2-((15,33(-1,2,2-(/(0)8(:(-5-((5-0)0(((-1,2,4-0234is2o;-3-(()o)8t:()oiX:ö460(íÍ80)ín8)8CO((()4Í//8::((ío-2-k.8/(iörí((o(: 53 (23,45)-4-((00/-1-(2-((13.35)-1,2,2-(/:/08(:(-3-((5-/08(:(-1,2,4-02a8;azo(-3-i()fOi5iii)oik:6p3r:(:Í3/íi:oö)b88(:()4i//0:i:1:O'2'koíb6o::/ii) 84: (23,45)4-280/-1:-(2-((:13,33(-1,2,2-(/ioiOti43-((5-((/iÓQy/«3t:i)-Í,2,8-4X3d(a20Í-3-ii(0)oi;:)oik(op3;)(iia:r!Ín8)806(:((4(/íö(idio-2- ka/po//((ο:) 57; (23.45444(00/-1-(3-((13,33)-1,2,3-4(310(::-3-((5-((/((:00/:/585)-1.2,S-oxadîszoÎ-S-iiis/ioOiloikiobOOtiismioeïoooOOpi/iôiidiô-S- k3/PO!)i(:ii-s))otáf:3z:./i;o/:á(: 33; 34- " „ , '$75 ' ο 4 ; 78 v J:uc>-, 1í"<<5í s\ î5ii<sFiop8/i{iÍ3//)soo)so8{({)-4-38e/4Í/:oii8;:)-2- ka/Pöoii/ii) 35: Λ'4S < , V 7o 7 15- 0 '2 le-18 23 1 (:f)CÍi(1 '7 ) C í, J\iq c\ C\0 " ! ο 7 kS/pOOipii; öÓ, -4-808:-- :-Í-<4G8,3o)-3'-:o-rb:8í'8X4asl4!'1,2,4-8kdö:azol-3-l(iíxsó(;(1-1,2,2-tb:netllOtk!dpootílá/o:ö8)aöé(;i1p::'rcl:dlo-G ksrbooltrtt:: bl. (28,4G)-4-ttoo:--G(2--({iS,3Si-G((§-!z8pnjp4-l<2,4-öXádiazpi--3-:hóíotiÍ!-iJ,2-i(1r:igttt-pík!öpg/!tiiáb;ioö1aóátit1p!d-ó!!dio-2-kívbonitrli-n-atáoszalfpoáí; »z. tz3,4Si-4-)sdpf--:-(28:ig;3aiG-(to-G-t:aortar::i)-1,2,4-oxad)so:ot-8-ii)(iiotit)-l.2,2-tnO(S(:i-c!k)opa:rtlla?8lri8538st:l)p|rt'otid!p-2- kerboíiitrtl: §3. i23^Sí-4-6uor'1'(2-(( íS.SSy-'í.S^-teírrtem’-S-íCS-Cpsfícíjn’^-ifbl.^^-osad^íroí-^-irjfn^tincikiopentiian-íínó^icetjrípífroiidin-S-' ksrbonïîrih Μ, t2G43)-4G88(-1-(2-t(!R.3S)-5-t3-(4-tkiOfÍ3ot!)-1,2.4-8X3d:az8!-54!1-2,2,3"ion:ó)4-oik!opsp(!!smiOö1acet4)p:o8!idt:i-2-károsodni; tdb.rtSi-rtrtinor-l-sZ'-riSjRl-ü-tS-ig-iXiooepst-l.gA-oxadiazßl'O-iti-G.zG-tniOed-clktopenSüarpiOoiacetthpviohdlo^- karceoltnl; 4:i- :·:.-!!"1-(ζ-;(13,·3ΐ\)-8-ίο-|4-::8808θ:;;-1,2,4'8χο8:;ιζο!-5-ΪΙ)-2,2,3-;όθ:'3?43:ΐ2Ιορο:ΐί:!δ:τ::θθ)3θο(ί()ρχΓθ!2ί:η-2·2ο·Γθο.!'42'!:- oistónszolscnái; 8?. (2S:43)-4-088í--1-(2-((1S.3RÍ-3-(3-!zcprop::-1,2,4-öxadlaz8Í-5-tt)-2,2,3-tOi-nas::-oikiop3n:i!a!