US20100009961A1 - Dipeptidyl peptidase-iv inhibitors - Google Patents

Dipeptidyl peptidase-iv inhibitors Download PDF

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Publication number
US20100009961A1
US20100009961A1 US12/492,254 US49225409A US2010009961A1 US 20100009961 A1 US20100009961 A1 US 20100009961A1 US 49225409 A US49225409 A US 49225409A US 2010009961 A1 US2010009961 A1 US 2010009961A1
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alkyl
mixture
title compound
afford
concentrated
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US12/492,254
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Heiko Kroth
Tim Feuerstein
Frank Richter
Jurgen Boer
Michael Essers
Bert Nolte
Matthias Schneider
Matthias Hochguertel
Fritz-Frieder Frickel
Arthur Taveras
Christoph Steeneck
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Alantos Pharmaceuticals Holding Inc
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Alantos Pharmaceuticals Holding Inc
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36694223&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20100009961(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Alantos Pharmaceuticals Holding Inc filed Critical Alantos Pharmaceuticals Holding Inc
Priority to US12/492,254 priority Critical patent/US20100009961A1/en
Publication of US20100009961A1 publication Critical patent/US20100009961A1/en
Priority to US13/006,363 priority patent/US8076330B2/en
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Definitions

  • the present invention relates to pyrrolidine and thiazolidine-based inhibitors of dipeptidyl peptidase-IV (DPP-IV) and to methods for treating diabetes, particularly Type-2 diabetes as well as impaired glucose tolerance, impaired glucose homeostasis and complications associated with diabetes by inhibiting DPP-IV with such cyclic amido and cyclic ureido pyrrolidine and thiazolidine inhibitors.
  • DPP-IV dipeptidyl peptidase-IV
  • Diabetes results from the occurrence of one or more of several causative factors, and is characterized by an abnormal elevation in levels of plasma glucose (hyperglycemia). Persistent or uncontrolled hyperglycemia results in an increased probability of premature morbidity and mortality. Abnormal glucose homeostasis is usually associated with changes in the lipid, lipoprotein and apolipoprotein metabolism, or due to other metabolic and hemodynamic diseases.
  • Type-2 diabetes mellitus or noninsulin dependent diabetes mellitus are especially at increased risk of suffering from macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nepHropathy, neuropathy and retinopathy.
  • Therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critical in the clinical management and treatment of Type-2 diabetes mellitus.
  • glitazone-type compounds i.e. 5-benzylthiazolidine-2,4-diones
  • glitazones are agonists of the peroxisome proliferator activated receptor (PPAR), which is attributed to be responsible for their improved insulin sensitization.
  • PPAR peroxisome proliferator activated receptor
  • serious side effects e.g. liver toxicity
  • some glitazones such as, for example, troglitazone.
  • DPP-IV dipeptidyl peptidase-IV
  • DPP-4 dipeptidyl peptidase-IV
  • DP-IV dipeptidyl peptidase-IV
  • DPP-IV is a membrane bound non-classical serine aminodipeptidase which is located in a variety of tissues (intestine, liver, lung, kidney) as well as on circulating T-lymphocytes (where the enzyme is known as CD-26). It is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (e.g. GHRH, NPY, GLP-2, VIP) in vitro.
  • GLP-1(7-36) certain endogenous peptides
  • glucagon glucagon
  • proteolytic activity against a variety of other peptides e.g. GHRH, NPY, GLP-2, VIP
  • GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine.
  • GLP-1(7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-1(7-36) are expected to be beneficial in the prevention and treatment of Type-2 diabetes, and potentially obesity.
  • GLP-1(7-36) continuous infusion
  • DPP-IV has been shown to be the primary degrading enzyme of GLP-1(7-36) in vivo.
  • GLP-1(7-36) is degraded by DPP-IV efficiently to GLP-1(9-36), which has been speculated to act as a physiological antagonist to GLP-1(7-36). Inhibition of DPP-IV in vivo should, therefore, potentiate endogenous levels of GLP-1(7-36) and attenuate formation of its antagonist GLP-1(9-36) and serve to ameliorate the diabetic condition.
  • GLP-1 and GIP are incretins that are produced upon ingestion of food, and which stimulate production of insulin.
  • Inhibition of DPP-IV causes decreased inactivation of the incretins, which in turn, results in an increase in their effectiveness in stimulating pancreatic production of insulin.
  • DPP-IV inhibition therefore, results in an increase in the level of serum insulin. Since the incretins are produced upon consumption of food only, DPP-IV inhibition is not expected to increase insulin levels when not required, thereby precluding excessive lowering of blood sugar (hypoglycemia). Inhibition of DPP-IV, is therefore, is expected to increase insulin levels without increasing the risk of hypoglycemia, thereby lowering deleterious side effects associated with currently used insulin secretagogues.
  • DPP-IV inhibitors have not been studied extensively as therapeutics for diseases other than diabetes, they are expected to have other potential therapeutic utilities.
  • the present invention relates to a class of pyrrolidine-based inhibitors of dipeptidyl peptidase-IV (DPP-IV).
  • DPP-IV dipeptidyl peptidase-IV
  • the present invention provides a new class of pyrrolidine and thiazolidine DPP-IV inhibiting compounds (“DPP-IV inhibitors”).
  • One aspect of the present invention includes a compound of formula (I):
  • E and G are independently 6-membered aryl, or 5-membered heteroaryl or 6-membered heteroaryl;
  • E may be substituted with one or more R 1 groups
  • G may be substituted with one or more R 2 groups
  • X and Y are divalent and are each independently: a bond, CR 4 R 5 , O, NR 4 , S, S ⁇ O, S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), S( ⁇ O) 2 N(R 4 ), C ⁇ N—OR 4 , —C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 R 5 ) C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 R 5 )C(R 4 R 5 )C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 )NR 4 —, —C(R 4 R 5 )O—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4
  • R 1 and R 2 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O
  • R 3 is absent or is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R a is hydrogen, CN, NO 2 , alkyl, haloalkyl, S(O) t NR 4 R 5 , S(O) t R 4 , C(O)OR 4 , C(O)R 4 , or C(O)NR 4 R 5 ; each occurrence of R 4 , R 5 , R 20 and R 21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl
  • R 50 is, in each occurrence, R 20 , CN, NO 2 , S(O) t NR 20 R 21 , S(O) t R 20 , C(O)OR 20 , C(O)R 20 C( ⁇ NR a )NR 20 R 21 , C( ⁇ NR 20 )NR 21 R a , C( ⁇ NOR 20 )R 21 or C(O)NR 20 R 21 ;
  • each occurrence of R 7 and R 8 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl
  • R 9 is H or C 1-6 alkyl
  • R 10 is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4 R 5
  • R 11 and R 12 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O
  • R 13a and R 13b are each independently R 5 or together are ⁇ O;
  • R 14a and R 14b are each independently R 5 or together are ⁇ O;
  • R 13c and R 14c are each independently R 5 ;
  • Q a is CH or N
  • U is —C(O)—, —C( ⁇ NR 4 )—, —(CR 4 R 5 —) p , NR 50 , S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), N(R 4 )(C ⁇ O), S( ⁇ O) 2 N(R 4 ), N(R 4 )S( ⁇ O) 2 , C ⁇ N—OR 4 , —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 ) p NR 50 —, N(R 50 )C(R 4 R 5 ) p , —O—C(R 4 R 5 )—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4 )—, —(C ⁇ NR a )—, N(C ⁇ O)NR NR 5 , N(C ⁇ O)
  • W is —CH 2 —, —S—, —CHF— or —CF 2 —;
  • Z is C or N
  • n 1, or 2;
  • n 0, 1, or 2;
  • p 0 to 6;
  • t 0, 1, or 2.
  • Another aspect of the present invention includes a method of preparing a compound of the following formula:
  • step (b) dehydrating the carboxamides of the compound from step (a) to cyano to provide a compound of formula:
  • a further aspect of the present invention provides a method of preparing a compound of the following formula:
  • step (b) dehydrating the carboxamide in the compound from step (a) to provide a compound of formula:
  • Another aspect of the present invention provides a compound of formula A compound of formula (I):
  • A is:
  • E and G are independently selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, and 5-6-membered saturated or partially saturated carbocyclic or heterocyclic rings;
  • E may be substituted with one or more R 1 groups
  • G may be substituted with one or more R 2 groups
  • R 1 and R 2 are independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)
  • R 3 is absent or is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R a is hydrogen, CN, NO 2 , alkyl, haloalkyl, S(O) t NR 4 R 5 , S(O) t R 4 , C(O)OR 4 , C(O)R 4 , or C(O)NR 4 R 5 ;
  • each occurrence of R 4 , R 5 , R 20 and R 21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R 4 and R 5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may be optionally containing a heteroatom selected from O, S, or NR 50 and the 3- to 8-
  • R 50 is, in each occurrence, R 20 , CN, NO 2 , S(O) t NR 20 R 21 , S(O) t R 20 , C(O)OR 20 , C(O)R 20 C( ⁇ NR a )NR 20 R 21 , C( ⁇ NR 20 )NR 21 R a , C( ⁇ NOR 20 )R 21 or C(O)NR 20 R 21 ;
  • each occurrence of R 7 and R 8 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl
  • R 9 is H or C 1-6 alkyl
  • R 10 is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4 R 5
  • R 11 and R 12 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (CO—C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R 13a and R 13b are each independently R 5 or together are ⁇ O;
  • R 14a and R 14b are each independently R 5 or together are ⁇ O;
  • R 13c and R 14c are each independently R 5 ;
  • Q a is CH or N
  • U is —C(O)—, —C( ⁇ NR 4 )—, —(CR 4 R 5 —) p , NR 50 , S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), N(R 4 )(C ⁇ O), S( ⁇ O) 2 N(R 4 ), N(R 4 )S( ⁇ O) 2 , C ⁇ N—OR 4 , —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 ) p NR 50 —, N(R 50 )C(R 4 R 5 ) p —, —O—C(R 4 R 5 )—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4 )—, —(C ⁇ NR a )—, N(C ⁇ O)NR 4 NR 5 , N(C ⁇
  • W is —CH 2 —, —S—, —CHF— or —CF 2 —;
  • Z is C or N
  • n 1, or 2;
  • n 0, 1, or 2;
  • p 0 to 6;
  • t 0, 1, or 2
  • R 1 or R 2 is present and is:
  • Another aspect of the present invention provides a compound of formula A compound of formula (I):
  • A is:
  • E, G, and M include a three ring system wherein M shares two carbon atoms with each of E and G;
  • E, G and M are each independently selected from a 5-7-membered saturated or partially saturated carbocyclic ring, a 5-7 membered saturated or partially saturated heterocyclic ring, a 5-6-membered aromatic ring, and a 5-6-membered heteroaromatic ring;
  • E may be substituted with one or more R 1 groups
  • G may be substituted with one or more R 2 groups
  • R 1 and R 2 are independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)
  • R 3 is absent or is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R a is hydrogen, CN, NO 2 , alkyl, haloalkyl, S(O) t NR 4 R 5 , S(O) t R 4 , C(O)OR 4 , C(O)R 4 , or C(O)NR 4 R 5 ;
  • each occurrence of R 4 , R 5 , R 20 and R 21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R 4 and R 5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may be optionally containing a heteroatom selected from O, S, or NR 50 and the 3- to 8-
  • R 50 is, in each occurrence, R 20 , CN, NO 2 , S(O) t NR 20 R 21 , S(O) t R 20 , C(O)OR 20 , C(O)R 20 C( ⁇ NR a )NR 20 R 21 , C( ⁇ NR 20 )NR 21 R a , C( ⁇ NOR 20 )R 21 or C(O)NR 20 R 21 ;
  • each occurrence of R 7 and R 8 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl
  • R 9 is H or C 1-6 alkyl
  • R 10 is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4 R 5
  • R 11 and R 12 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (CO—C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R 13a and R 13b are each independently R 5 or together are ⁇ O;
  • R 14a and R 14b are each independently R 5 or together are ⁇ O;
  • R 13c and R 14c are each independently R 5 ;
  • Q a is CH or N
  • U is —C(O)—, —C( ⁇ NR 4 )—, —(CR 4 R 5 —) p , NR 50 , S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), N(R 4 )(C ⁇ O), S( ⁇ O) 2 N(R 4 ), N(R 4 )S( ⁇ O) 2 , C ⁇ N—OR 4 , —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 ) p NR 50 —, N(R 50 )C(R 4 R 5 ) p —, —O—C(R 4 R 5 )—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4 )—, —(C ⁇ NR a )—, N(C ⁇ O)NR 4 NR 5 , N(C ⁇
  • W is —CH 2 —, —S—, —CHF— or —CF 2 —;
  • Z is C or N
  • n 1, or 2;
  • n 0, 1, or 2;
  • p 0 to 6;
  • t 0, 1, or 2
  • R 1 or R 2 is present and is:
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures, diasteromeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, tautomers, atropisomers, and rotamers, with all isomeric forms being included in the present invention.
  • Compounds described in this invention containing olefinic double bonds include both E and Z geometric isomers.
  • Also included in this invention are all salt forms, polymorphs, hydrates and solvates. All of the above mentioned compounds are included within the scope of the invention.
  • the present invention also provides methods of inhibiting the DPP-IV enzyme.
  • the present invention further provides methods of treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type-2 diabetes.
  • the present invention also provides methods for obtaining the DPP-IV inhibiting compounds and pharmaceutical compositions comprising them either singly or in combination with one or more additional therapeutic agents for the prevention or treatment of DPP-IV enzyme medicated diseases, particularly Type-2 diabetes.
  • alkyl or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups.
  • exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.
  • substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 4 )(R 5 )N—CO— wherein R 4 or R 5 are as defined below, except that at least one of R 4 or R 5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • groups halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloal
  • lower alk or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
  • alkoxy denotes an alkyl group as described above bonded through an oxygen linkage (—O—).
  • alkenyl denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain.
  • exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like.
  • substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 4 )(R 5 )N—CO— wherein R 4 or R 5 are as defined below, except that at least one of R 4 or R 5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • alkynyl denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain.
  • exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.
  • substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 4 )(R 5 )N—CO— wherein R 4 or R 5 are as defined below, except that at least one of R 4 or R 5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • cycloalkyl denotes optionally substituted, saturated cyclic hydrocarbon ring systems, including bridged ring systems, desirably containing 1 to 3 rings and 3 to 9 carbons per ring.
  • exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
  • substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • aromatic or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons.
  • exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl.
  • substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
  • heterocycle or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
  • heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl,
  • Heterocyclenyl denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
  • Ring sizes of rings of the ring system may include 5 to 6 ring atoms.
  • the designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • heterocyclenyl may be optionally substituted by one or more substituents as defined herein.
  • the nitrogen or sulpHur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Heterocyclenyl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A.
  • Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like.
  • Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl.
  • An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
  • Heterocyclyl or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms.
  • the designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • the heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein.
  • the nitrogen or sulpHur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Heterocyclyl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960).
  • Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Heteroaryl denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms.
  • the “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein.
  • the designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • a nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide.
  • Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960).
  • heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl,
  • amino denotes the radical —NH 2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group.
  • exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
  • cycloalkylalkyl denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
  • arylalkyl denotes an aryl group as described above bonded through an alkyl, as defined above.
  • heteroarylalkyl denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
  • halogen as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
  • haloalkyl denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
  • aminoalkyl denotes an amino group as defined above bonded through an alkyl, as defined above.
  • the pHrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic.
  • the ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S.
  • Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
  • tricyclic fused ring system wherein at least one ring is partially saturated denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic.
  • the ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S.
  • Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as, but not limited to
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • pHrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • a substituent is keto (i.e., ⁇ O) group, then 2 hydrogens on the atom are replaced.
  • moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted.
  • the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from, but not limited to:
  • cleave or “cleaving” means splitting a complex molecule into at least two separate molecules. “Cleavage products” are the separate molecules which result from cleaving.
  • metabolic refers to a composition which results from a metabolic process. Examples of the results of metabolism on the compounds of the present invention include addition of —OH, hydrolysis, and cleavage.
  • polymorphs refers to the various crystalline structures of the compounds of the present invention. This may include, but is not limited to, crystal morphologies (and amorphous materials), all crystal lattice forms, and all salts. Salts of the present invention can be crystalline and may exist as more than one polymorpH. Each polymorpH forms another aspect of the invention. Hydrates as well as anhydrous forms of the salt are also encompassed by the invention.
  • Troc is 2-(trimethylsilyl)ethoxycarbonyl
  • Et is ethyl (—CH 2 CH 3 ) or ethylene (—CH 2 CH 2 —).
  • Me is methyl (—CH 3 ) or methylene (—CH 2 —).
  • Boc is tert-butyloxycarbonyl.
  • pharmaceutically-acceptable tricyclic moiety is meant to include, but is not limited to, benzocycloheptapyridyl, benzodiazepinyl, and benzozapinyl
  • the DPP-IV inhibiting compounds are used in the manufacture of a medicament for the treatment of a disease mediated by an DPP-IV enzyme.
  • DPP-IV inhibiting compounds of the present invention are used in combination with another disease modifying drug.
  • diseases modifying drugs include, but are not limited to: (a) other dipeptidyl peptidase IV (DPP-IV) inhibitors such as Vildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS); (b) insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g.
  • the DPP-IV inhibiting compounds of the present invention are used in the treatment diseases or symptoms mediated by an DPP-IV enzyme.
  • diseases or symptoms mediated by a DPP-IV enzyme include, but are not limited to, Type II (Type-2) Diabetes and Related Disorders, such as hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its 30 sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nepHropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, foot ulcerations and unlcerative colitis, altered gastrointestinal motility, Syndrome X, ovarian hyperandrogenism, polycystic ovarian
  • Syndrome X also known as Metabolic Syndrome
  • obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk, growth hormone deficiency, neutropenia, neuronal disorders, tumor invasion and metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH), and sperm motility/male contraception.
  • BPH benign prostatic hypertrophy
  • the DPP-IV inhibiting compounds of the present invention are useful for the prevention, delay of progression or the treatment of an early cardiac or early cardiovascular diseases or damages, renal diseases or damages, heart Failure, or heart Failure associated diseases like (i) cardiovascular diseases or damages e.g.
  • cardiac hypertrophy cardiac remodelling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or in hypertrophic cardiomyopathy
  • cardiomyopathy such as dilated cardiomyopathy or hypertrophic cardiomyopathy, mesanglial hypertrophy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic and/or systolic dysfunction, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic medial thickening in arteries and/or large vessels, mesenteric vasculature hypertrophy or artherosclerosis, preferably artherosclerosis in mammalian patients with hypertension of diabetes; (ii) renal diseases or damages like renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nepHrosclerosis, hypertens
  • the DPP-IV inhibiting compounds of the present invention are used for the prevention, the delay of the onset, the delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability
  • the (i) neurodegenerative disorder is dementia, senile dementia, schizopHrenia, mild cognitive impairment, Alzheimer related dementia, Huntington's chores, tardive dyskinesia, hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve and brain trauma, vascular amyloidosis, cerebral haemorrhage I with amyloidosis, brain inflammation, Friedrich ataxia, acute confusion disorders, acute confusion disorders with apoptotic necrocytosis, amyotrophic lateral sclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorders like cognitive deficits associated with schizopHrenia, age-induced memory impairment, cognitive deficits associated
  • the DPP-IV inhibiting compounds of the present invention are used for stimulating an immune response in a subject having or at risk of having cancer
  • the cancer is selected from the group consisting of basal cell carcinomas including cancers of the binary tract, bladder, urinary system, bone, brain, breast, cervical, endometrial, ovarian, uterine, choriocarcinoma, central nervous system, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, esophageal, gastric, stomach, larynx, liver, pancreatic, colorectal, renal cancers; cancers of the urinary system; cancers of eye, head and neck, oral cavity, skin, prostate; cancers of biliary tract, testicular, thyroid; intra-epithelial neoplasm, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; and other cancers of the respiratory system, lung, small cell lung, non-
  • the DPP-IV inhibiting compounds of the present invention are useful for the treatment or prophylaxis of chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
  • chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
  • the DPP-IV inhibiting compounds of the present invention may be useful in the treatment of pain, neuropathic pain, rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalian patients undergoing surgery, chronic pain in advanced cancer, treatment of refractory diarrhea, biliary pain caused by gallstones.
  • the DPP-IV inhibiting compounds of the present invention are useful for the treatment of mammalian patients undergoing islet/pancreas transplantation, for the prevention or the delay of transplant rejection, or allograft rejection in transplantation, for improving pancreatic function by increasing the number and size of pancreatic beta-cells in the treatment of Type 1 diabetes patients, and for improving pancreatic function by increasing the number and size of pancreatic beta-cells in general.
  • the DPP-IV inhibiting compounds of the present invention are useful for the treatment of mammalian patients with acne, skin disorders (e.g. pigmentation disorders or psoriasis), scleroderma, mycoses; anxiety, anxiety neurosis, major depression disorder, drug abuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea; anorexia nervosa; epilepsy; migrane; encephalomyelitis; osteoarthritis, osteoporosis, calcitonin-induced osteoporosis; male and female sexual dysfunction, infertility; Type 1 diabetes; immunosuppression, HIV infection; hematopoiesis, anemia; and for weight reduction.