-)::ooiaodi!!1p::íO!!d:n-2-ka-oootk'4, o§. :80,45)-44-88:-1-:2-(: (S,3R)-2,2,3-to:'r:S(!!-3-(3-:pipdäO-3-:i1'1,2,4Oxadlazol-5-::)ciktopant!!a:T:!oo:aoetll1p4;8!sdsn-2-2aröor:!tn), p§, (2(3,431-4-t58or-s-(2-((1)4,33)-2,2,d-thtóaill-ártá-ípibdio-Géll-UX-oxadlazol-S-llcIkiopondlamiooiaoetttip síf-aljdjn-2-karbonUnL ;P (2(8.43)-4-))8000(2-((18841(-2,2 3 tomo(4-8-(3-(pioO:0-4-!)t- I.SJ-ozateazot-S-ziciklOnöisiilamlooiaoect-pviOlldsp-k-kas'Pool-n:, / -. i.2.3,43(-4-Űoor· 1-(2-((1 R:O3j-'2,2,.3-ííiniókl”3--3-(p--í8iom-i)1-1,2,4-oxad:azo!-G4ldk!opeoiila:nlOO)38s:!!)p!o8ltd!P'2-karöooitoi. ?2 i2S,4Si-4--3800i-(2'((13.3R1-2.2,3--)rto-ie):i--3-(3-(ploooo-2-Xi-1,2,4-8:<a!4iaz8)->-:i)o-k[ope!'i(ilami08Saoo(il}pi-;Okb!0-2-ka:'Pooi(8;,' · 1 i2S,45;-4'5oor-1 -(24(1(4,33)-2.2 3- m-neb)· 3-(3- rood-1,2 4-8xssllaz8l-5-4)oäklopsot::pm:oel3cai:Op:rfO::d:ii-2-kaib8n4dl *· (2S:48)'4-a80o1-(2-í(13.3R)-2,2;3-ííioístil-3-(3-moí-i-1JX-oxértlazol-S-thciklopsiitilsíninolacatlIípírrolídltl-G-kaiPopibst; 7§. (S)-1-(2-(<0R,5R)<l!5.8,8-t€bw^i-2t4-<jäoxo-3-‘SZiä>fetkb(3.2.1]oklän’1'iiartiiO8}aceni}pirf^dfn-2--l‘,gfb<Äif,· /(3 (83,45)-4 4:88:-1-(,;-(( 1)4.öR1-3,5.5,8-)88a:nf.4lt-3-azaö!űiklo(3,2 :)02-00-1-4(-:0:100)003):(),0-001.:010-2-1:.8:0004:11: 77, (23,4f4)-4-i!uoM -(2-((1 R,3Gt-3,0,5,8-(0)- am85!-Ü-aZ8biCik!o(3.2; í lokíán-1 -llamiooiaootillploslidin-Gka-éoolsIt; 78 (31-142-((1(2,5)4)-3.5,3,848()8010)4-3-008010(210)3 2.1)02^0-(-40:(::001000(:(1^::2:0310-2-23-000(18), /3. (3)-1 -(2'((13,5!3ΐ-5,3,§-::;:ΐ:ο0:-2-ί3χο-3'θχοΡίθί2Ιορ.2 l)oktao-14lao:lno1aoe):lip)r:oi!dio-2-ka:b8ni2:l; 53. i8)-1-(24(1l4.5R)-5.8,8-(om8sl'3-ovab:8:kS8(3.2 IjoRân-l •âianssiôîaœl-Qpiifol-ôm-g-kàrboOildi· 82 (2§,4^)^ΐΙ^1.(24πβ,§Η)-δ(δ(8.^σ(8δΙ·(8'δχ^ί^0{3,2,1.|ο2^η-1’)ί8)ηΐΓ:θ)δθό®)ρ{Γη3ΐ)0ΐη-2’28^ίί!ΐΐ,: 82 (23.48)-4-::-:8:-1-(2-(-13,53)-8.8,§4:4fi:e4l-3-oxgpte:2:o;3.2,1)ox2in-t -tlao5Íoo)a8st!!)pl:Tot!d:fí-2-kafboostot és 83,(2S.4R)-1-(2-((1S.3Ri-3-(3-(lH-1,2,445lazo;-1-41p:'8pä!1:'2,2:3-iboi&amp;i4-Päk:ßpoo(i(aio:oo)P8Si4)-4-::-ä8fplro5l(3äo-2-ks:rPoi54fi(. 4.- 53«fas ox I. Igénypont szennt- ()) képleté vogyuat oloakltàsàrs ogy, hogy a (11) koptok: vegyalotet. amaty szánod só vagy védett tor/nóoan van, ösázékaeesollnk a (11!) káplstö vágyóiéitól
    átlót i~ jdioníásg: távozó csoport klór. hrorn, jód, íezltátök, eiozlipiok Ós (Ottótok közül választva, a RG jáiönfésa hidrogén vagy védéooonortok aoetit, idflooraoe::!, artlszoltooik noz-i, tozll. -Rop vagy -C8z köze! választva, továbbá n, F4;. Rí, Rí, r-·, Ry rs eg Rh X és Y jelentőse ugyanaz,. mint az 1, Igényponí szopott meghatározásban,
    •S. A4 tgáaypopt szoöPtl ¢) Aépioííi vegyüK amoiy a(ilOiés ο (Ιοί; kópistö vegyötebk közöl választott
    ahoi az ν'· csoport Salontása SO? vagy CO: &amp; PG jslaptése hidrogén vpgy egy vôpocsoport aw -3οο: ρ; ΐν jalaatàso ugyanaz, ovni a?. 1. igénypont szerinti megnatározasban. 6, A 4, îgèdypoPt szerinti til) kápistá vogyüiet amely a fiH), (íi-6), íU-6). öl-?). ;li-3). (H-9) és (ii-10) képiotö vegyöletak Mzüi választott
    ahol az. «·, R,s csoport jelentése vgyanaz. nisnt az 1. igénypont szarinti meghstsrozésbon és a PG ysientöse hidrogén vagy egy védöcsopori. ami -Sec
  3. 7, Az 4. igénypont szer Imi fii) képteíö vegyoiet, emsiy a következők közöt választott: 1 tafcAHjtiitlRAivöO-iPidroziicesiä-iZika'tiiPiekk'kiopantii'ksfbamsi: 2 tilSGRAS-ftero-butoxl-'karbonllaminoi'S^.S-triinoilieikleparttiliniaill meiapszolfosiát: 3 ierc-botiSfiR 3S)'3-ia?idprastl:;-1O^-irlioekicIklopeniá-karbamót' 4 terc-buiíljflR 3S;-34arpífsameití)'t .2.2-iPm»e5e:Mopeíölljksíbamák 5. ('iS^RS-G-iifefG-öatóxikárOópiijapíífiói-S^^-iríPiakiCíkiopantán’korbopssv; A. terc-buílljilS,3S)-3-íompotaetil;-'i)2,2-tdmealcikiopePtiijk3rd3m3r: i* a tv kl, sí 3R; ' * a v ’ y i 2vt ok?pvrzw'