  • skin disorders e.g. pigmentation disorders or psoriasis
  • scleroderma mycoses
  • anxiety anxiety neurosis
  • major depression disorder drug abuse
  • alcohol addiction insomnia
  • chronic fatigue sleep apnea
  • anorexia nervosa epilepsy
  • the DPP-IV inhibiting compounds of the present invention are useful for the prevention, delay of progression or treatment of (i) bacterial infections from Escherichia coli, Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficile infection, Legionella, Pneumococcus, HaemopHilus, Klebsiella, Enterobacter, Citrobacter, Neisseria, Shigella, Salmonella, Listeria, Pasteurella, Streptobacillus, Spirillum, Treponema, Actinomyces, Borrelia, Corynebacterium, Nocardia, Gardnerella, Campylobacter, Spirochaeta, Proteus, Bacteriodes, Helicobacter pylori , and anthrax infection; (ii) mycobacterial infection from tuberculosis and leprosy; (iii) viral infection from HIV, Herpes simplex virus 1, Herpes simplex virus 2,
  • the compounds from this invention are suitable for oral, sublingual, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient.
  • parenteral including subcutaneous, intramuscular, and intravenous
  • ocular ophthalmic
  • pulmonary aserosol inhalation
  • nasal administration although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient.
  • the compounds from this invention are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the DPP-IV inhibiting compounds of the present invention are synthesized by the general method shown in Schemes 1-14.
  • bromotoluene derivatives were treated with n-butyllithium and heated, followed by treatment with dry-ice in an appropriate solvent to afford the desired compound.
  • the acid can be prepared by Grignard reaction followed by treatment with dry-ice in an appropriate solvent. Esterification of the compound followed by NBS bromination and subsequent conversion to the phosphonium salt in a suitable solvent and heating affords the desired compound.
  • Wittig reaction of the phosphonium salt with a suitable aldehyde in an appropriate solvent and heating, followed by saponification of the ester moiety and subsequent catalytic hydrogenation affords the desired compound. Cyclisation of the compound with polyphosphoric acid in sulfolane and heating affords the desired compound after purification.
  • R 1 ⁇ COOMe the tricyclic product from the polyphosphoric acid step was treated with thionylchloride in an alcohol. Reduction of the ketone with a metal hydride in an appropriate solvent yields the compound after purification. Treatment of the alcohol with thionylchloride in a suitable solvent affords the final desired compound.
  • bromotoluene derivatives are treated with Magnesium in a Grignard reaction followed by treatment with dry-ice in an appropriate solvent to yield the desired acid. This acid is then treated with sec-butyllithium in an appropriate solvent at lower temperature. The anion is added at lower temperature to a solution of a commercially available benzylchloride in an appropriate solvent to afford the desired compound. Cyclisation of the compound with polyphosphoric acid in sulfolane and heating affords the desired compound.
  • the tricyclic product from the polyphosphoric acid step with R 1 ⁇ R 2 ⁇ Cl was treated with KCN, a Pd-catalyst, a suitable ligand and a suitable base in an appropriate solvent to afford the dicyano compound, which was converted to the diacid by treatment with base in a suitable solvent.
  • Ester formation using thionylchloride in an alcohol and reduction of the ketone with a metal hydride in an appropriate solvent yields the compound after purification.
  • Treatment of the alcohol with thionylchloride in a suitable solvent affords the final desired compound.
  • prolinamide is treated with fumarylchloride in an appropriate solvent to afford the desired compound. This compound is then treated with oxalylchloride in dimethylformamide to afford the desired compound after purification.
  • the coupling product of prolinamide with fumarylchloride can be treated with trifluoroacetic acid anhydride in a suitable solvent to afford the desired compound. Ozonolysis of this compound at ⁇ 78° C. in a suitable solvent, followed by reductive workup affords the desired final compound as a mixture of the aldehyde and its methyl hemiacetal.
  • Substituted or unsubstituted tricyclic chlorides are treated in an appropriate solvent with an excess of suitable amines to afford the desired product after purification.
  • the reaction product contains additional amino protecting groups like Boc, they are cleaved by acid treatment to afford the desired compound.
  • Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative yields the final desired product after purification.
  • the amines are treated with a suitable aldehyde (D-CHO) via reductive amination to afford the final compound after purification.
  • Substituted or unsubstituted tricycles containing a nitrogen at the doubly benzylic position are treated with bromoacetylbromide and heated to afford the desired compounds. Treating these compounds with sodium azide or sodium cyanide in a suitable solvent and heating affords the desired azido or cyano compounds after purification. Catalytic hydrogenation or reduction with Lithium aluminium hydride in a suitable solvent affords the desired amine compounds. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative yields the final desired product after purification.
  • Substituted or unsubstituted tricyclic ketones with Y ⁇ C(R 4 ) ⁇ C(R 5 ) are treated with malonic acid at elevated temperatures to afford the desired product after purification. These compounds are converted to the corresponding amides by treatment with isobutylchloroformate and ammonia. The amides are then converted to the desired amine products with Y ⁇ C(R 4 ) ⁇ C(R 5 ) by reduction with lithium aluminium hydride or to the desired amine products with Y ⁇ C(R 4 R 5 )C(R 4 R 5 ) by reduction with lithium aluminium hydride followed by catalytic hydrogenation with a suitable catalyst. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired product after purification.
  • Treating tricyclic ketones in a Reformatskij reaction affords the desired product after purification.
  • Reduction with LiAlH 4 in a suitable solvent affords the alcohol products with R 3 ⁇ OH after purification.
  • Activation of one of the hydroxyl groups with sulfonylchlorides in a suitable solvent followed by treatment with NaN 3 affords the desired compounds after purification.
  • Reduction of the azide reaction products with a catalyst in a suitable solvent affords the desired amine compounds after purification.
  • Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired products after purification.
  • Treating the amines with R 3 ⁇ OH with acid in a suitable solvent yields the desired unsaturated amine products.
  • Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired products after purification.
  • Substituted or unsubstituted suberylchlorides are treated in a suitable solvent with a slight excess of AgCN and heated to afford the desired product after purification.
  • the nitrile containing compound is then treated with sodium hydride in a suitable solvent and heated.
  • the mixture is then treated at rt with a suitable dibromoalkene and heated to give an intermediate which after treatment with sodium azide or potassium phthalimide in an appropriate solvent and heating affords the desired compound after purification.
  • Treating the mixture after the addition of sodium hydride at rt with a suitable sulfamidate in an appropriate solvent affords the desired Teoc-protected compound after heating for several hours and subsequent purification.
  • the Teoc protecting group is removed by treatment with acid to afford the desired amine compounds.
  • the ester moieties are removed by treatment with base in an appropriate solvent to afford the desired dicarboxylic acid derivatives after purification.
  • a commercially available hydroxyl-proline derivative is treated with base and alkylated with allylbromide in an appropriate solvent to afford the allyl-protected amino acid after purification.
  • This compound is then treated at ⁇ 30° C. with an appropriate base, triflic anhydride and then an appropriately protected diamino acid in an appropriate solvent to afford the desired compound after purification.
  • the compound is treated with EDCI and base in an appropriate solvent to afford the desired compound after purification. Cleavage of Fmoc protecting group by treatment with an suitable base affords the desired product.
  • the free amine is then treated in the presence of an suitable polymer supported base with sulfonyl chlorides, acid chlorides or isocyanates to afford the desired compounds after purification. Removal of the Boc-protecting group with acid in a suitable solvent affords the final desired compounds after purification.
  • the primary amine is treated in an appropriate solvent with aldehydes or ketones in a reductive amination reaction to afford the desired products.
  • the commercially available N-Boc-protected hydroxy amino acid ester can be treated with trifluoroacetic acid anhydride.
  • the nucleopHilic displacement reaction of the triflate with commercially available amines affords the desired products, after saponification of the ester moiety with base and purification.
  • These compounds are then treated with EDCl and a base in an suitable solvent to afford the cyclic amides after purification. These compounds are converted to the desired products by removing the Boc-protection group.
  • the commercially available bridged piperazine derivate is treated with a commercially available aziridine ester in an appropriate solvent to afford the desired compound after purification.
  • the desired product reacts in presence of a base with an acid chloride or sulfonic acid chloride to yield the desired products after purification.
  • the free acids are treated with EDCI in the presence of an appropriate base and a suitable amine derivative to afford the desired compounds after purification.
  • the Cbz-protecting group is then removed by treatment with TMSI and subsequent purification to afford the desired final compounds.
  • each of the structures of “B” bonds to the “A” structures on its left side and to the “D” structures on its right side as each is depicted below.
  • the compound A-B-D chooses an “A” which includes the following:
  • A is desirably
  • the “B” structures are chosen from:
  • B is one of structure (a), (b), (c), and (d). More desirably, B is structure (b)
  • the “D” structures are chosen from:
  • E, G, and M represent a three ring system wherein M shares two carbon atoms with each of E and G;
  • E and G are each independently selected from 6-membered aryl, 5-membered heteroaryl; 6-membered heteroaryl; a 5-7-membered saturated or partially saturated carbocyclic ring; and a 5-7 membered saturated or partially saturated heterocyclic ring; desirably E and G are substituted phenyl; M is a 5-7-membered saturated or partially saturated carboxylic or heterocyclic ring, or a 5-6-membered aromatic or heteroaromatic ring.
  • E may be substituted with one or more R 1 groups
  • G may be substituted with one or more R 2 groups
  • X and Y are divalent and are each independently: a bond, CR 4 R 5 , O, NR 4 , S, S ⁇ O, S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), S( ⁇ O) 2 N(R 4 ), C ⁇ N—OR 4 , —C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 )NR 4 —, —C(R 4 R 5 )O—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4 )—, —(C ⁇ NR a )—, N(C ⁇ O)NR 4 NR 5 , N(C ⁇ O)R 4 , N(C ⁇ O)OR 4 , NS( ⁇ O) 2 NR 4 NR 5 ,
  • R 1 and R 2 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O
  • R 3 is absent or is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R 3 is absent or is —H, —OH, —CO 2 H, —CN, —CONR 4 R 5 , R 5 , aryl, NH(C ⁇ O)R 4 , NH(SO 2 )R 4 , heteroaryl —SO 3 H, —PO 3 H 2 , —CONR 4 R 5 , R 5 , aryl, NH(C ⁇ O)R 4 , or NH(SO 2 )R 4 , and more desirably, R 3 is —CONR 4 R 5 or tetrazolyl.
  • R a is hydrogen, CN, NO 2 , alkyl, haloalkyl, S(O) t NR 4 R 5 , S(O) t R 4 , C(O)OR 4 , C(O)R 4 , or C(O)NR 4 R 5 ;
  • each occurrence of R 4 , R 5 , R 20 and R 21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R 4 and R 5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may optionally contain a heteroatom selected from O, S, or NR 50 and the 3- to 8-membere
  • R 50 is, in each occurrence, R 20 , CN, NO 2 , S(O) t NR 20 R 21 , S(O) t R 20 , C(O)OR 20 , C(O)R 20 C( ⁇ NR a )NR 20 R 21 , C( ⁇ NR 20 )NR 21 R a , C( ⁇ NOR 20 )R 21 or C(O)NR 20 R 21 ;
  • each occurrence of R 7 and R 8 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl
  • R 9 is H or C 1-6 alkyl, desirably H.
  • R 10 is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (CO—C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (CO—C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C
  • R 11 and R 12 are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C( ⁇ NR a )NHR 4 , (C 0 -C 6 )-alkyl-C( ⁇ NR 4 )NHR a , (CO—C 6 )-alkyl-NR 4 C( ⁇ NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4
  • R 13a and R 13b are each independently R 5 or together are ⁇ O;
  • R 14a and R 14b are each independently R 5 or together are ⁇ O;
  • R 13c and R 14c are each independently R 5 ;
  • Q a is CH or N
  • Q b is CH or N
  • U is —C(O)—, —C( ⁇ NR 4 )—, —(CR 4 R 5 —) p , NR 50 , S( ⁇ O) 2 , C( ⁇ O), (C ⁇ O)N(R 4 ), N(R 4 )(C ⁇ O), S( ⁇ O) 2 N(R 4 ), N(R 4 )S( ⁇ O) 2 , C ⁇ N—OR 4 , —C(R 4 ) ⁇ C(R 5 )—, —C(R 4 R 5 ) p NR 50 —, N(R 50 )C(R 4 R 5 ) p —, —O—C(R 4 R 5 )—, —C(R 4 R 5 )S( ⁇ O) t —, —(C ⁇ O)O—, —(C ⁇ NR a )N(R 4 )—, —(C ⁇ NR a )—, N(C ⁇ O)NR 4 NR 5 , N(C ⁇
  • W is —CH 2 —, —S—, —CHF— or —CF 2 —;
  • Z is C or N
  • n 1, or 2;
  • n 0, 1, or 2;
  • p 0 to 6;
  • t 0, 1, or 2.
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures, diasteromeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, tautomers, atropisomers, and rotamers, with all isomeric forms being included in the present invention.
  • Compounds described in this invention containing olefinic double bonds include both E and Z geometric isomers.
  • Also included in this invention are all salt forms, polymorphs, hydrates and solvates. All of the above mentioned compounds are included within the scope of the invention.
  • the DPP-IV inhibition activity of the DPP-IV inhibitor compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring DPP-IV inhibitor activity is described.
  • prolinamide (5 g) was first treated with bromacetylbromide (4.2 ml) in CH 2 Cl 2 and then with trifluoracetic acid anhydride in CH 2 Cl 2 as described in WO 98/19998 to afford the title compound (7.85 g; 83%).
  • 1 HNMR ⁇ (CDCl 3 ) 2.05-2.40 (m, 4H), 3.51-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.70-4.86 (m, 1H).
  • L-prolinamide 25 g was dissolved in CH 2 Cl 2 (1200 ml) and triethylamine (30 ml) and 4-dimethylaminopyridine (1.9 g) added. The mixture was cooled to 0° C. and treated with fumaryl chloride (11.7 ml). The dark mixture was stirred at rt for 16 h and cooled to 0° C. TFAA (77 ml) was added dropwise under stirring and the solution allowed to warm to rt over 6 hours. The reaction mixture was stirred at rt for 1 to 2 days. Ice (500 g) was added followed by cautious addition of sat. NaHCO 3 (600 ml).
  • step E The title compound of step E (370 mg) above was dissolved in toluene (5 ml) and cooled to ⁇ 15° C. Thionyl chloride (286 mg) was slowly added and the reaction was allowed to come to RT and run overnight. The solution was neutralized with triethylamine and directly used in the next step.
  • the dark filtrate was poured into a separatory funnel and the phases were separated with the aid of additional Et 2 O (100 ml).
  • the aqueous phase was extracted with Et 2 O/CHCl 3 1:1 (2 ⁇ 100 ml).
  • the combined organic phases were washed with 10% NH 4 OH solution (4 ⁇ 110 ml, until the basic phase was no longer blue), with H 2 O (100 ml), and brine (100 ml).
  • the organic phase was separated, dried over MgSO 4 and concentrated.
  • the residue was mixed with NaOH (24.8 g) and diethylene glycol (275 ml) was added together with a few drops of H 2 O. The mixture was heated at 215-220° C. overnight.
  • the bromoethyl compound (1.42 g) was dissolved in anhydrous DMF (18 ml) and treated with potassium phthalimide (1.96 g). The suspension was stirred at 80° C. overnight. The solvent was removed and the residue partitioned between EtOAc (50 ml), H 2 O (50 ml) and brine (50 ml).
  • Step D If one were to follow a similar procedure as described in Preparative Example 54, but using 3-fluorobenzaldehyde in Step A and omitting Step D, one would obtain the desired compound.
  • hydroxylamine hydrochloride (401 mg) was suspended in anhydrous MeOH (14 ml) and a 5.5 M solution of sodium methoxide in MeOH (0.946 ml) added. This mixture was stirred at rt for 45 min and the title compound from Preparative Example 61 Step A (1400 mg) was added. The resulting mixture was heated in a closed vessel at 100° C. overnight and subsequently allowed to cool down to rt. Due to incomplete conversion, hydroxylamine hydrochloride (401 mg) and a 5.5 M solution of sodium methoxide in MeOH (0.946 ml) were added and the mixture was heated again at 100° C. for 20 h.
  • N-hydroxyamidine product from Preparative Example 66 Step A (300 mg) was dissolved in anhydrous dichloromethane (5 ml), the solution cooled down to 0° C. and triethylamine (147 ⁇ l) and trifluoroacetic anhydride (103 ⁇ l) added. The reaction mixture was stirred at rt overnight. Due to incomplete conversion, triethylamine (221 ⁇ l) and trifluoroacetic anhydride (155 ⁇ l) were added at 0° C. and stirring was continued at rt for 3 d. Dichloromethane (9 ml) and water (10 ml) were added to the stirred mixture.
  • Tosylmethyl isocyanide was dissolved in DMSO (10 ml) under N 2 at 10° C. and KOtBu (1.36 g) was added. The mixture was stirred for 5 min and MeOH (0.173 ml) was added. The title compound from Step B above (0.8 g) was immediately added to the mixture. After 10 min dibromoethane (1.51 ml) was added and stirring was continued for 1 h at rt. The mixture was diluted with EtOAc (10 ml) and sat. NH 4 Cl (30 ml) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (2 ⁇ 50 ml).
  • N-cyclohexylcarbodiimde-N′-methyl polystyrene resin (1.9 g) was suspended in 5 ml dichloromethane and agitated for 5 Min.
  • the mixture was agitated for 16 h, filtered and the resin washed with 2 ⁇ 5 ml dichloromethane and 5 ml methanol.
  • the combined filtrates were concentrated and the residue purified by flash chromatography (silica, CH 2 Cl 2 /MeOH, 9:1) to afford the title compound (500 mg; 91%).
  • Example numbers 336-399 were intentionally excluded.
  • Example numbers 435-499 were intentionally excluded.
  • Example numbers 536-599 were intentionally excluded.
  • Step A Step B Product 601 300 CH 3 NH 2 NH 3 602 300 NH 3 603 300 NH 3 604 61 NH 3 NH 3 605 61 CH 3 NH 2 NH 3 606 61 NH 3 607 61 NH 3 608 65 NH 3 NH 3 609 65 CH 3 NH 2 NH 3 610 65 NH 3 611 65 NH 3 612 300 NH 3 CH 3 NH 2 613 300 CH 3 NH 2 CH 3 NH 2 614 300 CH 3 NH 2 615 300 CH 3 NH 2 616 61 NH 3 CH 3 NH 2 617 61 CH 3 NH 2 CH 3 NH 2 618 61 CH 3 NH 2 619 61 CH 3 NH 2 620 65 NH 3 CH 3 NH 2 621 65 CH 3 NH 2 CH 3 NH 2 622 65 CH 3 NH 2 623 65 CH 3 NH 2 624 300 NH 3 (CH 3 ) 2 NH 625 300 CH 3 NH 2 (CH 3 ) 2 NH 625 300 CH
  • Example numbers 636-679 were intentionally excluded.
  • Example numbers 688-699 were intentionally excluded.
  • Example numbers 736-779 were intentionally excluded.
  • Example numbers 789-799 were intentionally excluded.

Abstract

The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • This application is a continuation of U.S. application Ser. No. 11/409,481, filed Apr. 21, 2006, now U.S. Pat. No. 7,553,861, the entire contents of which are incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to pyrrolidine and thiazolidine-based inhibitors of dipeptidyl peptidase-IV (DPP-IV) and to methods for treating diabetes, particularly Type-2 diabetes as well as impaired glucose tolerance, impaired glucose homeostasis and complications associated with diabetes by inhibiting DPP-IV with such cyclic amido and cyclic ureido pyrrolidine and thiazolidine inhibitors.
    • BACKGROUND OF THE INVENTION
  • Diabetes results from the occurrence of one or more of several causative factors, and is characterized by an abnormal elevation in levels of plasma glucose (hyperglycemia). Persistent or uncontrolled hyperglycemia results in an increased probability of premature morbidity and mortality. Abnormal glucose homeostasis is usually associated with changes in the lipid, lipoprotein and apolipoprotein metabolism, or due to other metabolic and hemodynamic diseases.
  • Patients afflicted with Type-2 diabetes mellitus or noninsulin dependent diabetes mellitus (NIDDM), are especially at increased risk of suffering from macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nepHropathy, neuropathy and retinopathy. Therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critical in the clinical management and treatment of Type-2 diabetes mellitus.
  • The currently available therapeutics for treating available Type-2 diabetes, although effective, have recognized limitations. Compounds based on sulfonylureas (e.g. tolbutamide, glipizide, etc.), which stimulate the pancreatic beta-cells to secrete more insulin, are limited by the development of inhibitor resistant tissues, causing them to become inefficient or ineffective, even at high doses. Biguanide compounds, on the other hand, increase insulin sensitivity so as to cause correction of hyperglycemia to some extent. However, clinically used biguanides such as phenformin and metformin can induce side-effects such as lactic acidosis, nausea and diarrhea.
  • The more recent glitazone-type compounds (i.e. 5-benzylthiazolidine-2,4-diones) substantially increase insulin sensitivity in muscle, liver and adipose tissue resulting in either partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. Currently used glitazones are agonists of the peroxisome proliferator activated receptor (PPAR), which is attributed to be responsible for their improved insulin sensitization. However, serious side effects (e.g. liver toxicity) have been known to occur with some glitazones such as, for example, troglitazone. Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-IV”, “DPP-4” or “DP-IV”) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type-2 diabetes. See for example, WO 97/40832, WO 98/19998, and U.S. Pat. No. 5,939,560.
  • DPP-IV is a membrane bound non-classical serine aminodipeptidase which is located in a variety of tissues (intestine, liver, lung, kidney) as well as on circulating T-lymphocytes (where the enzyme is known as CD-26). It is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (e.g. GHRH, NPY, GLP-2, VIP) in vitro.
  • The usefulness of DPP-IV inhibitors in the treatment of Type-2 diabetes is based on the fact that DPP-IV in vivo readily inactivates glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-1(7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-1(7-36) are expected to be beneficial in the prevention and treatment of Type-2 diabetes, and potentially obesity. To support this claim, exogenous administration of GLP-1(7-36) (continuous infusion) in diabetic patients has demonstrated efficacy in this patient population. GLP-1(7-36) is degraded rapidly in vivo and has been shown to have a short half-life in vivo (t1/2 of about 1.5 min). Based on a study of genetically bred DPP-IV KO mice and on in vivo/in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-1(7-36) in vivo. GLP-1(7-36) is degraded by DPP-IV efficiently to GLP-1(9-36), which has been speculated to act as a physiological antagonist to GLP-1(7-36). Inhibition of DPP-IV in vivo should, therefore, potentiate endogenous levels of GLP-1(7-36) and attenuate formation of its antagonist GLP-1(9-36) and serve to ameliorate the diabetic condition.
  • GLP-1 and GIP are incretins that are produced upon ingestion of food, and which stimulate production of insulin. Inhibition of DPP-IV causes decreased inactivation of the incretins, which in turn, results in an increase in their effectiveness in stimulating pancreatic production of insulin. DPP-IV inhibition therefore, results in an increase in the level of serum insulin. Since the incretins are produced upon consumption of food only, DPP-IV inhibition is not expected to increase insulin levels when not required, thereby precluding excessive lowering of blood sugar (hypoglycemia). Inhibition of DPP-IV, is therefore, is expected to increase insulin levels without increasing the risk of hypoglycemia, thereby lowering deleterious side effects associated with currently used insulin secretagogues. Although DPP-IV inhibitors have not been studied extensively as therapeutics for diseases other than diabetes, they are expected to have other potential therapeutic utilities.
    • SUMMARY OF THE INVENTION
  • The present invention relates to a class of pyrrolidine-based inhibitors of dipeptidyl peptidase-IV (DPP-IV). In particular, the present invention provides a new class of pyrrolidine and thiazolidine DPP-IV inhibiting compounds (“DPP-IV inhibitors”).
  • One aspect of the present invention includes a compound of formula (I):

  • A-B-D  (I)
  • and all stereoisomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof and all polymorphs; wherein A is:
  • Figure US20100009961A1-20100114-C00001
    Figure US20100009961A1-20100114-C00002
  • wherein
  • E and G are independently 6-membered aryl, or 5-membered heteroaryl or 6-membered heteroaryl;
  • E may be substituted with one or more R1 groups;
  • G may be substituted with one or more R2 groups;
  • X and Y are divalent and are each independently: a bond, CR4R5, O, NR4, S, S═O, S(═O)2, C(═O), (C═O)N(R4), S(═O)2N(R4), C═N—OR4, —C(R4R5)C(R4R5)—, —C(R4R5) C(R4R5)C(R4R5)—, —C(R4R5)C(R4R5)C(R4R5)C(R4R5)—, —C(R4)═C(R5)—, —C(R4R5)NR4—, —C(R4R5)O—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, NS(═O)2R4; or aryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may be optionally substituted;
  • R1 and R2 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all of which may be optionally substituted;
  • R3 is absent or is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocyclyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all of which may be optionally substituted;
  • Ra is hydrogen, CN, NO2, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, or C(O)NR4R5; each occurrence of R4, R5, R20 and R21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may optionally contain a heteroatom selected from O, S, or NR50 and the 3- to 8-membered ring may be optionally substituted;
  • R50 is, in each occurrence, R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(═NRa)NR20R21, C(═NR20)NR21Ra, C(═NOR20)R21 or C(O)NR20R21;
  • each occurrence of R7 and R8 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C1-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • R9 is H or C1-6 alkyl;
  • R10 is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C1-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, B(OH)2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • R11 and R12 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • R13a and R13b are each independently R5 or together are ═O;
  • R14a and R14b are each independently R5 or together are ═O;
  • R13c and R14c are each independently R5;
  • Qa is CH or N;
  • U is —C(O)—, —C(═NR4)—, —(CR4R5—)p, NR50, S(═O)2, C(═O), (C═O)N(R4), N(R4)(C═O), S(═O)2N(R4), N(R4)S(═O)2, C═N—OR4, —C(R4)═C(R5)—, —C(R4R5)pNR50—, N(R50)C(R4R5)p, —O—C(R4R5)—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR NR5, N(C═O)R4, N(C═O)ORa, NS(═O)2NR4NR4, NS(═O)2R4, or an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may be optionally substituted;
  • W is —CH2—, —S—, —CHF— or —CF2—;
  • Z is C or N;
  • m is 1, or 2;
  • n is 0, 1, or 2;
  • p is 0 to 6;
  • q is 0 to 6; and
  • t is 0, 1, or 2.
  • Another aspect of the present invention includes a method of preparing a compound of the following formula:
  • Figure US20100009961A1-20100114-C00003
  • comprising (a) coupling prolinamide with fumarylchloride to provide a compound of the following formula:
  • Figure US20100009961A1-20100114-C00004
  • (b) dehydrating the carboxamides of the compound from step (a) to cyano to provide a compound of formula:
  • Figure US20100009961A1-20100114-C00005
  • and (c) cleaving the C═C bond with an oxidizing agent either: (1) in the presence of methanol, and then adding a reducing agent to the reaction mixture, or (2) and reacting the cleavage products with a reducing agent and subsequently adding methanol to the cleavage product mixture.
  • A further aspect of the present invention provides a method of preparing a compound of the following formula:
  • Figure US20100009961A1-20100114-C00006
  • comprising: (a) coupling a compound of formula:
  • Figure US20100009961A1-20100114-C00007
  • with fumaryl chloride to provide a compound of formula
  • Figure US20100009961A1-20100114-C00008
  • (b) dehydrating the carboxamide in the compound from step (a) to provide a compound of formula:
  • Figure US20100009961A1-20100114-C00009
  • and (c) cleaving the C═C bond with an oxidizing agent either: (1) in the presence of methanol, and then adding a reducing agent to the reaction mixture, or (2) and reacting the cleavage products with a reducing agent and subsequently adding methanol to the cleavage product mixture.
  • Another aspect of the present invention provides a compound of formula A compound of formula (I):

  • A-B-D  (I)
  • wherein A is:
  • Figure US20100009961A1-20100114-C00010
  • B is:
  • Figure US20100009961A1-20100114-C00011
  • and
  • D is:
  • Figure US20100009961A1-20100114-C00012
  • wherein
  • E and G are independently selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, and 5-6-membered saturated or partially saturated carbocyclic or heterocyclic rings;
  • E may be substituted with one or more R1 groups;
  • G may be substituted with one or more R2 groups;
  • R1 and R2 are independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • R3 is absent or is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • Ra is hydrogen, CN, NO2, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, or C(O)NR4R5;
  • each occurrence of R4, R5, R20 and R21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may be optionally containing a heteroatom selected from O, S, or NR50 and the 3- to 8-membered ring may be optionally substituted;
  • R50 is, in each occurrence, R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(═NRa)NR20R21, C(═NR20)NR21Ra, C(═NOR20)R21 or C(O)NR20R21;
  • each occurrence of R7 and R8 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C1-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R9 is H or C1-6alkyl;
  • R10 is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, B(OH)2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R11 and R12 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (CO—C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R13a and R13b are each independently R5 or together are ═O;
  • R14a and R14b are each independently R5 or together are ═O;
  • R13c and R14c are each independently R5;
  • Qa is CH or N;
  • U is —C(O)—, —C(═NR4)—, —(CR4R5—)p, NR50, S(═O)2, C(═O), (C═O)N(R4), N(R4)(C═O), S(═O)2N(R4), N(R4)S(═O)2, C═N—OR4, —C(R4)═C(R5)—, —C(R4R5)pNR50—, N(R50)C(R4R5)p—, —O—C(R4R5)—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, NS(═O)2R4, or an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may be optionally substituted;
  • W is —CH2—, —S—, —CHF— or —CF2—;
  • Z is C or N;
  • m is 1, or 2;
  • n is 0, 1, or 2;
  • p is 0 to 6;
  • q is 0 to 6; and
  • t is 0, 1, or 2
  • wherein: when E and G are both phenyl either:
  • (1) at least one of R1 or R2 is present and is:
  • CF3, COR4, OR4, NR4R5, NO2, CN, SO20R4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, (C5-20)alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted; and wherein OR4 is alkoxy, OR4 is (C5-20) alkoxy; or (2) and when B is (b) R7 and R8 are not selected from hydrogen, hydroxy, hydroxymethyl, and phenyl; or (3) and when B is (b) or (f), R9 is: C1-6 alkyl.
  • Another aspect of the present invention provides a compound of formula A compound of formula (I):

  • A-B-D  (I)
  • wherein A is:
  • Figure US20100009961A1-20100114-C00013
    • B is:
  • Figure US20100009961A1-20100114-C00014
  • and
  • D is:
  • Figure US20100009961A1-20100114-C00015
  • wherein
  • E, G, and M include a three ring system wherein M shares two carbon atoms with each of E and G;
  • E, G and M are each independently selected from a 5-7-membered saturated or partially saturated carbocyclic ring, a 5-7 membered saturated or partially saturated heterocyclic ring, a 5-6-membered aromatic ring, and a 5-6-membered heteroaromatic ring;
  • E may be substituted with one or more R1 groups;
  • G may be substituted with one or more R2 groups;
  • R1 and R2 are independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • R3 is absent or is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O) t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted;
  • Ra is hydrogen, CN, NO2, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, or C(O)NR4R5;
  • each occurrence of R4, R5, R20 and R21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may be optionally containing a heteroatom selected from O, S, or NR50 and the 3- to 8-membered ring may be optionally substituted;
  • R50 is, in each occurrence, R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(═NRa)NR20R21, C(═NR20)NR21Ra, C(═NOR20)R21 or C(O)NR20R21;
  • each occurrence of R7 and R8 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R9 is H or C1-6 alkyl;
  • R10 is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(CO—C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, B(OH)2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R11 and R12 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (CO—C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R13a and R13b are each independently R5 or together are ═O;
  • R14a and R14b are each independently R5 or together are ═O;
  • R13c and R14c are each independently R5;
  • Qa is CH or N;
  • U is —C(O)—, —C(═NR4)—, —(CR4R5—)p, NR50, S(═O)2, C(═O), (C═O)N(R4), N(R4)(C═O), S(═O)2N(R4), N(R4)S(═O)2, C═N—OR4, —C(R4)═C(R5)—, —C(R4R5)pNR50—, N(R50)C(R4R5)p—, —O—C(R4R5)—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, NS(═O)2R4, or an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may be optionally substituted;
  • W is —CH2—, —S—, —CHF— or —CF2—;
  • Z is C or N;
  • m is 1, or 2;
  • n is 0, 1, or 2;
  • p is 0 to 6;
  • q is 0 to 6; and
  • t is 0, 1, or 2
  • wherein: when E and G are both phenyl either:
  • (1) at least one of R1 or R2 is present and is:
  • CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (CO—C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, (C5-20)alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted; and wherein OR4 is alkoxy, OR4 is (C5-20) alkoxy; or (2) and when B is (b) R7 and R8 are not selected from hydrogen, hydroxy, hydroxymethyl, and phenyl; or (3) and when B is (b) or (f), R9 is: C1-6 alkyl.
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures, diasteromeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, tautomers, atropisomers, and rotamers, with all isomeric forms being included in the present invention. Compounds described in this invention containing olefinic double bonds include both E and Z geometric isomers. Also included in this invention are all salt forms, polymorphs, hydrates and solvates. All of the above mentioned compounds are included within the scope of the invention.
  • The present invention also provides methods of inhibiting the DPP-IV enzyme.
  • The present invention further provides methods of treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type-2 diabetes.
  • The present invention also provides methods for obtaining the DPP-IV inhibiting compounds and pharmaceutical compositions comprising them either singly or in combination with one or more additional therapeutic agents for the prevention or treatment of DPP-IV enzyme medicated diseases, particularly Type-2 diabetes.
    • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((R4)(R5)N—CO— wherein R4 or R5 are as defined below, except that at least one of R4 or R5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
  • The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (—O—).
  • The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((R4)(R5)N—CO— wherein R4 or R5 are as defined below, except that at least one of R4 or R5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((R4)(R5)N—CO— wherein R4 or R5 are as defined below, except that at least one of R4 or R5 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
  • The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, including bridged ring systems, desirably containing 1 to 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
  • The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
  • Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
  • “Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulpHur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contents all of which are incorporated by reference herein. Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
  • “Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein. The nitrogen or sulpHur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • “Heterocyclyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • “Heteroaryl” denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, morpholino, oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.
  • The term “amino” denotes the radical —NH2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
  • The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
  • The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above.
  • The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
  • The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
  • The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
  • The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
  • The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above.
  • The pHrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
  • The pHrase “tricyclic fused ring system wherein at least one ring is partially saturated” denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
  • The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • The pHrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
  • Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from, but not limited to:
  • C1-C4 alkyl;
  • C2-C4 alkenyl;
  • C2-C4 alkynyl;
  • CF3;
  • halo;
  • OH;
  • O—(C1-C4 alkyl);
  • OCH2F;
  • OCHF2;
  • OCF3;
  • COCF3;
  • OC(O)—(C1-C4 alkyl);
  • OC(O)NH—(C1-C4 alkyl);
  • OC(O)N(C1-C4 alkyl)2;
  • OC(S)NH—(C1-C4 alkyl);
  • OC(S)N(C1-C4 alkyl)2;
  • ONO2;
  • SH;
  • S—(C1-C4 alkyl);
  • S(O)—(C1-C4 alkyl);
  • S(O)2—(C1-C4 alkyl);
  • SC(O)—(C1-C4 alkyl);
  • SC(O)O—(C1-C4 alkyl);
  • NH2;
  • N(H)—(C1-C4 alkyl);
  • N(C1-C4 alkyl)2;
  • N(H)C(O)—(C1-C4 alkyl);
  • N(CH3)C(O)—(C1-C4 alkyl);
  • N(H)C(O)—CF3;
  • N(CH3)C(O)—CF3;
  • N(H)C(S)—(C1-C4 alkyl);
  • N(CH3)C(S)—(C1-C4 alkyl);
  • N(H)S(O)2—(C1-C4 alkyl);
  • N(H)C(O)NH2;
  • N(H)C(O)NH—(C1-C4 alkyl);
  • N(CH3)C(O)NH—(C1-C4 alkyl);
  • N(H)C(O)N(C1-C4 alkyl)2;
  • N(CH3)C(O)N(C1-C4 alkyl)2;
  • N(H)S(O)2NH2);
  • N(H)S(O)2NH—(C1-C4 alkyl);
  • N(CH3)S(O)2NH—(C1-C4 alkyl);
  • N(H)S(O)2N(C1-C4 alkyl)2;
  • N(CH3)S(O)2N(C1-C4 alkyl)2;
  • N(H)C(O)O—(C1-C4 alkyl);
  • N(CH3)C(O)O—(C1-C4 alkyl);
  • N(H)S(O)2O—(C1-C4 alkyl);
  • N(CH3)S(O)2O—(C1-C4 alkyl);
  • N(CH3)C(S)NH—(C1-C4 alkyl);
  • N(CH3)C(S)N(C1-C4 alkyl)2;
  • N(CH3)C(S)O—(C1-C4 alkyl);
  • N(H)C(S)NH2;
  • NO2;
  • CO2H;
  • CO2—(C1-C4 alkyl);
  • C(O)N(H)OH;
  • C(O)N(CH3)OH:
  • C(O)N(CH3)OH;
  • C(O)N(CH3)O—(C1-C4 alkyl);
  • C(O)N(H)—(C1-C4 alkyl);
  • C(O)N(C1-C4 alkyl)2;
  • C(S)N(H)—(C1-C4 alkyl);
  • C(S)N(C1-C4 alkyl)2;
  • C(NH)N(H)—(C1-C4 alkyl);
  • C(NH)N(C1-C4 alkyl)2;
  • C(NCH3)N(H)—(C1-C4 alkyl);
  • C(NCH3)N(C1-C4 alkyl)2;
  • C(O)—(C1-C4 alkyl);
  • C(NH)—(C1-C4 alkyl);
  • C(NCH3)—(C1-C4 alkyl);
  • C(NOH)—(C1-C4 alkyl);
  • C(NOCH3)—(C1-C4 alkyl);
  • CN;
  • CHO;
  • CH2OH;
  • CH2O—(C1-C4 alkyl);
  • CH2NH2;
  • CH2N(H)—(C1-C4 alkyl);
  • CH2N(C1-C4 alkyl)2;
  • aryl;
  • heteroaryl;
  • cycloalkyl; and
  • heterocyclyl.
  • The term “cleave” or “cleaving” means splitting a complex molecule into at least two separate molecules. “Cleavage products” are the separate molecules which result from cleaving.
  • The term “metabolite” refers to a composition which results from a metabolic process. Examples of the results of metabolism on the compounds of the present invention include addition of —OH, hydrolysis, and cleavage.
  • The term “polymorphs” refers to the various crystalline structures of the compounds of the present invention. This may include, but is not limited to, crystal morphologies (and amorphous materials), all crystal lattice forms, and all salts. Salts of the present invention can be crystalline and may exist as more than one polymorpH. Each polymorpH forms another aspect of the invention. Hydrates as well as anhydrous forms of the salt are also encompassed by the invention.
  • “Teoc” is 2-(trimethylsilyl)ethoxycarbonyl
  • “Et” is ethyl (—CH2CH3) or ethylene (—CH2CH2—).
  • “Me” is methyl (—CH3) or methylene (—CH2—).
  • “Boc” is tert-butyloxycarbonyl.
  • “PHCH2” is benzyl.
  • The term “pharmaceutically-acceptable tricyclic moiety” is meant to include, but is not limited to, benzocycloheptapyridyl, benzodiazepinyl, and benzozapinyl
  • In another embodiment of the present invention, the DPP-IV inhibiting compounds are used in the manufacture of a medicament for the treatment of a disease mediated by an DPP-IV enzyme.
  • In another aspect, the DPP-IV inhibiting compounds of the present invention are used in combination with another disease modifying drug. Examples of other disease modifying drugs include, but are not limited to: (a) other dipeptidyl peptidase IV (DPP-IV) inhibitors such as Vildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS); (b) insulin sensitizers including (i) PPARγ agonists such as the glitazones (e.g. troglitazone, pioglitazone, edaglitazone, rosiglitazone, and the like) and other PPAR ligands, including PPARα/γ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) incretin and incretin mimetics such as (i) Exenatide available from Amylin Pharmaceuticals, (i) amylin and amylin mimetics such as pramlintide acetate, available as Symlin®, (iii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists, (iv) GIP, GIP mimetics and GIP receptor agonists; (e) sulfonylureas and other insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, meglitinides, and repaglinide; (f) α-glucosidase inhibitors (such as acarbose and miglitol); (g) glucagon receptor antagonists; (h) PACAP, PACAP mimetics, and PACAP receptor agonists; (i) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants such as cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors such as avasimibe, and (viii) anti-oxidants such as probucol; (J) PPARδ agonists such as GW-501516 from GSK; (k) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentemine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, MTP inhibitors, squalene synthase inhibitor, lipoxygenase inhibitor, ACAT inhibitor, Neuropeptide Cannabinoid CB-1 receptor antagonists, CB-1 receptor inverse agonists and antagonists, fatty acid oxidation inhibitors, appetite suppressants (1) adrenergic receptor agonists, melanocortin receptor agonists, in particular—melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists; (m) ileal bile acid transporter inhibitors; (n) agents intended for use in inflammatory conditions such as aspirin, non steroidal anti-inflammatory drugs, glucocorticoids, azalfidine, and selective cyclooxygenase-2 inhibitors; (o) antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, fosinoprol, ramipril, spirapril, tandolapril), angiotensin-II (AT-1) receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan), beta blockers and calcium channel blockers; and (p) glucokinase activators (GKAs); (q) agents which can be used for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders or a drug for improving memory such as anti-inflammatory drugs, antioxidants, neuroprotective agents, glutamate receptor antagonists, acetylcholine esterase inhibitors, butyrylcholinesterase inhibitors, MAO inhibitors, dopamine agonists or antagonists, inhibitors of gamma and beta secretases, inhibitors of amyloid aggregation, amyloid beta peptide, antibodies to amyloid beta peptide, inhibitors of acetylcholinesterase, glucokinase activators, agents directed at modulating GABA, NMDA, cannabinoid, AMPA, kainate, phosphodiesterase (PDE), PKA, PKC, CREB or nootropic systems; (r) leukocyte growth promotors intended for the treatment and prevention of reduced bone marrow production, infectious diseases, hormone dependent disorders, inflammatory diseases, HIV, allergies, leukocytopenia, and rheumatism; (s) SGLT2 inhibitor; (t) glycogen phosphorylase inhibitor; (u) aP2 inhibitors; (v) aminopeptidase N inhibitor (w) vasopeptidase inhibitors like neprilysin inhibitors and/or ACE inhibitors or dual NEP/ACE inhibitor; (x) growth hormone secretagogue for enhancing growth hormone levels and for treating growth retardation/dwarfism or metabolic disorders or where the disorder is an injury, or a wound in need of healing, or a mammalian patient recovering from surgery; (y) 5-HT 3 or 5-HT 4 receptor modulators (tegaserod, cisapride, nor-cisapride, renzapride, zacopride, mosapride, prucalopride, buspirone, norcisapride, cilansetron, ramosetron, azasetron, ondansetron, etc.); (Za) aldose reductase inhibitors; (Zb) sorbitol dehydrogenase inhibitors; (Zc) AGE inhibitors; (Zd) erythropoietin agonist such as EPO, EPO mimetics, and EPO receptor agonists.