  4. 8, Metäasz5.!itbns3v4lRs3SA3't-00töxi-karboptis5aiPO-ä!2<3'i!'imei(l-4'plkföpentitrPsiti-0szior' ö. tero-butiiji lS,3R;-3-S3Zidomeiii)-1 ,2.2-tPmat4cáiöpef:tll)kafbe:?iák " an. ο. \ -A imakkik φοΎ- w 11 f1R.3St-3-j{;arc-eptoxikarboml)amiPo)-2.2 S-trimotsIcikiopePiaP-ka/boosav: 12 torc-bo(:lí{1S.3S)-3'Ícianörneö'í)'1:2.2'fHmetllclkiopentil)kerb3:Tiát, 13 f 1R.8R;-i-S!Pmo-3,5.S.$- tetrametil-3-azabíoálola.2 1}oki8n-2.4-dlon: 14 fiR.5R;·-3.58,3-retrameiA3·axaix.Aioi321 iokten-t-amin, 15 i1R.5R;-i-armno-5,8,3-ietramarm3-oxabloklolS 2 iJöMén-S-ön. 16.(1 R. 5R)-3:8!3-títr?:atik3-öxabffiíkiöl3,2.1Igktén-1 - a ? rí Ir · ; (ISsí; 3ío-tóv 3-x\abampG? i'okmo : ai nas 18. 3-((;'iS3S1-3-ar:5iiX''2;2.3'tfimaölcikkapeptjil;pgtii)-1.2,4-o:<3d:a8oP3-a;!T:ei8i;:4.f5:gr?)k;o;io
    §. zsyegyàszAZ sfTíSsv az M, igAeygstÄ bszzneszAA szaapa $ yap-asA vagAneisj vagy eanek egy gyëgyàsâZÂA WgOWà S^ât OÄä easzaayAgsèîSi ZisgéazAve egy gyÁgyfezisiag sAfogsghatA eörgAZÁM siggezea'eb AsgAöAnysggáí zsgy SzeMM §<.A S· tgtnygoM $«f gyêgyazzAë fcésÂèby feássAs. AsgazAia, gag szfcup: sidat seteaze; zzAez&amp;Anzié bajáim W. Az ;-3. sgenypentek AéimAyAs szsAA vagyásA 5? esAbèîesz zsgy a A» Avez szWaAasnyeA HeMèsèbéA vagy «egÄAÄsn vaa feihâSKrsÀfâsiâ.. It Az A3. ;gAaygöAzA Wi&amp;iyäA? szeméi vegyaA az Âà KAzelèSèbaA vAà AlAssznAásfe: aaysgasera-he-egsAgiA: 3. 3AA3 «ÄK ÄÄ gMWÂWÏa; WÂfêÂj mmsáéAéáazmAöésa Âàslle.w§ég; sAàaâs; eresAaAsU SAgseaAs agrCKiÂÇiSZZg. diSaapiAénAiâ «ggSS ΖΑΑΖΖΐδΑΑΑΖίΑϊ ÿegy sâsggiAézaA SZëAÔAiàAéyet ZAzëÜÀÀ S §Α3ΖΑ, szmsôszôréaf'AmegaAg, «agae ygreyamM petífAass éféASegség, seasapaAA isiAopgssg nenesAaAoAs SAnaAsàeîsgsÀg és ne« eK'îwtes sziaatahepaaiüz. weextegerx-ratiV betegségek: fcoy«^ betegségek és szorongásos betegségek 12> Az A3, igegypoeteA báswiytes szóAna vagyötet (3 a rebgAé weetexszíoí AiagAsözÁsebea zagy 3AZteésznxzz ag a Wteóíy «AkeAézabeA (iii? a sebayogy A-aPan. OA AZ iáWArneítetesAbtey A A fáiAsÁróasSÁgiteabae sete feteASzeAWA.
HUE10729125A 2009-01-09 2010-01-07 A dipeptidil-peptidáz-IV inhibitorai HUE035693T2 (hu)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IN65CH2009 2009-01-09