  • In a further aspect, the DPP-IV inhibiting compounds of the present invention are used in the treatment diseases or symptoms mediated by an DPP-IV enzyme. Examples of diseases or symptoms mediated by a DPP-IV enzyme include, but are not limited to, Type II (Type-2) Diabetes and Related Disorders, such as hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its 30 sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nepHropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, foot ulcerations and unlcerative colitis, altered gastrointestinal motility, Syndrome X, ovarian hyperandrogenism, polycystic ovarian syndrome, premenstrual syndrome, other disorders where insulin resistance is a component. In Syndrome X, also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk, growth hormone deficiency, neutropenia, neuronal disorders, tumor invasion and metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH), and sperm motility/male contraception.
  • In a further aspect, the DPP-IV inhibiting compounds of the present invention are useful for the prevention, delay of progression or the treatment of an early cardiac or early cardiovascular diseases or damages, renal diseases or damages, heart Failure, or heart Failure associated diseases like (i) cardiovascular diseases or damages e.g. cardiac hypertrophy, cardiac remodelling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or in hypertrophic cardiomyopathy, cardiomyopathy such as dilated cardiomyopathy or hypertrophic cardiomyopathy, mesanglial hypertrophy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic and/or systolic dysfunction, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic medial thickening in arteries and/or large vessels, mesenteric vasculature hypertrophy or artherosclerosis, preferably artherosclerosis in mammalian patients with hypertension of diabetes; (ii) renal diseases or damages like renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nepHrosclerosis, hypertensive nepHrosclerosis or mesanglial hypertrophy; (iii) Heart Failure to be treated is secondary to idiopathic dilated cardiomyopathy and/or coronary ischemic disease;
  • In another aspect, the DPP-IV inhibiting compounds of the present invention are used for the prevention, the delay of the onset, the delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability wherein the (i) neurodegenerative disorder is dementia, senile dementia, schizopHrenia, mild cognitive impairment, Alzheimer related dementia, Huntington's chores, tardive dyskinesia, hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve and brain trauma, vascular amyloidosis, cerebral haemorrhage I with amyloidosis, brain inflammation, Friedrich ataxia, acute confusion disorders, acute confusion disorders with apoptotic necrocytosis, amyotrophic lateral sclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorders like cognitive deficits associated with schizopHrenia, age-induced memory impairment, cognitive deficits associated with psychosis, cognitive impairment associated with diabetes, cognitive deficits associated with post-stroke, memory defects associated hypoxia, cognitive and attention deficits associated with senile dementia, attention deficits disorders, memory problems associated with mild cognitive impairment, impaired cognitice function associated with vascular dementia, cognitive problems associated with brain tumors, Pick's disease, cognitive deficits due to autism, cognitive deficits post electroconvulsive therapy, cognitive deficits associated with traumatic brain injury, amnesic disorders, deliriums, vitamin deficiency, dementias, impaired cognitive function associated with Parkinson's disease, attention-deficit disorders; (iii) prevention of memory impairment as a result of Alzheimer disease, Creutzfeld-Jakob disease, Pick disease, Huntington disease, AIDS, brain injury, brain aneurysm, epilepsy, stroke, toxicant exposure, mental retardation in children, Huntington's disease; (iv) to improve learning speed and potential in educational and rehabilitation contexts.
  • In another aspect, the DPP-IV inhibiting compounds of the present invention are used for stimulating an immune response in a subject having or at risk of having cancer wherein the cancer is selected from the group consisting of basal cell carcinomas including cancers of the binary tract, bladder, urinary system, bone, brain, breast, cervical, endometrial, ovarian, uterine, choriocarcinoma, central nervous system, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, esophageal, gastric, stomach, larynx, liver, pancreatic, colorectal, renal cancers; cancers of the urinary system; cancers of eye, head and neck, oral cavity, skin, prostate; cancers of biliary tract, testicular, thyroid; intra-epithelial neoplasm, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; and other cancers of the respiratory system, lung, small cell lung, non-small cell lung; lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma; melanoma, myeloma, neuroblastoma, retinoblastoma, fibrosarcoma (bone or connective tissue sarcoma), rhabdomyosarcoma; and other cancers including neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma;
  • In a further aspect, the DPP-IV inhibiting compounds of the present invention are useful for the treatment or prophylaxis of chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
  • In another aspect, the DPP-IV inhibiting compounds of the present invention may be useful in the treatment of pain, neuropathic pain, rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalian patients undergoing surgery, chronic pain in advanced cancer, treatment of refractory diarrhea, biliary pain caused by gallstones.
  • In a further aspect, the DPP-IV inhibiting compounds of the present invention are useful for the treatment of mammalian patients undergoing islet/pancreas transplantation, for the prevention or the delay of transplant rejection, or allograft rejection in transplantation, for improving pancreatic function by increasing the number and size of pancreatic beta-cells in the treatment of Type 1 diabetes patients, and for improving pancreatic function by increasing the number and size of pancreatic beta-cells in general.
  • Furthermore, the DPP-IV inhibiting compounds of the present invention are useful for the treatment of mammalian patients with acne, skin disorders (e.g. pigmentation disorders or psoriasis), scleroderma, mycoses; anxiety, anxiety neurosis, major depression disorder, drug abuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea; anorexia nervosa; epilepsy; migrane; encephalomyelitis; osteoarthritis, osteoporosis, calcitonin-induced osteoporosis; male and female sexual dysfunction, infertility; Type 1 diabetes; immunosuppression, HIV infection; hematopoiesis, anemia; and for weight reduction.
  • In a further aspect, the DPP-IV inhibiting compounds of the present invention are useful for the prevention, delay of progression or treatment of (i) bacterial infections from Escherichia coli, Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficile infection, Legionella, Pneumococcus, HaemopHilus, Klebsiella, Enterobacter, Citrobacter, Neisseria, Shigella, Salmonella, Listeria, Pasteurella, Streptobacillus, Spirillum, Treponema, Actinomyces, Borrelia, Corynebacterium, Nocardia, Gardnerella, Campylobacter, Spirochaeta, Proteus, Bacteriodes, Helicobacter pylori, and anthrax infection; (ii) mycobacterial infection from tuberculosis and leprosy; (iii) viral infection from HIV, Herpes simplex virus 1, Herpes simplex virus 2, Cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Epstein Barr virus, rotavirus, adenovirus, influenza A virus, respiratory syncytial virus, varicella-zoster virus, small pox, monkey pox and SARS; (iv) fungal infection from candidiasis, ringworm, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, aspergillosis, chromomycosis, mycetoma infections, pseudallescheriasis, Tinea versicolor infection; (v) parasite infection from amebiasis, Trypanosoma cruzi, Fascioliasis, Leishmaniasis, Plasmodium, Onchocerciasis, Paragonimiasis, Trypanosoma brucei, Pneumocystis, Trichomonas vaginalis, Taenia, Hymenolepsis, Echinococcus, Schistosomiasis, neurocysticerosis, Necator americanus, and Trichuris trichuria.
  • The compounds from this invention are suitable for oral, sublingual, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compounds from this invention are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • The DPP-IV inhibiting compounds of the present invention are synthesized by the general method shown in Schemes 1-14.
  • Generic Schemes
  • General synthetic schemes for the preparation of tricyclic building blocks of this invention:
  • Figure US20100009961A1-20100114-C00016
  • Commercially available bromotoluene derivatives were treated with n-butyllithium and heated, followed by treatment with dry-ice in an appropriate solvent to afford the desired compound. Alternatively, the acid can be prepared by Grignard reaction followed by treatment with dry-ice in an appropriate solvent. Esterification of the compound followed by NBS bromination and subsequent conversion to the phosphonium salt in a suitable solvent and heating affords the desired compound. Wittig reaction of the phosphonium salt with a suitable aldehyde in an appropriate solvent and heating, followed by saponification of the ester moiety and subsequent catalytic hydrogenation affords the desired compound. Cyclisation of the compound with polyphosphoric acid in sulfolane and heating affords the desired compound after purification. For R1═COOMe the tricyclic product from the polyphosphoric acid step was treated with thionylchloride in an alcohol. Reduction of the ketone with a metal hydride in an appropriate solvent yields the compound after purification. Treatment of the alcohol with thionylchloride in a suitable solvent affords the final desired compound. In order to obtain the compounds with R1═R2═COOMe, the tricyclic product from the polyphosphoric acid step with R1═COOH and R2=Br was treated with CuCN in a suitable solvent, followed by saponification of the nitrile to the acid. Ester formation using thionylchloride in an alcohol and reduction of the ketone with a metal hydride in an appropriate solvent yields the compound after purification. Treatment of the alcohol with thionylchloride in a suitable solvent affords the final desired compound.
  • Alternative synthetic scheme for the preparation of tricyclic building blocks of this invention:
  • Figure US20100009961A1-20100114-C00017
  • Commercially available bromotoluene derivatives are treated with Magnesium in a Grignard reaction followed by treatment with dry-ice in an appropriate solvent to yield the desired acid. This acid is then treated with sec-butyllithium in an appropriate solvent at lower temperature. The anion is added at lower temperature to a solution of a commercially available benzylchloride in an appropriate solvent to afford the desired compound. Cyclisation of the compound with polyphosphoric acid in sulfolane and heating affords the desired compound. To obtain the compounds with R1═R2═COOMe, the tricyclic product from the polyphosphoric acid step with R1═R2═Cl was treated with KCN, a Pd-catalyst, a suitable ligand and a suitable base in an appropriate solvent to afford the dicyano compound, which was converted to the diacid by treatment with base in a suitable solvent. Ester formation using thionylchloride in an alcohol and reduction of the ketone with a metal hydride in an appropriate solvent yields the compound after purification. Treatment of the alcohol with thionylchloride in a suitable solvent affords the final desired compound.
  • General synthetic scheme for the preparation of aldehyde building blocks of this invention:
  • Figure US20100009961A1-20100114-C00018
  • Commercially available prolinamide is treated with fumarylchloride in an appropriate solvent to afford the desired compound. This compound is then treated with oxalylchloride in dimethylformamide to afford the desired compound after purification. Alternatively, the coupling product of prolinamide with fumarylchloride can be treated with trifluoroacetic acid anhydride in a suitable solvent to afford the desired compound. Ozonolysis of this compound at −78° C. in a suitable solvent, followed by reductive workup affords the desired final compound as a mixture of the aldehyde and its methyl hemiacetal.
  • Treatment of 2-Aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide, prepared according to WO 01/68603, in the same manner as described above yields the desired final compound containing a cyclopropyl moiety at the 4,5-position of the pyrrolidine moiety.
  • General synthetic scheme for the preparation of tricyclic compounds of this invention with R3═H:
  • Figure US20100009961A1-20100114-C00019
  • The reaction of substituted or unsubstituted tricyclic chlorides with an amino derivative in a suitable solvent as described above affords the desired final product after purification. Substituted or unsubstituted tricyclic chlorides are treated in an appropriate solvent with an excess of suitable amines to afford the desired product after purification. In case the reaction product contains additional amino protecting groups like Boc, they are cleaved by acid treatment to afford the desired compound. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative yields the final desired product after purification. Alternatively, the amines are treated with a suitable aldehyde (D-CHO) via reductive amination to afford the final compound after purification.
  • General synthetic scheme for the preparation of tricyclic compounds of this invention with Z=N:
  • Figure US20100009961A1-20100114-C00020
  • Substituted or unsubstituted tricycles containing a nitrogen at the doubly benzylic position are treated with bromoacetylbromide and heated to afford the desired compounds. Treating these compounds with sodium azide or sodium cyanide in a suitable solvent and heating affords the desired azido or cyano compounds after purification. Catalytic hydrogenation or reduction with Lithium aluminium hydride in a suitable solvent affords the desired amine compounds. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative yields the final desired product after purification.
  • General synthetic scheme for the preparation of tricyclic compounds of this invention having H, OH or no substituent at R3
  • Figure US20100009961A1-20100114-C00021
  • Substituted or unsubstituted tricyclic ketones with Y═C(R4)═C(R5) are treated with malonic acid at elevated temperatures to afford the desired product after purification. These compounds are converted to the corresponding amides by treatment with isobutylchloroformate and ammonia. The amides are then converted to the desired amine products with Y═C(R4)═C(R5) by reduction with lithium aluminium hydride or to the desired amine products with Y═C(R4R5)C(R4R5) by reduction with lithium aluminium hydride followed by catalytic hydrogenation with a suitable catalyst. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired product after purification.
  • Treating tricyclic ketones in a Reformatskij reaction affords the desired product after purification. Reduction with LiAlH4 in a suitable solvent affords the alcohol products with R3═OH after purification. Activation of one of the hydroxyl groups with sulfonylchlorides in a suitable solvent followed by treatment with NaN3 affords the desired compounds after purification. Reduction of the azide reaction products with a catalyst in a suitable solvent affords the desired amine compounds after purification. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired products after purification.
  • Treating the amines with R3═OH with acid in a suitable solvent yields the desired unsaturated amine products. Using these amines for a nucleopHilic displacement reaction in a suitable solvent with a suitable bromo derivative described above yields the final desired products after purification.
  • General synthetic schemes (7-9) for the preparation of tricyclic compounds of this invention with R3=nitrile, amide, tetrazolyl or N-alkyl-tetrazolyl
  • Figure US20100009961A1-20100114-C00022
  • Substituted or unsubstituted suberylchlorides are treated in a suitable solvent with a slight excess of AgCN and heated to afford the desired product after purification. The nitrile containing compound is then treated with sodium hydride in a suitable solvent and heated. The mixture is then treated at rt with a suitable dibromoalkene and heated to give an intermediate which after treatment with sodium azide or potassium phthalimide in an appropriate solvent and heating affords the desired compound after purification. Treating the mixture after the addition of sodium hydride at rt with a suitable sulfamidate in an appropriate solvent affords the desired Teoc-protected compound after heating for several hours and subsequent purification.
  • Catalytic hydrogenation of compounds with R′═N3 in a suitable solvent and in the presence of a slight excess of acid affords the free amine compounds. Coupling of these amines with a suitable aldehyde (CHO-D) via reductive amination and subsequent purification affords the final desired compounds with R3═CN.
  • Figure US20100009961A1-20100114-C00023
  • Catalytic hydrogenation of compounds with R3═CN and R′═N3 in a suitable solvent and in the presence of a slight excess of acid affords the free amine compounds. Treatment of the hydrogenation products with sulphuric acid affords the desired compounds after purification. In case R1═R2≠COOH, the amines are reacted with a suitable aldehyde (D-CHO) in an appropriate solvent to yield the desired final compounds with R3═CONH2 and R1═R2≠COOH, CONR4R5, COOMe. In case R1═COOH, the amines are treated with Boc2O in a suitable solvent to afford the Boc-protected amines. These compounds are then treated with ethylchloroformate, followed by treatment with an amine to yield the desired compounds after purification. The compounds are then treated with acid, followed by reaction with a suitable aldehyde (D-CHO) in an appropriate solvent to yield the desired final compounds with R3═CONH2 and R1═CONR4R5 after purification.
  • The compounds with R3═CN and R′═N-phthaloyl are treated with an excess of trimethylsilyl azide and Bu2SnO in an appropriate solvent and heating to afford the desired compounds with R3=tetrazolyl and R′═N-phthaloyl. In case R1═R2≠COOH, the compounds are treated with hydrazine hydrate at elevated temperature in an appropriate solvent to yield the desired amines with R3=tetrazoyl. The reaction of these amines with a suitable aldehyde (D-CHO) in an appropriate solvent affords the desired final compound with R3=tetrazoyl and R1═R2≠COOH, CONR4R5, COOMe after purification. In case R1═COOMe, the compounds are treated with an appropriate amine in a suitable solvent to afford the free amine compounds. Protection of the amines with Boc2O affords the Boc-protected products after purification. Saponification of the ester moieties affords the desired fNH-Boc-protected carboxylic acid derivatives. The acid derivates are then treated with ethylchloroformate, followed by an amine to afford the desired products after acid treatment. The reaction of these amines with a suitable aldehyde (D-CHO) in an appropriate solvent affords the desired final compound with R3=tetrazoyl and R1═CONR4R5 after purification.
  • Figure US20100009961A1-20100114-C00024
  • The NH Teoc-protected compounds with R3═CN and R1═R2═COOMe or R1═R2=Hal were treated with hydroxylamine hydrochloride and an excess of base at elevated temperatures in an appropriate solvent to afford the desired compounds with R3═CONH2 after purification. The same NH Teoc protected compounds are also reacted with sodium azide and ammonium chloride in a suitable solvent to yield the desired compounds with R3=tetrazoyl after purification. Further reaction of the compound with R3=tetrazoyl with methyl iodide and base in a suitable solvent leads to the formation of the desired compound with R3═N-Me-tetrazoyl after purification. For the compounds with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═COOMe, Hal, the Teoc protecting group is removed by treatment with acid to afford the desired amine compounds. The reaction of these amines with a suitable aldehyde (D-CHO) in an appropriate solvent affords the desired final compound with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═COOMe, Hal after purification. For the compounds with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═COOMe, the ester moieties are removed by treatment with base in an appropriate solvent to afford the desired dicarboxylic acid derivatives after purification. Treatment of these compounds with ethylchloroformate, followed by an amine yields the desired amine compounds with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═CONR4R5 after purification. Cleavage of the Teoc protecting group with acid affords the corresponding amine compounds. The reaction of these amines with a suitable aldehyde (D-CHO) in an appropriate solvent affords the desired final compounds with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═CONR4R5 after purification. To obtain the desired final compounds with R3=tetrazoyl, N-Me-tetrazoyl and R1═R2═COOH after purification, the amide formation steps 2 and 3 are omitted.
  • General synthetic scheme for the preparation of tricyclic compounds of this invention with R3=heteroaryl (e.g., oxadiazolone or trifluororoxadiazole)
  • Figure US20100009961A1-20100114-C00025
  • The NH Teoc-protected compounds with R3═CN and R1═R2═COOMe were treated with hydroxylamine hydrochloride and a base at elevated temperatures, followed by diethylcarbonate in an appropriate solvent to afford the desired compounds with R3=oxadiazolone after purification. In case trifluoroacetic acid anhydride and base are used in a suitable solvent for step 2 of the above scheme, the desired compounds with R3═CF3-oxadiazole are obtained after purification. The compounds with R3=oxadiazolone and R3═CF3-oxadiazole are then treated with base to afford the dicarboxylic acid derivatives. These acids are treated with ethylchloroformate, followed by an amine to afford the desired NH-Teoc protected compounds with R3=oxadiazolone, CF3-oxadiazole and R1═R2═CONR4R5 after purification. Cleavage of the Teoc protecting group with acid affords the corresponding amine compounds. The reaction of these amines with a suitable aldehyde (D-CHO) in an appropriate solvent affords the desired final compounds with R3=oxadiazolone, CF3-oxadiazole and R1═R2═CONR4R5 after purification.
  • General synthetic scheme for the preparation of tricyclic compounds of this invention with R3=tetrazole and Y═CONR4
  • Figure US20100009961A1-20100114-C00026
  • Anthraquinone derivatives are treated with sodium azide and sulphuric acid in a suitable solvent to yield the desired compounds. These compounds are then treated with alkyl halides and base in a suitable solvent to obtain the desired compounds after purification. Reaction of theses compounds with tosylmethyl isocyanide and base in a suitable solvent, followed by treatment with dibromoethane and potassium phthalimide affords the desired compounds with R3=CN and R′═N-phthaloyl after purification. The reaction of these compounds with trimethylsilyl-azide and dibutyltin oxide in a suitable solvent affords the compounds with R3=tetrazoyl and R′═N-phthaloyl. Cleavage of the protecting group with hydrazine hydrate affords the desired amines, which are reacted with a suitable aldehyde (D-CHO) in an appropriate solvent to afford the desired final compound with R3=tetrazoyl. The desired final compound with R3=tetrazoyl and R4═H can be obtained by omitting the alkylation step with alkyl halides in the above scheme.
  • General synthetic scheme for the preparation of compounds with bridged piperazinones of this invention with R14a,b=(═O)
  • Figure US20100009961A1-20100114-C00027
  • A commercially available hydroxyl-proline derivative is treated with base and alkylated with allylbromide in an appropriate solvent to afford the allyl-protected amino acid after purification. This compound is then treated at −30° C. with an appropriate base, triflic anhydride and then an appropriately protected diamino acid in an appropriate solvent to afford the desired compound after purification. After cleavage of the ester moiety with palladium(0) in an appropriate solvent, the compound is treated with EDCI and base in an appropriate solvent to afford the desired compound after purification. Cleavage of Fmoc protecting group by treatment with an suitable base affords the desired product. The free amine is then treated in the presence of an suitable polymer supported base with sulfonyl chlorides, acid chlorides or isocyanates to afford the desired compounds after purification. Removal of the Boc-protecting group with acid in a suitable solvent affords the final desired compounds after purification.
  • Starting with the enantiomers of the amino acid derivatives above, and proceeding through the general procedures as described above, the enantiomeric piperazinone derivatives can be made.
  • General synthetic scheme for the preparation of compounds with bridged piperazinones of this invention with R13a,b=(═O)
  • Figure US20100009961A1-20100114-C00028
  • After removing the Fmoc group of the commercially available amino acid with Et2NH, the primary amine is treated in an appropriate solvent with aldehydes or ketones in a reductive amination reaction to afford the desired products. Alternatively, the commercially available N-Boc-protected hydroxy amino acid ester can be treated with trifluoroacetic acid anhydride. The nucleopHilic displacement reaction of the triflate with commercially available amines affords the desired products, after saponification of the ester moiety with base and purification. These compounds are then treated with EDCl and a base in an suitable solvent to afford the cyclic amides after purification. These compounds are converted to the desired products by removing the Boc-protection group. These compounds are then reacted in a suitable solvent with a cyclic sulfamidate, derived from a serine derivative, in the presence of base. Saponification of the ester of the reaction product with a suitable base yields the desired acid compounds after purification. Further treatment of the free acids with EDCI in the presence of an appropriate base and a suitable amine derivative, followed by acidic removal of the Boc-protecting group yields the desired compounds after purification.
  • Starting with the enantiomers of the amino acid and amine derivatives above, and proceeding through the general procedures as described above, the enantiomeric piperazinone derivatives can be made.
  • General synthetic scheme for the preparation of compounds with bridged piperazines of this invention with R13a,b and R14a,b═H
  • Figure US20100009961A1-20100114-C00029
  • The commercially available bridged piperazine derivate is treated with a commercially available aziridine ester in an appropriate solvent to afford the desired compound after purification. After acidic removal of the Boc-protection group, the desired product reacts in presence of a base with an acid chloride or sulfonic acid chloride to yield the desired products after purification. After basic saponification, the free acids are treated with EDCI in the presence of an appropriate base and a suitable amine derivative to afford the desired compounds after purification. The Cbz-protecting group is then removed by treatment with TMSI and subsequent purification to afford the desired final compounds.
  • Starting with the enantiomers of the amine and aziridine derivatives above, and proceeding through the general procedures as described above, the enantiomeric piperazine derivatives can be made.
  • As can be seen by the generic schemes, each of the structures of “B” bonds to the “A” structures on its left side and to the “D” structures on its right side as each is depicted below. The compound A-B-D chooses an “A” which includes the following:
  • Figure US20100009961A1-20100114-C00030
  • A is desirably
  • Figure US20100009961A1-20100114-C00031
  • The “B” structures are chosen from:
  • Figure US20100009961A1-20100114-C00032
  • Desirably, B is one of structure (a), (b), (c), and (d). More desirably, B is structure (b)
  • The “D” structures are chosen from:
  • Figure US20100009961A1-20100114-C00033
  • The substituents are selected as follows:
  • E, G, and M represent a three ring system wherein M shares two carbon atoms with each of E and G;
  • E and G are each independently selected from 6-membered aryl, 5-membered heteroaryl; 6-membered heteroaryl; a 5-7-membered saturated or partially saturated carbocyclic ring; and a 5-7 membered saturated or partially saturated heterocyclic ring; desirably E and G are substituted phenyl; M is a 5-7-membered saturated or partially saturated carboxylic or heterocyclic ring, or a 5-6-membered aromatic or heteroaromatic ring.
  • E may be substituted with one or more R1 groups;
  • G may be substituted with one or more R2 groups;
  • X and Y are divalent and are each independently: a bond, CR4R5, O, NR4, S, S═O, S(═O)2, C(═O), (C═O)N(R4), S(═O)2N(R4), C═N—OR4, —C(R4R5)C(R4R5)—, —C(R4)═C(R5)—, —C(R4R5)NR4—, —C(R4R5)O—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, NS(═O)2R4; or aryl, heteroaryl, cycloalkyl or heterocyclic ring, all may be optionally substituted;
  • R1 and R2 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all of which may be optionally substituted. Desirably, R1 and R2 may be defined independently as —H, —F, —Cl, —CONR4R5, —CO2H, —CN or —SO2NR4R5R2.
  • R3 is absent or is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all of which may be optionally substituted. Desirably, R3 is absent or is —H, —OH, —CO2H, —CN, —CONR4R5, R5, aryl, NH(C═O)R4, NH(SO2)R4, heteroaryl —SO3H, —PO3H2, —CONR4R5, R5, aryl, NH(C═O)R4, or NH(SO2)R4, and more desirably, R3 is —CONR4R5 or tetrazolyl.
  • Ra is hydrogen, CN, NO2, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, or C(O)NR4R5;
  • each occurrence of R4, R5, R20 and R21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are all optionally substituted, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and may optionally contain a heteroatom selected from O, S, or NR50 and the 3- to 8-membered ring may be optionally substituted. Desirably, R4 and R5 are each independently —H or alkyl.
  • R50 is, in each occurrence, R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(═NRa)NR20R21, C(═NR20)NR21Ra, C(═NOR20)R21 or C(O)NR20R21;
  • each occurrence of R7 and R8 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C1-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted. Desirably, R7 and R8 are independently H or alkyl.
  • R9 is H or C1-6 alkyl, desirably H.
  • R10 is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (CO—C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (CO—C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, B(OH)2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl are all optionally substituted. Desirably R10 is CN.
  • R11 and R12 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (CO—C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl all may be optionally substituted;
  • R13a and R13b are each independently R5 or together are ═O;
  • R14a and R14b are each independently R5 or together are ═O;
  • R13c and R14c are each independently R5;
  • Qa is CH or N;
  • Qb is CH or N;
  • U is —C(O)—, —C(═NR4)—, —(CR4R5—)p, NR50, S(═O)2, C(═O), (C═O)N(R4), N(R4)(C═O), S(═O)2N(R4), N(R4)S(═O)2, C═N—OR4, —C(R4)═C(R5)—, —C(R4R5)pNR50—, N(R50)C(R4R5)p—, —O—C(R4R5)—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, NS(═O)2R4, or an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may be optionally substituted. Desirably, U is CH2.
  • W is —CH2—, —S—, —CHF— or —CF2—;
  • Z is C or N;
  • m is 1, or 2;
  • n is 0, 1, or 2;
  • p is 0 to 6;
  • q is 0 to 6; and
  • t is 0, 1, or 2.
    • EXAMPLES
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures, diasteromeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, tautomers, atropisomers, and rotamers, with all isomeric forms being included in the present invention. Compounds described in this invention containing olefinic double bonds include both E and Z geometric isomers. Also included in this invention are all salt forms, polymorphs, hydrates and solvates. All of the above mentioned compounds are included within the scope of the invention.
  • The DPP-IV inhibition activity of the DPP-IV inhibitor compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring DPP-IV inhibitor activity is described.
  • The synthesis of DPP-IV inhibiting compounds of the invention and their biological activity assay are described in the following examples which are not intended to be limiting in any way.
    • Examples and Methods
  • All reagents and solvents were obtained from commercial sources and used without further purification. Proton (1H) spectra were recorded on a 250 MHz NMR spectrometer in deuterated solvents. Chromatography was performed using Roth silica gel (Si 60, 0.06-0.2 mm) and suitable organic solvents as indicated in specific examples. For flash chromatography Roth silica gel (Si 60, 0.04-0.063 mm) was used. Thin layer chromatography (TLC) was carried out on silica gel plates with UV detection. Preparative thin layer chromatography (Prep-TLC) was conducted with 0.5 mm or 1 mm silica gel plates (Merck Si 60, F254) and the solvents indicated in the specific examples.
    • Preparative Example 1
  • Figure US20100009961A1-20100114-C00034
  • Commercially available prolinamide (5 g) was first treated with bromacetylbromide (4.2 ml) in CH2Cl2 and then with trifluoracetic acid anhydride in CH2Cl2 as described in WO 98/19998 to afford the title compound (7.85 g; 83%). 1HNMR δ (CDCl3) 2.05-2.40 (m, 4H), 3.51-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.70-4.86 (m, 1H).
    • Preparative Example 2
  • Figure US20100009961A1-20100114-C00035
    • Step A
  • Commercially available L-prolinamide (25 g) was dissolved in CH2Cl2 (1200 ml) and triethylamine (30 ml) and 4-dimethylaminopyridine (1.9 g) added. The mixture was cooled to 0° C. and treated with fumaryl chloride (11.7 ml). The dark mixture was stirred at rt for 16 h and cooled to 0° C. TFAA (77 ml) was added dropwise under stirring and the solution allowed to warm to rt over 6 hours. The reaction mixture was stirred at rt for 1 to 2 days. Ice (500 g) was added followed by cautious addition of sat. NaHCO3 (600 ml). After the evolution of gas had ceased, the organic phase was separated and washed with sat. NaHCO3 (350 ml), H2O (350 ml), and brine (200 ml). The organic phase was dried over MgSO4 and concentrated to afford the title compound (28.6 g; 98%).
  • 1HNMR δ (CDCl3) 2.12-2.30 (m, 8H), 3.58-3.69 (m, 2H), 3.73-3.89 (m, 2H), 4.72-4.83 (m, 2H), 7.26 (s, 2H).
    • Step B
  • The title compound from Step A above (9.6 g) was dissolved in CHCl3 (90 ml) and MeOH (90 ml) and cooled to −78° C. At −78° C. a slow flow of ozone (originating from an O2 cylinder) was passed through the mixture for 3 h. The mixture was purged with N2 and dimethylsulfide (6 ml) added. The mixture was stirred for 1 h, allowed to reach rt and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 100:0->92:8) to afford the title compound as a mixture of the aldehyde and methoxy hemiacetal in a ratio of ˜1:9 (8.9 g; 69%).
  • 1HNMR δ (D2O) 2.10-2.38 (m, 4H), 3.32 (s, 3H), 3.60-3.84 (m, 2H), 4.72-4.81 (m, 1H), 5.5 (s, 9/10H), 7.9 (s, 1/10H).
    • Preparative Example 3
  • Figure US20100009961A1-20100114-C00036
    • Step A
  • Commercially available 2-cyano-3-methylpyridine (25 g) was dissolved in t-butanol (50 ml) and stirred at 80° C. Concentrated sulphuric acid (25 ml) was slowly added over a period of 45 minutes. After complete addition of the acid stirring was continued at 80° C. for 1 h. The reaction was diluted with water (50 ml) and toluene (125 ml). The pH was adjusted to 10 with 25% aqueous ammonia (110 ml). The separated organic phase was concentrated in vacuum affording the desired product (27 g, 90%).
  • 1HNMR δ (CDCl3) 1.4 (s, 9H), 2.7 (s, 3H), 7.2-7.3 (m, 1H), 7.6 (m, 1H), 8.1 (s br, 1H), 8.4 (m, 1H)
    • Step B
  • The title compound of Step A (12 g) above was dissolved in THF (150 ml) and cooled to −64° C. n-Butyllithium (1.6 M in hexane, 77 ml) was added over a period of 30 min. After addition of sodium bromide (0.6 g) stirring was continued for 30 min at −64° C. m-Chlorobenzylchloride (11 g) was added while the temperature was kept below −55° C. The mixture was stirred for 2 hours at −60° C. and for further 2 h at −110° C. Subsequently, the reaction was quenched with water (100 ml) and concentrated. The aqueous phase was extracted with chloroform (3×100 ml). The combined organic phase was dried over MgSO4 and concentrated in vacuum affording the title compound (22 g; 82%).
  • 1HNMR δ (CDCl3) 1.4 (s, 9H), 2.9-3.0 (m, 2H), 3.4-3.5 (m, 2H), 7.0-7.4 (m, 6H), 8.0 (s br, 1H), 8.4 (m, 1H)
    • Step C
  • The title compound of Step B (21.5 g) above was dissolved in phosphorus oxychloride (80 ml) and refluxed for 5 h. The reaction was concentrated and neutralized with 50% aqueous NaOH. The solid was separated and washed with hot isopropanol to afford the title compound (10.4 g; 63%)
  • 1HNMR δ (CDCl3) 2.9-3.0 (m, 2H), 3.0-3.2 (m, 2H), 7.0-7.3 (m, 4H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H), 8.5-8.6 (m, 1H)
    • Step D
  • The title compound of Step C (10 g) above was dissolved in trifluorosulfonic acid (80 ml) and stirred at 60° C. for 1 h. At rt 6 N aqueous HCl (80 ml) was dropwise added. The reaction was refluxed for 1 h and subsequently, poured on ice. After neutralization with 50% aqueous NaOH the precipitate was separated, washed with water and recrystallized from isopropanol/water (3.1) affording the title compound. The mother liquor was concentrated and the residue washed with water and chloroform to afford additional title compound (9.4 g; 94%).
  • 1HNMR δ (MeOD-d4) 3.3-3.4 (m, 2H), 3.4-3.5 (m, 2H), 7.5 (m, 2H), 8.1-8.2 (m, 2H), 8.7 (d, 1H), 8.9 (d, 1H)
    • Step E
  • The title compound of Step D (700 mg) above was dissolved in MeOH (10 ml) and cooled to 0° C. NaBH4 (95 mg) was added in one portion. The mixture was allowed to warm to RT and stirred for 1 h. The reaction was acidified with 1 N HCl and subsequently, brought to pH 12 with 1 N NaOH. The mixture was poured in water (100 ml) and extracted with CHCl3 (100 ml). The organic phase was dried over MgSO4 and concentrated affording the title compound (705 mg; 100%).
  • 1HNMR δ (MeOD-d4) 3.0-3.4 (m, 4H), 6.1 (s, 1H), 7.1.7.3 (m, 3H), 7.5-7.6 (m, 2H), 8.3.8.4 (m, 1H)
    • Step F
  • The title compound of step E (370 mg) above was dissolved in toluene (5 ml) and cooled to −15° C. Thionyl chloride (286 mg) was slowly added and the reaction was allowed to come to RT and run overnight. The solution was neutralized with triethylamine and directly used in the next step.
    • Preparative Example 4
  • Figure US20100009961A1-20100114-C00037
    • Step A
  • The title compound from Preparative Example 3 Step E (285 mg) was dissolved in ethanol (10 ml) and 10% Pd/C (100 mg) and ammonium formiate (916 mg) were added. The mixture was refluxed for 2 h. Subsequently, the reaction was treated with water (20 ml) and extracted twice with chloroform (50 ml). The combined organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane 1:4) to afford the title compound (200 mg; 82%).
  • 1HNMR δ (MeOD-d4) 2.9-3.1 (m, 2H), 3.3-3.6 (m, 2H), 6.3 (s, 1H), 7.0-7.3 (m, 4H), 7.4 (m, 1H), 7.8 (m, 1H), 8.3 (m, 1H)
    • Step B
  • The title compound of Step A (200 mg) above was dissolved in toluene (5 ml) and cooled to −15° C. Thionyl chloride (235 mg) was slowly added and the reaction was allowed to come to RT and run overnight. The solution was neutralized with triethylamine directly used.
    • Preparative Example 5
  • Figure US20100009961A1-20100114-C00038
  • To a cooled solution (12° C.) of commercially available ethylenediamine (30 ml) was added within 5 min commercially available dibenzosuberylchloride (3.3 g). The mixture was stirred at rt for 1 h and then K2CO3 (5.8 g) was added. After an additional 30 min at rt, the mixture as filtered, the salts washed with 5 ml ethylenediamine and the filtrates concentrated. The residue was dissolved in 80 ml EtOAc, 20 ml H2O and 5 ml NH4OH-solution (25%). The organic phase was separated, dried over MgSO4 and concentrated to afford the title compound (3.4 g; 93%; MH+=253).
    • Preparative Example 6-9
  • The title compounds from Preparative Example 6 to 9 were prepared according to the procedure described in Preparative Example 5 using the chlorides and amines as indicated in the Table below. In case the chlorides did not dissolve in the amines after 10 Min, CH3CN or THF was added until a clear solution was obtained.
  • Preparative 1. Yield
    Example Chloride Amine Product 2. MH+
    6
    Figure US20100009961A1-20100114-C00039
         		NH4OH
    Figure US20100009961A1-20100114-C00040
         		1. 61% 2. 1H-NMR δ (CDCl3) 2.0 (s, 2H), 3.10-3.24 (m, 2H), 3.31-3.45 (m, 2H), 5.43 (s, 1H), 7.10-7.19 (m, 6H), 7.36-7.41 (m, 2H)
    7
    Figure US20100009961A1-20100114-C00041
    Figure US20100009961A1-20100114-C00042
    Figure US20100009961A1-20100114-C00043
         		1. 97% 2. 281
    8
    Figure US20100009961A1-20100114-C00044
    Figure US20100009961A1-20100114-C00045
    Figure US20100009961A1-20100114-C00046
         		1. 60% 2. 288
    9
    Figure US20100009961A1-20100114-C00047
    Figure US20100009961A1-20100114-C00048
    Figure US20100009961A1-20100114-C00049
         		1. 78% 2. 1H-NMR δ (CD3OD) 2.6-2.8 (m, 4H), 3.0-3.2 (m, 2H), 3.3-3.6 (m, 2H), 5.2 (s, 1H), 7.1-7.2 (m, 4H), 7.3-7.4 (m, 1H), 7.5 (m, 1H), 8.2-8.3 (m, 1H)
    • Preparative Example 10
  • Figure US20100009961A1-20100114-C00050
    • Step A
  • Commercially available dibenzosuberylchloride (300 mg) and 4-N-Boc-amino-piperidine (290 mg) were suspended in CH3CN (10 ml). After 10 min K2CO3 (545 mg) was added and the mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc (30 ml) and H2O (15 ml), the organic phase separated, dried over MgSO4 and concentrated to afford the title compound (460 mg; 89%; MH+=393).
    • Step B
  • The title compound from Step A above (460 mg) was dissolved in a solution of 4 M HCl in dioxane (20 ml). The mixture was stirred at rt for 2 h and concentrated to afford the title compound (335 mg; 97%; MH+=293).
    • Preparative Example 11-12
  • The title compounds from Preparative Example 11 and 12 were prepared according to the procedure described in Preparative Example 10 using the chlorides and amines as indicated in the Table below.
  • Preparative 1. Yield
    Example Chloride Amine Product 2. MH+
    11
    Figure US20100009961A1-20100114-C00051
    Figure US20100009961A1-20100114-C00052
    Figure US20100009961A1-20100114-C00053
         		1. 64% 2. 279
    12
    Figure US20100009961A1-20100114-C00054
    Figure US20100009961A1-20100114-C00055
    Figure US20100009961A1-20100114-C00056
         		1. 56% 2. 265
    • Preparative Example 13
  • Figure US20100009961A1-20100114-C00057
    • Step A
  • To a suspension of AgCN (4.7 g) in CH3CN (60 ml) under nitrogen was added at rt a solution of commercially available dibenzosuberylchloride (6 g) in CH3CN (60 ml) and benzene (10 ml). The mixture was heated at reflux for 2 h, cooled to rt and filtered. The salts were washed with 20 ml CH3CN and the filtrates concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane, 1:9) to afford the title compound (5 g; 87%; MNa+=242).
    • Step B
  • A suspension of LiAlH4 (360 mg) in Et2O (20 ml) was slowly treated with a solution of AlCl3 (950 mg) in Et2O (20 ml). The mixture was stirred at rt for 10 min and then the title compound from Step A above (1.03 g) was added within 5 min. The mixture was stirred at rt for 10 min and then refluxed for 8 h. After the addition of H2O (20 ml) and 25% NH4OH (6 ml), the mixture was filtered and the salts washed with H2O (20 ml) and Et2O (10 ml). The organic phase was separated, dried over MgSO4 and concentrated to afford the title compound (157 mg; 15%; MH+=224).
    • Preparative Example 14
  • Figure US20100009961A1-20100114-C00058
    • Step A
  • To a solution of commercially available iminodibenzyl (5 g) in toluene (25 ml) was added commercially available bromoacetylbromide (4.35 ml). The mixture was heated under reflux for 2 h 30 Min, cooled and concentrated. A portion of the crude product (800 mg) was dissolved in DMA (6 ml) and treated with NaN3 (815 mg). The mixture was heated at 60-70° C. overnight and diluted with EtOAc (30 ml) and H2O (10 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was treated with EtOAc/cyclohexane (1:9) (2 ml), sonicated for 2 min and the solvents removed by syringe. The residue was dried to afford the title compound (483 mg; 69%; MH+=279).
    • Step B
  • The title compound from Step A above (483 mg) was dissolved in MeOH (25 ml) and 10% Pd/C (100 mg) added. The mixture was hydrogenated for 1 h, filtered and the catalyst washed with MeOH (10 ml). The filtrates were concentrated and the residue purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (415 mg; 95%; MH+=253).
    • Step C
  • To a suspension of LiAlH4 (242 mg) in THF (6 ml) was added a solution of the title compound from Step B above (322 mg) in THF (6 ml). The mixture was heated under reflux for 2 h 30 min. The mixture was cooled to 0° C., quenched with H2O (0.3 ml) and diluted with 15% NH4OH-solution (0.3 ml) and H2O (0.8 ml). The mixture was stirred at rt for 45 Min, filtered and the salts washed with THF (8 ml). The filtrates were concentrated and the residue purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (79 mg; 26%; MH+=239).
    • Preparative Example 15
  • Figure US20100009961A1-20100114-C00059
    • Step A
  • A mixture of commercially available dibenzosuberenol (1.5 g) and malonic acid (830 mg) was heated at 160-170° C. for 2 h. A mixture of H2O (5 ml) and 0.1 M HCl (5 ml) was added and the mixture cooled to rt. The mixture was diluted with EtOAc (100 ml) and H2O (10 ml), the organic phase separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/acetone, 98:2->CH2Cl2/acetone, 9:1) to afford the title compound (775 mg; 43%; MNa+=273).
    • Step B
  • A mixture of title compound from Step A above (775 mg) and triethylamine (0.59 ml) in THF (20 ml) was cooled to −40° C. and treated with isobutylchloroformate. After stirring at −40° C. for 1 h, the mixture was filtered and the salts washed with THF (5 ml). The filtrates were then treated at 0° C. with 25% NH4OH (15 ml) for 1 h 30 min. The mixture was diluted with EtOAc (60 ml), the organic phase separated, dried over MgSO4 and concentrated. The residue was treated with CHCl3 (1.5 ml), the solvent removed by syringe and the residue dried to afford the title compound (677 mg; 88%; MH+=250).