Publications (1)

Publication Number Publication Date
HUE035693T2 true HUE035693T2 (hu) 2018-05-28

Family

ID=42316906

Family Applications (1)

Application Number Title Priority Date Filing Date
HUE10729125A HUE035693T2 (hu) 2009-01-09 2010-01-07 A dipeptidil-peptidáz-IV inhibitorai

Country Status (17)

Country Link
US (1) US8466145B2 (hu)
EP (1) EP2376447B1 (hu)
JP (2) JP2012514630A (hu)
KR (1) KR101750420B1 (hu)
CN (2) CN102272099A (hu)
AU (1) AU2010204144B2 (hu)
BR (1) BRPI1006970A2 (hu)
CA (1) CA2749301C (hu)
ES (1) ES2653563T3 (hu)
HU (1) HUE035693T2 (hu)
IL (1) IL213105A (hu)
MX (1) MX2011007340A (hu)
NZ (1) NZ593361A (hu)
PL (1) PL2376447T3 (hu)
PT (1) PT2376447T (hu)
SG (1) SG172924A1 (hu)
WO (1) WO2010079413A2 (hu)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102272099A (zh) * 2009-01-09 2011-12-07 幽兰研究实验室有限公司 二肽基肽酶iv抑制剂
CN103787960A (zh) * 2014-02-27 2014-05-14 江苏省激素研究所股份有限公司 一种2-氯-5-三氯甲基吡啶的合成方法
CN104496876A (zh) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 一种羟基金刚烷酰胺衍生物、其制备方法和用途
CN105596333A (zh) * 2016-02-02 2016-05-25 白强 一种防治糖尿病及其并发症的药物组合物及其应用
CN108707143B (zh) * 2018-06-26 2020-06-26 中昱医学检验(广州)有限公司 一种dpp-4抑制剂及其制备和在糖尿病中的应用

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1567902A (en) * 1975-10-15 1980-05-21 Glaxo Lab Ltd 1-aminoalkyl-7,7-dimethylnorbornanes
DE2659052A1 (de) * 1976-12-27 1978-07-06 Nattermann A & Cie N-substituierte 1,2,2-trimethyl-3- carbamoyl-cyclopentan-carbonsaeuren(1) und deren physiologisch vertraegliche salze
DE3402623A1 (de) * 1984-01-26 1985-08-01 Bayer Ag, 5090 Leverkusen Neue diisocyanate und ihre verwendung zur herstellung von polyurethankunststoffen
IT1201489B (it) * 1985-11-13 1989-02-02 Chiesi Farma Spa Derivati di tiazolidina,loro procedimento di preparazione e formulazioni farmaceutiche
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
JP2001517246A (ja) * 1997-06-23 2001-10-02 田辺製薬株式会社 α▲下４▼β▲下１▼媒介細胞接着の阻止剤
CO5150173A1 (es) 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
TWI243162B (en) 2000-11-10 2005-11-11 Taisho Pharmaceutical Co Ltd Cyanopyrrolidine derivatives
ES2291477T3 (es) 2001-06-27 2008-03-01 Smithkline Beecham Corporation Fluoropirrolidinas como inhibidores de dipeptidil peptidasa.
UA74912C2 (en) 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
DE60316416T2 (de) 2002-03-25 2008-06-26 Merck & Co., Inc. Heterocyclische beta-aminoverbindungen als inhibitoren der dipeptidylpeptidase zur behandlung bzw. prävention von diabetes
JP4564952B2 (ja) 2003-01-17 2010-10-20 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病の治療および予防のためのジペプチジルペプチダーゼ阻害薬としての３−アミノ−４−フェニルブタン酸誘導体
TW200519105A (en) * 2003-10-20 2005-06-16 Lg Life Science Ltd Novel inhibitors of DPP-IV, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
WO2005075426A1 (en) 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Novel dipeptidyl peptidase iv inhibitors; processes for their preparation and compositions thereof
ES2375625T3 (es) * 2004-02-05 2012-03-02 Kyorin Pharmaceutical Co., Ltd. Derivados de biciclo éster.
CA2555399A1 (en) 2004-02-20 2005-09-01 Novartis Ag Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders
WO2005095339A1 (en) * 2004-03-31 2005-10-13 Pfizer Products Inc. Dicyanopyrrolidines as dipeptidyl peptidase iv inhibitors
WO2006012441A1 (en) * 2004-07-23 2006-02-02 Susan Marie Royalty Peptidase inhibitors
WO2006011035A1 (en) 2004-07-23 2006-02-02 Glenmark Pharmaceuticals Ltd. Novel dipeptidyl peptidase iv inhibitors; process for their preparation and compositions containing them
ATE553077T1 (de) * 2004-07-23 2012-04-15 Nuada Llc Peptidaseinhibitoren
JP4959569B2 (ja) * 2004-10-12 2012-06-27 グレンマーク・ファーマシューティカルズ・エスエー 新規なジペプチジルペプチダーゼｉｖ阻害剤、それらを含む医薬品組成物、およびそれらを調製するためのプロセス
US7985759B2 (en) * 2006-04-03 2011-07-26 Matrix Laboratories Ltd. Dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them
JP2009190971A (ja) * 2006-06-06 2009-08-27 Mitsubishi Tanabe Pharma Corp ２−シアノピロリジン誘導体
EP2035395A2 (en) * 2006-06-27 2009-03-18 Glenmark Pharmaceuticals S.A. Novel processes for the preparation of dpp iv inhibitors
EP2123636B1 (en) * 2007-03-22 2012-03-21 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
CN102272099A (zh) * 2009-01-09 2011-12-07 幽兰研究实验室有限公司 二肽基肽酶iv抑制剂