    • Step C
  • To a suspension of LiAlH4 (513 mg) in THF (15 ml) was added a solution of the title compound from Step B above (677 mg) in THF (25 ml). The mixture was heated under reflux for 2 h. The mixture was cooled to 0° C., quenched with H2O (0.65 ml) and diluted with 4 M NaOH-solution (2.5 ml). The mixture was stirred at rt for 45 Min, filtered and the salts washed with THF (15 ml). The filtrates were concentrated and the residue purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (560 mg; 88%; MH+=236).
    • Step D
  • The title compound from Step C above (350 mg) was dissolved in MeOH (15 ml) and 10% Pd/C (300 mg) and 1 M HCl (1.5 ml) were added. The mixture was hydrogenated overnight, filtered and the catalyst washed with MeOH (10 ml). The filtrates were concentrated and the residue dissolved in EtOAc (30 ml) and sat. NaHCO3 (10 ml). The organic phase was separated and the aqueous phase extracted with EtOAc (20 ml). The combined organic phase was dried over MgSO4 and concentrated to afford the title compound (232 mg; 66%; MH+=238).
    • Preparative Example 16
  • Figure US20100009961A1-20100114-C00060
    • Step A
  • The intermediate from Preparative Example 14 Step A (1 g) was dissolved in DMA (6 ml) and treated with NaCN (368 mg). The mixture was heated at 60-70° C. overnight and diluted with EtOAc (50 ml) and H2O (15 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/acetone, 98:2) to afford the title compound (282 mg; 34%; MH+=263).
    • Step B
  • To a suspension of LiAlH4 (123 mg) in THF (6 ml) was added a solution of the title compound from Step A above (282 mg) in THF (6 ml). The mixture was heated at 50° C. for 2 h, cooled to 0° C. and treated with H2O (0.2 ml) and 4 M NaOH (0.8 ml). The mixture was stirred at rt for 45 Min, treated with MgSO4 and filtered. The filtrate was concentrated and the residue purified by chromatography on silica (CH2Cl2/MeOH, 95:5->CH2Cl2/MeOH, 9:1) to afford the title compound (32 mg; 12%; MH+=253).
    • Preparative Example 17
  • Figure US20100009961A1-20100114-C00061
    • Step A
  • To a suspension of magnesium (701 mg) in Et2O (7 ml) was slowly added ethylbromide (2.15 ml). After the formation of the Grignard reagent, the mixture was cooled to 5° C. and a solution of diethylamine (3 ml) in Et2O (5 ml) was slowly added. The mixture was refluxed for 30 Min, cooled to 5° C. and treated with a mixture of commercially available dibenzosuberone (3 g) and tert-butylacetate (1.95 ml) in Et2O (15 ml). The mixture was heated under reflux for 2 h, cooled to rt and poured onto ice-water containing an excess of NH4Cl. The mixture was extracted with CH2Cl2 (3×100 ml), the organic phase dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane, 1:9) to afford the title compound (3.5 g; 75%; MNa+=347).
    • Step B
  • To a suspension of LiAlH4 (346 mg) in THF (12 ml) was added a solution of the title compound from Step A above (2 g) in THF (12 ml). The mixture was heated under reflux for 2 h, cooled to 0° C. and treated 4 M NaOH (4.5 ml). The mixture was stirred at rt for 45 min and filtered. The filtrate was concentrated and the residue dissolved in EtOAc (100 ml), H2O (10 ml) and sat. NH4Cl (10 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane, 3:7) to afford the title compound (937 mg; 60%; MNa+=277).
    • Step C
  • The title compound from Step B above (937 mg) was dissolved in benzene (1.5 ml) and pyridine (1.5 ml). The mixture was cooled to 5° C. and treated with a solution of p-tosylchloride in benzene (1.5 ml). The mixture was stirred at rt for 7 h, diluted with EtOAc (40 ml) and washed with 0.1 M HCl (10 ml), sat. NaHCO3 (10 ml) and brine (10 ml). The organic phase was separated, dried over MgSO4 and concentrated. The crude intermediate was dissolved in DMA (9 ml) and treated with NaN3 (1.2 g). The mixture was heated at 70° C. overnight and the DMA removed. The residue was dissolved in EtOAc (50 ml), sat. NaHCO3 (10 ml) and brine (10 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane, 1:4) to afford the title compound (704 mg; 68%; MNa+=302).
    • Step D
  • The title compound from Step C above (200 mg) was dissolved in MeOH (8 ml) and 10% Pd/C (40 mg) added. The mixture was hydrogenated for 1 h 30 Min, filtered and the catalyst washed with MeOH (10 ml). The filtrates were concentrated to afford the title compound (175 mg; 96%; MH+=254).
    • Step E
  • The title compound from Step D above (75 mg) was dissolved in EtOH (1 ml) and a 4 M solution of HCl in dioxane (1 ml) added. The mixture was stirred at rt for 12 h and concentrated. The residue was dissolved in EtOAc (20 ml) and sat. NaHCO3 (5 ml). The organic phase was separated, dried over MgSO4 and concentrated to afford the title compound (67 mg; 96%; M+—NH3=219).
    • Preparative Example 18
  • Figure US20100009961A1-20100114-C00062
    • Step A
  • The title compound from Preparative Example 13 Step A (1.1 g) was dissolved in THF (5 ml) and added to a suspension of NaH (132 mg) in THF (5 ml). The mixture was heated under reflux for 1 h, cooled to rt and treated with 1,2-dibromoethane (0.9 ml) in THF (1 ml). The mixture was heated under reflux for 4 h, cooled to rt and filtered. The salts were washed with THF (5 ml) and the filtrates concentrated. The residue was dissolved in DMA (12 ml) and treated with NaN3 (1.6 g). The mixture was heated at 60-70° C. overnight and the DMA removed. The residue was dissolved in EtOAc (40 ml) and H2O (10 ml), the organic phase separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane, 1:9) to afford the title compound (1.14 g; 78%; MH+=289).
    • Step B
  • The title compound from Step A above (510 mg) was dissolved in MeOH (20 ml) and 10% Pd/C (150 mg) and 2 M HCl (0.9 ml) added. The mixture was hydrogenated for 1 h 30 Min, filtered and the catalyst washed with MeOH (10 ml). The filtrates were concentrated and the residue purified by chromatography on silica (CH2Cl2/MeOH, 95:5 to CH2Cl2/MeOH, 4:1) to afford a mixture of the title compound and the cyclic amidine (450 mg; 96%; MH+=263).
    • Step C
  • The title compounds from Step B above (350 mg) were treated with 2 ml 57% H2SO4. The mixture was heated at 100° C. for 3 h, cooled to rt and diluted with H2O (10 ml). The mixture was made alkaline (pH˜11) by adding 10% NaOH and extracted with EtOAc (3×30 ml). The organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 9:1 to CH2Cl2/MeOH (7 M NH3), 9:1) to afford a mixture of the title compound and the cyclic amidine (223 mg; 60%; MH+=281).
    • Preparative Example 19
  • Figure US20100009961A1-20100114-C00063
    • Step A
  • Commercially available (S)-2-aminopropan-1-ol (2.0 g) was dissolved in CH2Cl2 (20 ml) and Boc2O (6.4 g) was added. After stirring for 4 h at room temperature the solvent was removed to afford the title compound (4.7 g, 99%).
  • 1H-NMR δ (CDCl3): 1.10 (s, 3H), 1.50 (s, 9H), 2.40 (s, 1H), 3.45-3.70 (m, 2H), 3.75-3.80 (m, 1H), 4.80 (s, 1H).
    • Step B
  • Imidazole (4.1 g) was dissolved in CH2Cl2 (50 ml) and cooled to 0° C. Thionyl chloride (1.3 ml) dissolved in CH2Cl2 (10 ml) was added dropwise and the resulting suspension was allowed to warm to rt. Stirring was continued for 1 h at rt and then the mixture was cooled to −78° C. A solution of the title compound from Step A above (1.8 g) in CH2Cl2 (50 ml) was added over a period of 1 h and the resulting mixture was allowed to warm to rt and stirred overnight. The mixture was filtered through celite and the filter aid was washed well with CH2Cl2. The organic phase was diluted with CH2Cl2, washed with water and brine, dried over MgSO4, filtered and concentrated to a volume of approx. 100 ml.
  • A solution of NaIO4 (4.3 g) in water (100 ml) was added and the mixture was cooled to 0° C. Ru(IV)O2 hydrate (150 mg) was added and the black suspension was stirred for 2 h at 0° C. It was then warmed to rt and stirred overnight. The mixture was filtered through celite and the filtrate was extracted with CH2Cl2. The combined organic phase was washed with brine, dried and filtered. Treatment of the filtrate with activated charcoal (2 g) for 30 min removed traces of ruthenium. The mixture was filtered again and evaporated to yield the title compound (1.5 g, 63%).
  • 1H-NMR δ (CDCl3): 1.45 (s, 3H), 1.49 (s, 9H), 4.14 (dd, 1H), 4.29-4.42 (m, 1H), 4.61 (dd, 1H).
    • Preparative Example 20
  • The title compound from Preparative Example 20 was prepared according to the procedure described in Preparative Example 19 using the aminoalcohol as indicated in the Table below.
  • Prepar-
    ative
    Exam- 1. Yield
    ple Aminoalcohol Product 2. 1H-NMR
    20
    Figure US20100009961A1-20100114-C00064
    Figure US20100009961A1-20100114-C00065
         		1. 69% 2. 1H-NMR δ (CDCl3): 1.45 (s, 3 H), 1.49 (s, 9 H), 4.14 (dd, 1 H), 4.29-4.42 (m, 1 H), 4.61 (dd, 1 H).
    • Preparative Example 21
  • Figure US20100009961A1-20100114-C00066
    • Step A
  • To a stirred solution of the commercially available 2-(S)-amino propanol (17.4 g) in water (200 ml) was added a solution of triethylamine (32 ml) in dioxane (200 ml). To the solution was added commercially available 1-[2-(Trimethylsilyl)ethoxy-carbonyloxy]pyrrolidin-2,5-dione (60 g). The mixture was stirred at rt overnight, then diluted with water (200 ml), acidified with 1 N HCl, and extracted with Et2O (2×500 ml). The combined organic phase was washed with brine, dried over MgSO4 and evaporated to afford the title compound (44.2 g; 87%).
  • 1H-NMR δ (CDCl3): 0.02 (s, 9H), 0.90-1.05 (m, 2H), 1.20 (d, 3H), 2.80 (br s, 1H), 3.40-3.80 (m, 3H), 4.10-4.20 (m, 2H), 4.85 (s, 1H).
    • Step B
  • Imidazole (96 g) was dissolved in CH2Cl2 (1200 ml) and cooled to 0° C. Thionyl chloride (30.8 ml) was diluted with CH2Cl2 (600 ml) and added dropwise. The resulting suspension was allowed to warm to rt. Stirring was continued for 1 h at rt and then the mixture was cooled to −78° C. A solution of the title compound from Step A above (44.2 g) in CH2Cl2 (1200 ml) was added over a period of 1 h and the resulting mixture was allowed to warm to rt and stirred overnight. The mixture was filtered through celite, the filter aid was washed well with CH2Cl2. The organic phase was washed with water (2×700 ml), dried over MgSO4, filtered and concentrated to a volume of approx. 1000 ml.
  • A solution of NaIO4 (100 g) in water (1000 ml) was added and the mixture was cooled to 0° C. RuO2×H2O (1 g) was added and the black suspension was stirred for 2 h at 0° C. It was then warmed to rt and stirred overnight. The phases were separated and the organic phase was treated with granulated charcoal (˜20 g). The mixture was stirred for approx. 1 h, filtered through celite and the filtrate was dried with MgSO4, filtered and evaporated to yield the title compound (50.7 g, 89%).
  • 1H-NMR δ (CDCl3): 0.02 (s, 9H), 1.00-1.15 (m, 2H), 1.50 (d, 3H), 4.15 (dd, 1H), 4.35-4.45 (m, 3H), 4.65 (dd, 1H).
    • Preparative Example 22-23
  • Following a similar procedure as that described in Preparative Example 21 but using the aminoalcohols as indicated in the Table below, the title compounds were obtained.
  • Prepar-
    ative
    Exam- 1. Yield
    ple Aminoalcohol Product 2. 1H-NMR
    22
    Figure US20100009961A1-20100114-C00067
    Figure US20100009961A1-20100114-C00068
         		1. 58% 2. 1H-NMR δ (CDCl3): 0.02 (s, 9 H), 1.00-115 (m, 2 H), 4.00-4.10 (m, 2 H), 4.25-4.40 (m, 2 H), 4.55-4.65 (m, 2 H).
    23
    Figure US20100009961A1-20100114-C00069
    Figure US20100009961A1-20100114-C00070
         		1. 32% (M + Na)+ = 318
    • Preparative Example 24-46
  • If one were to follow a similar procedure as that described in Preparative Example 21 but using the aminoalcohols as indicated in the Table below, one would obtain the desired products.
  • Prepar-
    ative
    Example Aminoalcohol Product
    24
    Figure US20100009961A1-20100114-C00071
    Figure US20100009961A1-20100114-C00072
    25
    Figure US20100009961A1-20100114-C00073
    Figure US20100009961A1-20100114-C00074
    26
    Figure US20100009961A1-20100114-C00075
    Figure US20100009961A1-20100114-C00076
    27
    Figure US20100009961A1-20100114-C00077
    Figure US20100009961A1-20100114-C00078
    28
    Figure US20100009961A1-20100114-C00079
    Figure US20100009961A1-20100114-C00080
    29
    Figure US20100009961A1-20100114-C00081
    Figure US20100009961A1-20100114-C00082
    30
    Figure US20100009961A1-20100114-C00083
    Figure US20100009961A1-20100114-C00084
    31
    Figure US20100009961A1-20100114-C00085
    Figure US20100009961A1-20100114-C00086
    32
    Figure US20100009961A1-20100114-C00087
    Figure US20100009961A1-20100114-C00088
    33
    Figure US20100009961A1-20100114-C00089
    Figure US20100009961A1-20100114-C00090
    34
    Figure US20100009961A1-20100114-C00091
    Figure US20100009961A1-20100114-C00092
    35
    Figure US20100009961A1-20100114-C00093
    Figure US20100009961A1-20100114-C00094
    36
    Figure US20100009961A1-20100114-C00095
    Figure US20100009961A1-20100114-C00096
    37
    Figure US20100009961A1-20100114-C00097
    Figure US20100009961A1-20100114-C00098
    38
    Figure US20100009961A1-20100114-C00099
    Figure US20100009961A1-20100114-C00100
    39
    Figure US20100009961A1-20100114-C00101
    Figure US20100009961A1-20100114-C00102
    40
    Figure US20100009961A1-20100114-C00103
    Figure US20100009961A1-20100114-C00104
    41
    Figure US20100009961A1-20100114-C00105
    Figure US20100009961A1-20100114-C00106
    42
    Figure US20100009961A1-20100114-C00107
    Figure US20100009961A1-20100114-C00108
    43
    Figure US20100009961A1-20100114-C00109
    Figure US20100009961A1-20100114-C00110
    44
    Figure US20100009961A1-20100114-C00111
    Figure US20100009961A1-20100114-C00112
    45
    Figure US20100009961A1-20100114-C00113
    Figure US20100009961A1-20100114-C00114
    46
    Figure US20100009961A1-20100114-C00115
    Figure US20100009961A1-20100114-C00116
    • Preparative Example 47
  • Figure US20100009961A1-20100114-C00117
    • Step A
  • A suspension of NaH (132 mg) in THF (10 ml) was added to a solution of Preparative Example 13 Step A (1.1 g) in THF (20 ml) and heated at 60° C. for 1 h. Then the mixture was cooled to 0° C. and a solution of Preparative Example 19 (1.2 g) in THF (10 ml) was added. The suspension was heated at 60° C. for 4 h and then diluted with ethyl acetate. The organic phase was washed with water, brine and dried over MgSO4. Removal of the solvents and column chromatography (EtOAc/hexane, 1:4) afford the title compound (1.7 g, 90%, MH+=377).
    • Step B
  • The title compound from Step A above (1.5 g) was dissolved in 57% H2SO4 and the solution was heated at 100° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was discarded and 50%-aqueous KOH solution added to the aqueous phase until pH>8. The aqueous phase was extracted with ethyl acetate (2×75 ml). The organic phase was washed with water, brine, dried over MgSO4 and evaporated to afford the title compound. (600 mg, 53%).
  • 1H-NMR δ (CDCl3): 0.95 (d, 3H), 1.82 (s, 2H), 2.37-2.58 (m, 2H), 2.82-2.92 (m, 1H), 3.18 (s, 4H), 5.60 (s, 2H), 7.08-7.24 (m, 6H), 7.40-7.48 (m, 2H).
    • Preparative Example 48
  • The title compound was prepared according to the procedure described in Preparative Example 47 using the sulfamidate from Preparative Example 20 as indicated in the Table below.
  • Preparative 1. Yield
    Example Nitrile Sulfamidate Product 2. 1H-NMR
    48
    Figure US20100009961A1-20100114-C00118
    Figure US20100009961A1-20100114-C00119
    Figure US20100009961A1-20100114-C00120
         		1. 80% 2. 1H-NMR δ (CDCl3): 0.95 (d, 3 H), 1.82 (s, 2 H), 2.37-2.58 (m, 2 H), 2.82-2.92 (m, 1 H), 3.18 (s, 4 H), 5.60 (s, 2 H), 7.08-7.24 (m, 6 H), 7.40-7.48 (m, 2 H).
    • Preparative Example 49
  • Figure US20100009961A1-20100114-C00121
    • Step A
  • Commercially available 2,5-dibromotoluene (8.28 ml) was dissolved in hexane (90 ml) and treated with a 1.6 M solution of butyllithium in hexane (160 ml). The mixture was heated at 60° C. for 20 h, cooled to rt and poured onto a mixture of dry ice in Et2O (750 ml). The mixture was allowed to warm to rt, filtered and the precipitate washed with 90 ml Et2O. The precipitate was titrated with 140 ml glacial acetic acid to afford the title compound (10 g; 92%).
  • 1H-NMR δ (DMSO-d6) 2.58 (s, 3H), 7.80-7.90 (m, 3H)
    • Step B
  • The title compound from Step A above (13 g) was suspended in MeOH (300 ml) and slowly treated with thionyl chloride (15.7 ml). The mixture was heated under reflux for 2 h to become a clear solution. The solvents were concentrated to afford the title compound (13.3 g; 88%; MH+=209).
    • Step C
  • The title compound from Step B above (13.3 g) was dissolved in CCl4 (500 ml) and commercially available N-bromosuccinimide (10.7 g) added. The mixture was heated to 80° C. and commercially available AIBN (327 mg) added. The mixture was then irradiated with a 100 W light bulb and heated at 100-105° C. for 2 h 30 min. The cooled mixture was filtered and the precipitate washed with 50 ml CCl4. The filtrates were concentrated and the residue dissolved in CH3CN (180 ml). The mixture was treated with triphenylphosphine (16 g) and heated under reflux for 3 h. The mixture was concentrated to ˜100 ml and Et2O (500 ml) added. The mixture was allowed to stand at rt for 30 Min, filtered and the precipitate washed with Et2O (30 ml) to afford the title compound (20 g; 57%).
    • Step D
  • The title compound from Step C above (20 g) was suspended in CH3CN (160 ml) and commercially available 4-Fluorobenzaldehyde (5.4 ml) added. The mixture was then treated with commercially available DBN (10 ml) and heated at 100° C. for 1 h. The mixture was concentrated to half its volume and poured into H2O (150 ml). The mixture was extracted with EtOAc (2×150 ml), the organic phase washed with 5% HCl (2×75 ml), dried over MgSO4 and concentrated. The residue was suspended in H2O (240 ml) and MeOH (20 ml) and KOH (20 g) added. The mixture was heated at 100° C. for 16 h, cooled to rt and washed with CH2Cl2 (3×75 ml). The aqueous phase was acidified (pH˜1) by adding conc. HCl, filtered, the precipitate washed with H2O (20 ml) and air-dried. The residue was dissolved in MeOH (900 ml) and 10% Pd/C (1.5 g) added. The mixture was hydrogenated for 1 h, filtered, the catalyst washed with MeOH (50 ml) and concentrated to afford the title compound (8.6 g; 82%; MH+=289).
    • Step E
  • The title compound from Step D above (1.44 g) was suspended in sulfolane (9 ml) and treated with polyphosphoric acid (30 g). The mixture was heated under N2 at 170-175° C. for 3 h and poured onto ice-water (150 ml). The mixture was stirred at rt for 1 h, extracted with EtOAc (2×150 ml), dried over MgSO4 and concentrated. The residue was dissolved in MeOH (20 ml) and treated with thionyl chloride (1 ml). The mixture was heated under reflux for 1 h and concentrated. The residue was dissolved in Et2O (100 ml) and washed with sat. NaHCO3 (30 ml) and brine (30 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2) to afford the title compound (960 mg; 67%; MH+=285).
    • Step F
  • The title compound from Step E (1420 mg) was dissolved in CHCl3 (20 ml) and MeOH (20 ml) and treated with NaBH4 (230 mg). The mixture was stirred at rt for 1 h and poured onto ice-water (150 ml). The mixture was extracted with EtOAc (2×150 ml), the organic phase dried over MgSO4 and concentrated to afford the title compound (1420 mg; 99%, M++Na=309).
    • Step G
  • The title compound from Step F above (1420 mg) was dissolved in THF (20 ml) and treated with thionyl chloride (0.91 ml). The mixture was stirred at rt for 16 h and concentrated without heating. The residue was dissolved in CH3CN (17 ml) and treated with AgCN (785 mg). The mixture was heated at 90° C. for 2 h 30 Min, filtered and the salts washed with CH3CN (40 ml). The filtrates were concentrated and the residue purified by chromatography on silica (CH2Cl2) to afford the title compound (1160 mg; 79%; MH+=296).
    • Step H
  • The title compound from Step G above (1327 mg) was dissolved in degassed THF (15 ml) and added to a suspension of NaH (119 mg) in degassed THF (5 ml). The mixture was heated at 90° C. for 1 h 15 min and cooled to rt. The mixture was then treated with 1,2-dibromoethane (0.81 ml) in THF (1 ml) and the mixture was heated at 90° C. for 4 h 30 min. The mixture was cooled to rt, diluted with 100 ml EtOAc, 10 ml brine and 10 ml sat. NH4Cl. The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in DMA (10 ml) and treated with NaN3 (720 mg). The mixture was heated at 60° C. for 16 h and diluted with EtOAc (100 ml) and brine (15 ml). The organic phase was separated, washed with 0.1 m HCl (15 ml) and brine (15 ml). The organic phase was dried over MgSO4, concentrated and the residue purified by chromatography on silica (EtOAc/cyclohexane, 1:4) to afford the title compound (931 mg; 57%; MH+=365).
    • Step I
  • The title compound from Step H above (1050 mg) was dissolved in MeOH (40 ml). The mixture was treated with concentrated HCl (0.25 ml) and 10% Pd/C (250 mg). The mixture was hydrogenated for 1 h, filtered and the catalyst washed with MeOH (20 ml). The filtrates were concentrated to afford a mixture of the title compound and the cyclic amidine in a 9:1 ratio (950 mg; 97%; MH+=339).
    • Step J
  • The title compounds from Step I above (950 mg) were treated with 57% H2SO4 (5 ml) and heated under N2 at 90° C. for 3 h. The mixture was cooled, diluted with H2O (80 ml) and made alkaline (pH˜10) by adding 50% NaOH. The mixture was washed with EtOAc (20 ml) and the aqueous phase diluted with dioxane (40 ml). The mixture was treated with an excess of Boc2O and stirred at rt for 16 h while the pH was kept at pH˜10.0. The mixture was acidified to pH˜4.0 by adding 1 M HCl and extracted with EtOAc (2×150 ml). The organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to elute the cyclic amidine side product, followed by CH2Cl2/MeOH (4:1) to afford the title compound (282 mg, 23%; MNa+=465).
    • Step K
  • The title compound from Step J above (135 mg) was dissolved in THF (6 ml) and triethylamine (0.056 ml). The mixture was cooled to −40° C. and treated with ethyl chloroformate (0.031 ml). The mixture was stirred at −40° C. for 1 h, diluted with 4 ml THF and treated at 0° C. with 33% aqueous ammonia solution (10 ml). The mixture was stirred at 0° C. for 1 h and then 1 h at rt. The mixture was diluted with EtOAc (80 ml) and washed with brine (25 ml), sat. NH4Cl (25 ml and brine (25 ml). The organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (97 mg, 72%, MNa+=464).
    • Step L
  • The title compound from Step K above (94 mg) was treated with 4 M solution of HCl in dioxane (2.5 ml) and the flask was agitated for 30 min. The mixture was concentrated and the residue dissolved in 5 ml H2O. The mixture was filtered through a Millex VV (0.1 μM) filter unit and the filtrate concentrated to afford the title compound (65.8 mg, 82%, MH+=342).
    • Preparative Example 50
  • Figure US20100009961A1-20100114-C00122
    • Step A
  • The title compound from Preparative Example 13 Step A (3.3 g) was dissolved in THF (5 ml) and slowly added to a suspension of NaH (540 mg) in THF (10 ml). The mixture was heated at reflux for 30 min, cooled to rt and treated with 1,2-dibromoethane (4 ml). The reaction was stirred at 60° C. overnight, cooled to rt and filtered. The solvent was removed affording the title compound (4.8 g; 98%)
  • 1HNMR δ CDCl3 2.9-3.2 (m, 6H), 3.2-3.4 (m, 2H), 7.1-7.3 (m, 6H), 7.9-8.0 (m, 2H)
    • Step B
  • The title compound from Step A above (1.5 g) and potassium phthalimide (13.8 g) were suspended in DMF (20 ml) and stirred at 100° C. overnight. The precipitate was removed and the reaction was concentrated in vacuum. Chromatography of the residue on silica (EtOAc/cyclohexane) afforded the title compound (1.4 g; 78%).
  • 1HNMR δ CDCl3 2.8-2.9 (m, 2H), 3.0-3.2 (m, 2H), 3.4-3.6 (m, 2H), 3.6-3.8 (m, 2H), 7.1-7.3 (m, 6H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 7.9-8.0 (m, 2H)
    • Step C
  • The title compound from Step B above (1.40 g) was dissolved in toluene (30 ml) and treated with dibutyltin oxide (446 mg) and trimethylsilylazide (2.3 ml). The mixture was heated under a N2 atmosphere at 90° C. overnight. Additional dibutyltin oxide (200 mg) and trimethylsilylazide (2.3 ml) were added and the reaction was continued for 24 h at 90° C. The solvent was removed and the residue was treated with EtOAc (30 ml) and 1 N HCl (30 ml) at 50° C. for 1 h. The phases were separated and the organic phase was concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (600 mg, 39%, MH+=436).
    • Step D
  • The title compound from Step C above (200 mg) was dissolved in ethanol (5 ml) and treated with hydrazine hydrate (100 mg) at rt. The solution was heated at 80° C. for 2 h and then stirred for 1 h at rt. The reaction was filtered and the filtrate was concentrated. The residue was treated with CHCl3 and filtered again. The filtrate was concentrated to afford the title compound (60 mg, 43%, MH+=306).
    • Preparative Example 51
  • Figure US20100009961A1-20100114-C00123
    • Step A
  • Commercially available 2-bromo-4-fluorotoluene (5 g) was diluted with diethyl ether (10 ml). About ⅓ of the resulting solution was added to magnesium turnings (761 mg) which were overlayed with Et2O (25 ml). The remaining 2-bromo-4-fluorotoluene solution was added dropwise after the reaction started. The reaction was kept at reflux for 2 h. The Grignard reagent was poured onto a mixture of crushed dry ice in Et2O (750 ml). The resulting mixture was allowed to warm to rt. The solvent was removed, the resulting residue was treated with EtOAc (100 ml) and extracted with aqueous 1 N HCl (100 ml). The organic phase was dried over MgSO4, filtered and concentrated to afford the title compound (2.3 g; 56%).
  • 1H-NMR δ CDCl3 2.5 (s, 3H), 7.0-7.2 (m, 2H), 7.7 (m, 1H)
    • Step B
  • The title compound from Step A above (2.3 g) was dissolved in THF (50 ml). Methyl iodide (0.95 ml) and N,N-diisopropylethylamine (3.2 ml) were added. The reaction was stirred at rt for 2 h. The reaction mixture was filtered and concentrated to afford the title compound (2.3 g; 90%).
  • 1H-NMR δ CDCl3 2.6 (s, 3H), 3.9 (s, 3H), 7.0-7.2 (m, 2H), 7.6-7.7 (m, 1H)
    • Step C
  • The title compound from Step B above (8.9 g) and commercially available N-bromosuccinimide (14 g) were suspended in CCl4 (500 ml). The mixture was heated to 80° C. and AIBN (270 mg) added. The mixture was irradiated with a 100 W light bulb and heated at 100-105° C. for 3.5 h. The cooled mixture was filtered. The filtrate was concentrated and the residue dissolved in CH3CN (150 ml). The mixture was treated with triphenylphosphine (14 g), heated under reflux for 3 h and then concentrated. The residue was suspended in CH3CN (160 ml) and treated with commercially available 3-fluorobenzaldehyde (6.5 g) and DBN (13 ml). The mixture was heated under reflux for 3 h. The reaction was concentrated to half its volume and poured into H2O (150 ml). The mixture was extracted with EtOAc (3×150 ml), the organic phase separated and concentrated. The residue was suspended in 1:1 H2O/MeOH-mixture (100 ml) and treated with KOH (30 g). The mixture was stirred at 60° C. overnight, cooled to rt and washed with CHCl3 (3×100 ml). The aqueous phase was acidified (pH˜1) by adding conc. HCl and extracted with EtOAc. The organic phase was separated and concentrated. The crude residue was suspended in sulfolane (20 ml) and treated with polyphosphoric acid (25 g). The mixture was heated under N2 at 200° C. for 2 h, poured onto ice-water (150 ml) and stirred at rt overnight. The mixture was extracted with EtOAc and concentrated. The residue was dissolved in Et2O and extracted with H2O. The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/Cyclohexane) to afford the title compound (4.0 g; 31%; MH+=245).
    • Step D
  • The title compound from Step C above (5.4 g) was dissolved in CHCl3 (5 ml) and MeOH (30 ml) and treated with NaBH4 (1.4 g). The mixture was stirred at rt for 1 h and concentrated. The residue was suspended in CHCl3 (50 ml) and extracted with aqueous HCl (50 ml; pH=1). The organic phase was separated, concentrated, then resuspended in toluene and concentrated again. The residue was dissolved in toluene (50 ml). SOCl2 (3.94 ml) was added at 0° C. The reaction was stirred overnight at RT. The solvent was removed and the remaining material was suspended in toluene and concentrated. The residue was dissolved in CH3CN (50 ml) and treated with AgCN (2.96 g). The mixture was heated at reflux for 2 h and then stirred at 60° C. overnight. The mixture was filtered and the filtrate concentrated. The residue was purified by chromatography on silica (EtOAc/Cyclohexane) to afford the title compound (4.4 g; 78%).
  • 1H-NMR δ CDCl3 3.1-3.2 (m, 4H), 5.3 (s, 1H), 6.7-6.9 (m, 3H), 7.0-7.2 (m, 2H), 7.4 (m, 1H)
    • Step E
  • The title compound from Step D above (1.5 g) was dissolved in THF (5 ml) and slowly added at rt to a suspension of NaH (212 mg) in THF (10 ml). The mixture was heated at 60° C. for 30 min, then cooled to 0° C. and treated with 1,2-dibromoethane (2.3 ml). The reaction was stirred at 60° C. for 3 h, cooled to rt and filtered. The filtrate was concentrated to afford the title compound (2.1 g; 99%).
  • 1H-NMR δ CDCl3 2.8-3.0 (m, 4H), 3.0-3.2 (m, 2H), 3.2-3.4 (m, 2H), 6.8-7.2 (m, 4H), 7.6 (m, 1H), 7.8-7.9 (m, 1H)
    • Step F
  • The title compound from Step E above (2.1 g) and potassium phthalimide (5.4 g) were suspended in DMF (30 ml) and stirred at 60° C. overnight. The solvent was removed and the residue dissolved in CHCl3, filtrated and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (1.91 g; 76%)
  • 1HNMR δ CDCl3 2.8-3.2 (m, 4H), 3.4-3.6 (m, 2H), 3.7-3.9 (m, 2H), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 1H), 7.7-8.0 (m, 6H)
    • Step G
  • The title compound from Step F (1.90 g) was dissolved in toluene (20 ml) and treated with dibutyltin oxide (553 mg) and trimethylsilylazide (3.7 ml). The mixture was heated under a N2 atmosphere at 90° C. for 4 d. The reaction was quenched with aqueous 1 N HCl (20 ml) and stirred for 1 h at 50° C. The phases were separated, the aqueous phase was extracted with toluene and the combined organic phase concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (600 mg, 33%, MH+=472).
    • Step H
  • The title compound from Step G above (300 mg) was dissolved in ethanol (5 ml) and treated with hydrazine hydrate (127 mg). The solution was stirred at 80° C. for 2 h and subsequently stirred for 1 h at rt. The solvent was removed and the residue treated with 1 N HCl (20 ml) and CHCl3 (10 ml). The aqueous phase was separated, filtered and concentrated affording the title compound (240 mg, 100% MH+=342).
    • Preparative Example 52
  • Figure US20100009961A1-20100114-C00124
    • Step A
  • Commercially available 2,4-dichlorotoluene (24.6 g) and dry copper(I) cyanide (50 g) in N-methylpyrrolidone (130 ml) were heated under reflux (200-216° C.) for 4 d. While hot (110° C.), the mixture was poured into a flask containing 33% aq. NH4OH solution (390 ml) and toluene (100 ml) and stirred to break up the lumps. After the mixture was cooled to rt, Et2O (100 ml) was added and filtered through cloth. The precipitate was washed (2×100 ml Et2O/CHCl3 1:1). The dark filtrate was poured into a separatory funnel and the phases were separated with the aid of additional Et2O (100 ml). The aqueous phase was extracted with Et2O/CHCl3 1:1 (2×100 ml). The combined organic phases were washed with 10% NH4OH solution (4×110 ml, until the basic phase was no longer blue), with H2O (100 ml), and brine (100 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was mixed with NaOH (24.8 g) and diethylene glycol (275 ml) was added together with a few drops of H2O. The mixture was heated at 215-220° C. overnight. The cooled mixture was diluted with H2O (220 ml) and acidified to pH 1 with 10% aq. HCl. The suspension was filtered and the precipitate washed with 0.1 N HCl (50 ml). The solid was crystallised from glacial acetic acid to afford the title compound (18.4 g, 78%; MH+=181).
    • Step B
  • Following a similar procedure as that described in Preparative Example 49 Step B, the title compound from Step A above (22.1 g) was reacted to afford the title compound (30.0 g, 100%).
  • 1H-NMR (CDCl3) δ: 2.65 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 7.32 (d, 1H), 8.04 (dd, 1H), 8.56 (d, 1H).
    • Step C
  • Following a similar procedure as that described in Preparative Example 49 Step C, the title compound from Step B above (30.0 g) was reacted. Differing from the cited example, the final mixture was allowed to stand over the weekend to form the precipitate. After filtration, the crude title compound was obtained (38.0 g, 100%; [M-Br]+=469).
    • Step D
  • Following a similar procedure as that described in Preparative Example 49 Step D, the title compound from Step C above (38.0 g) was reacted. Differing from the cited example, the hydrogenation was run for 2 days. (29.2 g, 77%; MH+=289).
    • Step E
  • Following a similar procedure as that described in Preparative Example 49 Step E, the title compound from Step D above (4.32 g) was reacted and the title compound obtained (1.77 g, 41%; MH+=285).
    • Step F
  • Following a similar procedure as that described in Preparative Example 49 Step F, the title compound from Step E above (2.39 g) was reacted and the title compound obtained (2.45 g, 100%; MNa+=309).
    • Step G
  • Following a similar procedure as that described in Preparative Example 49 Step G, the title compound from Step F above (3.07 g) was reacted and the title compound was obtained (2.17 g, 69%; MH+=296).
    • Step H
  • The title compound from Step G above (2.17 g) was dissolved in THF (30 ml) and added to a suspension of NaH (250 mg) in THF (9 ml). The mixture was heated at 90° C. for 1 h 15 min and cooled to rt. The mixture was then treated with 1,2-dibromoethane (1.6 ml) in THF (3.7 ml) and the mixture was heated at 90° C. for 4 h 30 min. The mixture was cooled to rt, diluted with 200 ml EtOAc, 20 ml brine and 20 ml sat. NH4Cl. The organic phase was separated, dried over MgSO4 and the residue purified by chromatography on silica (CH2Cl2) to afford the bromoethyl intermediate (1.42 g, 50%; [MNH4]+=419) and starting material (636 mg, 24%). The bromoethyl compound (1.42 g) was dissolved in anhydrous DMF (18 ml) and treated with potassium phthalimide (1.96 g). The suspension was stirred at 80° C. overnight. The solvent was removed and the residue partitioned between EtOAc (50 ml), H2O (50 ml) and brine (50 ml). The aqueous phase was extracted with EtOAc (2×50 ml) and the combined organic phase dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH) to afford the title compound (1525 mg; 92%; MH+=469).
    • Step I
  • The title compound from Step H above (1475 mg) was dissolved in anhydrous toluene (25 ml) and treated with dibutyltin oxide (784 mg) and trimethylsilylazide (8.3 ml). The mixture was heated under a N2 atmosphere at 90° C. for 3 days. The solvent was removed, the residue dissolved in MeOH (10 ml) and concentrated. The residue was partitioned between EtOAc (100 ml) and 10%. NaHCO3 (100 ml). The aqueous phase was extracted with EtOAc (2×70 ml) and the combined organic phase dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH) to afford the title compound (1216 mg, 75%, MH+=512).
    • Step J
  • The title compound from Step I above (1216 mg) was dissolved in anhydrous MeOH (14 ml) and Et3N (0.66 ml). The mixture was cooled to 5° C. and N,N′-dimethylamino-propylamine (0.71 ml) added. The mixture was stirred at rt for 25 h and subsequently evaporated, toluene (10 ml) added, evaporated again and dried in HV. The residue was dissolved in dioxane (8 ml) and H2O (8 ml). To the slightly turbid solution was added Boc2O (2.6 g) and Et3N (1.2 ml) and the mixture was stirred at rt overnight. After evaporation of the solvent, H2O (20 ml) was added and the solution acidified to pH˜4.0 by adding 1 M HCl and the aqueous solution extracted with EtOAc (3×50 ml). The combined organic phase was washed with brine (15 ml), separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH) to afford the title compound (567 mg, 50%, MNa+=504).
    • Preparative Example 53
  • Figure US20100009961A1-20100114-C00125
    • Step A
  • The title compound from Preparative Example 52 (215 mg) was dissolved in THF (4 ml) and 33% NH4OH solution (40 ml) was added. The solution was stirred in a closed vessel at 80° C. overnight. The reaction mixture was allowed to cool to rt and subsequently evaporated to dryness. The crude product, which consisted of a mixture of the amide (MNa+=489) and the free acid (MNa+=490), was dissolved in anhydrous THF (8.5 ml) and triethylamine (0.28 ml) added. The ensuing precipitate was dissolved by adding anhydrous CH3CN (6 ml). The mixture was cooled to −40° C. and ethylchloroformate (0.17 ml) was slowly added. The mixture was stirred at −25° C. for 1 h and allowed to warm to 0° C. At 0° C. 7 M NH3/MeOH-solution (10 ml) was added and the mixture was stirred at 0° C. for 30 min and for 1 h at rt. The mixture was concentrated and the residue dissolved in H2O (14 ml) and THF (3 ml). The pH was adjusted to pH˜4.0 by adding 0.1 N HCl and the aqueous phase—after addition of brine (10 ml)—extracted with EtOAc containing 10% THF (4×33 ml) and CH2Cl2 containing 10% THF (1×25 ml)). The combined organic phase was washed with brine (15 ml), dried over MgSO4 and concentrated to afford the title compound (241 mg; 100%, MNa+=489).
    • Step B
  • The title compound from Step A above (240 mg) was suspended/dissolved in CH2Cl2/MeOH 4:1 (5 ml) and a 4 M solution of HCl in dioxane (7 ml) added after which a clear solution was obtained. The mixture was stirred at rt for 3 h and concentrated. The residue was partitioned between EtOAc containing 10% THF (25 ml) and 0.01 N HCl (25 ml). The organic phase was extracted with H2O (25 ml) and 0.01 N HCl (25 ml). The combined aqueous phase was concentrated to afford the title compound (162 mg, 90%, MH+=367).
    • Preparative Example 54
  • Figure US20100009961A1-20100114-C00126
    • Step A
  • The title compound from Preparative Example 49 Step C (47.6 g) was suspended in CH3CN (350 ml) and commercially available 3-bromobenzaldehyde (13.9 ml) added. After the addition of DBN (24 ml), the mixture was heated at 100° C. for 1 h. The mixture was cooled and the precipitate collected by filtration to afford the trans-olefin (7.5 g). The mother liquor was concentrated to half its volume and poured into H2O (300 ml). The mixture was extracted with EtOAc (2×300 ml), the organic phase washed with 5% HCl (2×80 ml), dried over MgSO4 and concentrated. To this residue was added the trans olefin from above and the mixture was suspended in H2O (500 ml), MeOH (60 ml) and dioxane (60 ml). After the addition of KOH (47 g), the mixture was heated at 60° C. for 16 h, cooled to rt and washed with CH2Cl2 (3×100 ml). The aqueous phase was made acidic (pH˜1) by adding conc. HCl, filtered, the precipitate washed with H2O (150 ml) and air-dried to afford the title compound as a mixture of cis/trans-olefins (26.5 g; 88%; MH+=347).
    • Step B
  • The title compound from Step A above (6 g) was dissolved in MeOH (450 ml) and EtOAc (150 ml). After the addition of a suspension of 5% Pt/C (2.5 g) in 10% HCl (5 ml) and MeOH (10 ml), the mixture was hydrogenated for 6 h. The mixture was filtered, the catalyst washed with MeOH (60 ml) and the filtrates evaporated to afford the title compound (5.5 g, 91%).
  • 1HNMR δ (DMSO-d6) δ 2.81-2.90 (m, 2H), 3.13-3.27 (m, 2H), 7.23-7.32 (m, 2H), 7.39-7.45 (m, 1H), 7.51 (s, 1H), 7.85-7.95 (m, 3H)
    • Step C
  • The title compound from Step B above (4 g) was suspended in sulfolane (9 ml) and treated with polyphosphoric acid (30 g). The mixture was heated under N2 at 175-180° C. for 2 h 30 min and poured into ice-water (250 ml). The mixture was stirred at rt overnight and the precipitate collected by filtration to afford the crude title compound (3.56 g; 94%; MH+=331).