Also Published As

Publication number Publication date
US20110257164A1 (en) 2011-10-20
IL213105A0 (en) 2011-07-31
CA2749301A1 (en) 2010-07-15
US8466145B2 (en) 2013-06-18
PL2376447T3 (pl) 2018-04-30
AU2010204144B2 (en) 2012-02-16
NZ593361A (en) 2012-12-21
RU2011133213A (ru) 2013-02-20
AU2010204144A1 (en) 2011-06-23
JP5775235B2 (ja) 2015-09-09
ES2653563T3 (es) 2018-02-07
WO2010079413A2 (en) 2010-07-15
EP2376447A2 (en) 2011-10-19
JP2012514630A (ja) 2012-06-28
WO2010079413A3 (en) 2010-12-02
CA2749301C (en) 2019-06-11
BRPI1006970A2 (pt) 2015-09-15
PT2376447T (pt) 2017-11-15
EP2376447B1 (en) 2017-08-09
MX2011007340A (es) 2011-07-21
IL213105A (en) 2015-09-24
JP2015091889A (ja) 2015-05-14
KR20110105820A (ko) 2011-09-27
CN105384726A (zh) 2016-03-09
CN102272099A (zh) 2011-12-07
SG172924A1 (en) 2011-08-29
KR101750420B1 (ko) 2017-06-26
EP2376447A4 (en) 2012-06-20

Similar Documents

Publication Publication Date Title
CA2682846C (en) Novel dipeptidyl peptidase iv inhibitors and processes for their preparation and pharmaceutical compositions containing them
US10689347B2 (en) Substituted heterocyclyl derivatives as CDK inhibitors
EP2991994B1 (en) Thiazolopyrrolidine inhibitors of ror-gamma
US9458171B2 (en) Pyrrolidinyl sulfone RORγ modulators
JP4199298B2 (ja) Ｐｐａｒアゴニスト活性を有する誘導体
CZ20012297A3 (cs) Piperidiny jako modulátory CCR5
US20180186739A1 (en) Spiro[cyclobutane-1,3&#39;-indolin]-2&#39;-one derivatives as bromodomain inhibitors
JP2017514856A (ja) 糖尿病などの疾患の治療用のピロリジンｇｐｒ４０モジュレータ
JP5775235B2 (ja) ジペプチジルペプチダーゼｉｖ阻害剤
US20050192324A1 (en) Novel dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
CA3226724A1 (en) Cyanopyridine and cyanopyrimidine bcl6 degraders
NZ571319A (en) Novel dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them
JP5665057B2 (ja) Ｈｄｌ上昇剤
RU2574410C2 (ru) Ингибиторы дипептидилпептидазы iv