    • Step D
  • The title compound from Step C above (3.5 g) was dissolved in N-methyl pyrrolidone (25 ml) and CuCN (900 mg) added. The mixture was heated at 200° C. for 8 h, cooled to rt and diluted with H2O (200 ml) and 1 M HCl (50 ml). The mixture was extracted with EtOAc (3×100 ml) and the combined organic phase washed with H2O (100 ml) and brine (100 ml). The organic phase was dried over MgSO4 and evaporated. The residue was dissolved in dioxane (50 ml) and conc. HCl (50 ml) added. The mixture was heated at 90° C. for 18 h and the solvents evaporated. The residue was suspended in MeOH (75 ml), treated with SOCl2 (1.5 ml) and heated under reflux for 1 h 30 min. The mixture was concentrated to half its volume, diluted with Et2O (300 ml) and washed with sat. NaHCO3 (80 ml) and brine (80 ml). The organic phase was separated, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica (EtOAc/hexane, 1:4) to afford the title compound (1040 mg; 27%; MH+=325).
    • Step E
  • The title compound from Step D above (1040 mg) was dissolved in CHCl3 (15 ml) and MeOH (15 ml) and the NaBH4 (150 mg) added. The mixture was stirred at rt for 1 h, diluted with ice water (80 ml) and extracted with EtOAc (2×100 ml). The organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/acetone, 98:2->CH2Cl2/acetone, 95:5) to afford the title compound (817 mg, 78%, MNa+=349).
    • Step F
  • The title compound from Step E above (817 mg) was dissolved in THF (10 ml) and treated with SOCl2 (0.46 ml). The mixture was stirred at rt overnight and the solvents evaporated. The residue was dissolved in CH3CN (10 ml) and benzene (5 ml) and added to a suspension of AgCN (406 mg) in CH3CN (10 ml). The mixture was heated at 90° C. for 5 h, filtered and the salts washed with CH3CN (10 ml). The filtrates were evaporated and the residue purified by chromatography on silica (CH2Cl2/acetone, 98:2) to afford the title compound (572 mg, 68%, MH+=336).
    • Step G
  • The title compound from Step F above (676 mg) was suspended in THF (20 ml) and DMF (5 ml) and treated under a N2 atmosphere with NaH (106 mg). The mixture was heated at ˜95° C. for 75 Min, cooled to rt and treated with a solution of 1,2-dibromoethane (0.7 ml) in THF (3 ml). The mixture was then heated at 95° C. for 10 h, cooled to rt and treated with sat. NH4Cl (15 ml) and EtOAc (100 ml). The organic phase was separated, washed with brine (15 ml), dried over MgSO4 and concentrated. The residue was dissolved in DMA (8 ml) and treated with potassium phthalimide (554 mg). The mixture was heated at 60° C. overnight, the solvent removed and the residue dissolved in EtOAc (50 ml) and H2O (15 ml). The organic phase was separated, washed with brine (15 ml) and concentrated. The residue was purified by chromatography on silica (CH2Cl2/acetone, 98:2) to afford the title compound (740 mg, 72%, MNH4 +=526).
    • Step H
  • The title compound from Step G above (600 mg) was suspended in toluene (5 ml) and treated with dibutyltin oxide (138 mg) and trimethylsilylazide (1.45 ml). The mixture was heated under a N2 atmosphere at 90-95° C. for 3 d and the solvent evaporated. The residue was suspended in MeOH (10 ml) and the solvent evaporated. The residue was dissolved in EtOAc (30 ml) water (10 ml). The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 95:5) to afford the title compound (415 mg, 68%, MH+=552).
    • Step I
  • The title compound from Step H above (415 mg) was dissolved in MeOH (6 ml) and triethylamine (0.23 ml). The mixture was cooled to 0° C. and 3-dimethylaminopropylamine (0.23 ml) added. The mixture was stirred at 0° C. for 10 min and at rt overnight. The mixture was concentrated, dissolved in MeOH (10 ml), again concentrated and dried in HV. The residue was dissolved in dioxane (5 ml) and H2O (5 ml) and the pH adjusted to pH=8-9 by adding 1 M KOH. The mixture was then treated with Boc2O (870 mg) and stirred overnight. The mixture was adjusted to pH=4 by adding 1 M HCl and diluted with EtOAc (150 ml). The organic phase was separated and the aqueous phase extracted with EtOAc (2×75 ml). The combined organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH, 95:5->4:1) to afford the title compound (227 mg, 58%, MH+=522).
    • Step J
  • The title compound from Step I above (227 mg) was dissolved in dioxane (10 ml) and 1 M KOH (3.75 ml) added. The mixture was stirred at rt overnight and the pH adjusted to pH=4 by adding 1 M HCl. The mixture was extracted with EtOAc, containing 10% THF (2×150 ml). The organic phase was separated, dried over MgSO4 and concentrated to afford the title compound (177 mg, 82%; MH+=494).
    • Preparative Example 55
  • Figure US20100009961A1-20100114-C00127
  • If one were to follow a similar procedure as described in Preparative Example 54, but using 3-fluorobenzaldehyde in Step A and omitting Step D, one would obtain the desired compound.
    • Preparative Example 56
  • Figure US20100009961A1-20100114-C00128
    • Step A
  • The title compound from Preparative Example 54 (177 mg) was dissolved in THF (6 ml) and triethylamine (0.2 ml) added. The precipitate was dissolved/suspended by adding CH3CN (3 ml). The mixture was cooled to −40° C. and ethylchloroformate (0.1 ml) was slowly added. The mixture was stirred at −25° C. for 1 h and allowed to warm to 0° C. At 0° C. 7 M NH3/MeOH-solution (7 ml) was added and the mixture was stirred at 0° C. for 30 min and 1 h at rt. The mixture was concentrated and the residue dissolved in H2O (10 ml) and THF (2 ml). The pH was adjusted to pH˜4.0 by adding 100 mM HCl and the aqueous phase extracted with EtOAc (4×30 ml) containing 10% THF. The organic phase was dried over MgSO4 and concentrated to afford the title compound (110 mg; 62%, MNa+=514).
    • Step B
  • The title compound from Step A above (103 mg) was dissolved in THF (2 ml) and a 4 M solution of HCl in dioxane (5 ml) added. The mixture was stirred at rt for 2 h and concentrated. The residue was dissolved in H2O (20 ml) and washed with EtOAc (2×8 ml). The aqueous phase was concentrated, the residue dissolved in 50 mM HCl (6 ml) and filtered through a Millex VV (0.1 μM) filter unit. The filtrate was concentrated to afford the title compound (90 mg, 94%, MH+=392).
    • Preparative Example 57
  • Figure US20100009961A1-20100114-C00129
  • If one were to follow a similar procedure as described in Preparative Example 56, but using the title compound from Preparative Example 55, one would obtain the desired compound.
    • Preparative Example 58
  • Figure US20100009961A1-20100114-C00130
    • Step A
  • A suspension of NaH (66 mg) in THF (10 ml) was added to a solution of the title compound from Preparative Example 13 Step A (0.57 g) in THF (20 ml) and heated at 65° C. for 1 h. Then the mixture was cooled to 0° C. and a solution of Preparative Example 21 (0.74 g) in THF (10 ml) was added. The suspension was heated at 65° C. for 5 h and then diluted with ethyl acetate. The organic phase was washed with water, brine and dried over MgSO4. Removal of the solvents and column chromatography (EtOAc/hexane, 1:4) afford the title compound (630 mg, 58%, MH+=421).
    • Step B
  • The title compound from Step A above (632 mg) was dissolved in DMF (10 ml) and treated with NaN3 (1.2 g) and NH4Cl (963 mg). The mixture was heated under a N2 atmosphere at 110° C. for 3 d and the solvent evaporated. Column chromatography (CH2Cl2/MeOH, 9:1) afford the title compound (350 mg, 51%, MH+=464).
    • Step C
  • The title compound from Step B above (350 mg) was dissolved in THF (10 ml) and treated with TBAF.3H2O. The mixture was stirred at rt for 4 h and the solvent evaporated. Preparative TLC using CH2Cl2/MeOH (4:1) afford the title compound (121 mg, 50%, MH+=320).
    • Preparative Example 59
  • Figure US20100009961A1-20100114-C00131
    • Step A
  • Commercially available 2-Brom-5-chlor-toluene (123 g) was diluted with Et2O (70 ml) and 10% of this solution was added to a mixture of Mg (15.2 g) and iodine (3 crystals) in Et2O (250 ml). After the Grignard reaction had started, the remaining starting material was added at such a rate to maintain gentle reflux. After the complete addition of the starting material, the mixture was heated at 60° C. oil-bath temperature for 45 Min. The mixture was then cooled to rt and poured onto a mixture of dry-ice in Et2O (1800 ml). The mixture was allowed to warm to rt over a period of 2 h and the solvent removed. The residue was dissolved with EtOAc (1200 ml) and washed with 3 N HCl (3×1000 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated to afford the title compound (94.3 g, 92%)
  • 1HNMR δ (DMSO-d6) 2.51 (s, 3H), 7.33 (dd, 1H), 7.39 (d, 1H), 7.81 (d, 1H), 12.9 (br-s, 1H)
    • Step B
  • The title compound from Step A above (47 g) was dissolved in THF (500 ml) and the mixture cooled to −60° C. At −60° C. a 1.3 M solution of sec-BuLi (455 ml) in hexane was slowly added as to keep the internal temperature below −30° C. The precipitate began to dissolve after the addition of more than half of the sec-BuLi solution. After the complete addition of sec-BuLi, the deep red solution was stirred at −50° C. for 1 h. The anion solution was then transferred via canula to a cooled (−40° C.) solution of commercially available 3-chlor-benzylbromide (62.3 g) in THF (150 ml). The addition of the anion was at such a rate as to maintain −40° C. during the addition. After the addition of the anion was completed, the mixture was stirred at −40° C. for 1 h and was then allowed to warm to rt over a period of 3 h. The reaction was quenched by adding 2 M NaOH (1000 ml) and the THF removed in vacuo. The remaining solution was extracted with cyclohexane (2×500 ml) and the aqueuous phase acidified to PH=1 by adding conc. HCl. The mixture was extracted with EtOAc (3×400 ml), the organic phase dried over MgSO4, filtered and concentrated to afford the title compound (71 g, 87%).
  • 1HNMR δ (acetone-d6) 2.83-2.91 (m, 2H), 3.22-3.31 (m, 2H), 7.13-7.40 (m, 6H), 7.98 (d, 1H).
    • Step C
  • The title compound from Step B above (71 g) was suspended in sulfolane (250 ml) and PPA (700 g) added. The mixture was stirred with a mechanical stirrer and heated at 170° C. oil-bath temperature for 9 h. The hot mixture (˜120° C.) was then poured onto crushed-ice (4000 g) and stirred overnight. The precipitate was allowed to settle for 30 Min and the aqueous phase decanted. The residue was dissolved in Et2O (1500 ml) and washed with 1 M NaOH (2×500 ml). The organic phase was dried over MgSO4, filtered and concentrated to afford the title compound (50 g, 75%).
  • 1HNMR δ (CDCl3) 3.16 (s, 4H), 7.23 (d, 2H), 7.32 (dd, 2H), 8.0 (d, 2H)
    • Step D
  • The title compound from Step C above (25 g) was dissolved in toluene (160 ml) and added to a mixture of KCN (11.7 g), dipiperidinomethane (7.26 ml), sulfolane (2 ml) and 1,4-Bis-(diphenylphosphino)-butane (6 g). The mixture was degassed by sonication under a stream of nitrogen and then palladium(II)-acetate (1.6 g) was added. The mixture was then heated in a sealed glass reaction vessel at 160° C. oil-bath temperature for 18 h. The mixture was cooled to rt, diluted with CH2Cl2 (800 ml) and washed with H2O (300 ml) and brine (300 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated. The residue was diluted with EtOAc (90 ml) and sonicated. The suspension was then treated with cyclohexane (400 ml) and allowed to stand for 30 Min. The precipitate was collected by filtration and air-dried to afford the title compound (18 g, 77%, MH+=259).
    • Step E
  • The title compound from Step D above (18 g) was suspended in EtOH (75 ml) and H2O (20 ml) and the KOH (19.3 g) added. The mixture was heated at 100° C. oil-bath temperature for 12 h, concentrated and the residue dissolved in H2O (500 ml). The aqueous phase was acidified to pH=1 by adding conc. HCl and the precipitate collected by filtration and air-dried to afford the title compound (19.5 g, 95%, MH+=297).
    • Step F
  • The title compound from Step E above (19.5 g) was suspended in MeOH (600 ml) and treated with thionyl chloride (29 ml). The mixture was then heated at 90° C. oil-bath temperature for 3 h, the hot mixture filtered and concentrated. The residue was dissolved in CH2Cl2 (800 l) and washed with sat. NaHCO3 (200 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated to afford the title compound (18.8 g, 88%, MH+=325).
    • Step G
  • The title compound from Step F above (18.8 g) was dissolved in CHCl3 (250 ml) and MeOH (250 ml). The mixture was then treated with NaBH4 (2.47 g) in small portions. After the complete addition of the reducing agent, the mixture was stirred at rt for 1 h. The mixture was poured into ice-water (800 ml), the organic phase separated and the aqueous phase extracted with EtOAc (300 ml). The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (CH2Cl2 to CH2Cl2/acetone, 98:2 to CH2Cl2/acetone, 95:5) to afford the title compound (11.9 g, 63%, MNa+=349).
    • Step H
  • The title compound from Step G above (11.9 g) was dissolved in THF (150 ml) and the mixture cooled to 0° C. At 0° C. thionyl chloride (6.5 ml) was added and the mixture was allowed to warm to rt overnight. The solvent was then removed in vacuo to afford the crude title compound.
  • 1HNMR δ (CDCl3) 2.93-3.05 (m, 2H), 3.70-3.80 (m, 2H), 3.90 (s, 6H), 6.10 (s, 1H), 7.40 (d, 2H), 7.78-7.86 (m, 4H).
    • Step I
  • The title compound from Step H above was dissolved in CH3CN (300 ml) and benzene (95 ml). After the addition of AgCN (5.9 g) the mixture was heated at 95° C. oil-bath temperature for 2 h 45 Min. The mixture was filtered while hot and the salts washed with CH2Cl2 (100 ml). The filtrate was concentrated and the residue purified by chromatography on silica (CH2Cl2/acetone, 98:2) to afford the title compound (11.3 g, 92%, MH+=336).
    • Preparative Example 60
  • Figure US20100009961A1-20100114-C00132
    • Step A
  • The title compound from Preparative Example 59 Step C (9.5 g) was dissolved in CHCl3 (100 ml) and MeOH (60 ml) at 0° C. The mixture was then treated with NaBH4 (1.64 g) in small portions. After the complete addition of the reducing agent, the mixture was stirred at rt for 3 h. Water (50 ml) was added and the mixture was concentrated to half of its volume and extracted with EtOAc (2×150 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over MgSO4 and concentrated. The crude product was used without further purification (9 g, 90%, MNa+=301).
    • Step B
  • The crude title compound from Step A above (9 g) was dissolved in THF (100 ml) and the mixture was cooled to 0° C. At 0° C. thionyl chloride (7.1 ml) was added and the mixture was allowed to warm to rt overnight. The solvent was then removed in vacuo to afford the title compound (9.2 g).
    • Step C
  • The title compound from Step B above (9.2 g) was dissolved in CH3CN (180 ml) and benzene (60 ml). After the addition of solid AgCN (5.2 g) the mixture was heated at 90° C. oil-bath temperature for 2.5 h. The mixture was filtered while hot through celite and the salts washed with CH2Cl2 (200 ml). The filtrate was concentrated to give the crude title compound (8.66 g, 93%, MH+=288).
    • Preparative Example 61
  • Figure US20100009961A1-20100114-C00133
    • Step A
  • The title compound from Preparative Example 59 (3.8 g) was suspended in THF (50 ml) and DMF (35 ml). The mixture was treated under a N2 atmosphere with NaH (408 mg) and the mixture was heated at 95° C. oil-bath temperature for 90 Min, cooled to rt and treated with the title compound from Preparative Example 21 (4.78 g). The mixture was then heated at 90-95° C. for 4 h, cooled to rt and quenched with sat. NH4Cl (75 ml) and brine (90 ml). The organic phase was separated and the aqueous layer extracted with EtOAc (2×50 ml). The combined organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 95:5) to afford the title compound (5 g, 82%, MH+=537).
    • Step B
  • The title compound from Step A above (5 g) was dissolved in DMA (90 ml) and treated with NaN3 (5.9 g) and NH4Cl (4.8 g). The mixture was heated under a N2 atmosphere at 100-105° C. for 50 h. The cooled mixture concentrated and the residue dissolved in EtOAc (600 ml) and H2O (200 ml). The aqueous layer was acidified to pH=4 by adding 1 M HCl and the organic phase separated. The aqueous phase was extracted with EtOAc (2×80 ml) and the combined organic extracts washed with 100 mM HCl (200 ml) and brine (200 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH 9:1->4:1) to afford the title compound (4 g, 74%, MH+=580).
    • Step C
  • The title compound from Step B above (4 g) was dissolved in dioxane (153 ml). After the addition of 1 M KOH (42.5 ml), the mixture was stirred at rt overnight. The mixture was concentrated and then 43 ml 1 M HCl added. The precipitate was dissolved in EtOAc (100 ml) and H2O (100 ml) and the organic phase separated. The aqueous phase was extracted with EtOAc (100 ml) and the organic phase combined. The solvent was then removed to afford the title compound (3.9 g, quanta, MH+=552).
    • Preparative Example 62-64
  • Following a similar procedure as that described in Preparative Example 61 but using the sulfamidates and compounds from the Preparative Examples as indicated in the Table below, the title compounds were obtained.
  • Preparative Preparative
    Example Example Sulfamidate Title compound MH+
    62 59
    Figure US20100009961A1-20100114-C00134
    Figure US20100009961A1-20100114-C00135
         		538
    63 59
    Figure US20100009961A1-20100114-C00136
    Figure US20100009961A1-20100114-C00137
         		566
    64 60
    Figure US20100009961A1-20100114-C00138
    Figure US20100009961A1-20100114-C00139
         		475
    • Preparative Example 65
  • If one were to treat the title compound from Preparative Example 59 according to the procedures described in Preparative Example 61, but using the sulfamidate as indicated in the table below, one would obtain the title compound.
  • Preparative Preparative
    Example Example Sulfamidate Title compound
    65 59
    Figure US20100009961A1-20100114-C00140
    Figure US20100009961A1-20100114-C00141
    • Preparative Example 66
  • Figure US20100009961A1-20100114-C00142
    • Step A
  • The title compound from Preparative Example 61 Step A (1000 mg) was suspended in MeOH (10 ml) and hydroxylamine hydrochloride (517 mg) and a 5.5 M solution of sodium methoxide in MeOH (1.4 ml) added. The mixture was heated in a pressure bottle at 110° C. for 12 h and then the solvent removed. The residue was purified by chromatography on silica (cyclohexane/EtOAc 1:3->1:1) to afford the title compound (210 mg, 20%, MH+=570).
    • Step B
  • The title compound from Step A above (180 mg) was dissolved in MeOH (10 ml) and sodium methoxide (233 mg) and diethyl carbonate (1130 mg) added. The mixture was heated at 110° C. in a pressure bottle overnight. The solvent was removed and the residue purified by chromatography on silica (CHCl3) to afford the title compound (110 mg, 58%, M+−27=568).
    • Step C
  • The title compound from Step B above (110 mg) was dissolved in THF (25 ml) and treated with 1M KOH (6 ml). After stirring at rt overnight, 1M HCl (2.8 ml) was added and the solvents removed to afford the crude title compound (105 mg, quant., M+−27=540).
    • Preparative Example 67
  • Figure US20100009961A1-20100114-C00143
    • Step A
  • Hydroxylamine hydrochloride (401 mg) was suspended in anhydrous MeOH (14 ml) and a 5.5 M solution of sodium methoxide in MeOH (0.946 ml) added. This mixture was stirred at rt for 45 min and the title compound from Preparative Example 61 Step A (1400 mg) was added. The resulting mixture was heated in a closed vessel at 100° C. overnight and subsequently allowed to cool down to rt. Due to incomplete conversion, hydroxylamine hydrochloride (401 mg) and a 5.5 M solution of sodium methoxide in MeOH (0.946 ml) were added and the mixture was heated again at 100° C. for 20 h. After cooling down to rt, the salts were filtered off and washed with EtOAc (15 ml) and CHCl3 (15 ml). The united organic phases were evaporated and the residue purified by chromatography on silica (cyclohexane/EtOAc 8:2->6:4) to afford the title compound from Preparative Example 66 Step A (300 mg, 20%, MH+=570) and the title compound (1130 g, 74%, MNa+=577).
    • Step B
  • The title compound from Step A above (1380 g) was dissolved in THF (30 ml) and treated with 1M KOH (9 ml). After stirring at rt overnight, 1M KOH (9 ml) was added and stirring continued for 22 h. The reaction mixture was acidified with 4 M HCl to pH 2-3, extracted with EtOAc/THF 10/1 (4×40 ml) and the combined organic extracts washed with brine (20 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated to afford the title compound (1220 mg, quant., M+−27=499, MNa+=549).
    • Preparative Example 68
  • Figure US20100009961A1-20100114-C00144
    • Step A
  • The N-hydroxyamidine product from Preparative Example 66 Step A (300 mg) was dissolved in anhydrous dichloromethane (5 ml), the solution cooled down to 0° C. and triethylamine (147 μl) and trifluoroacetic anhydride (103 μl) added. The reaction mixture was stirred at rt overnight. Due to incomplete conversion, triethylamine (221 μl) and trifluoroacetic anhydride (155 μl) were added at 0° C. and stirring was continued at rt for 3 d. Dichloromethane (9 ml) and water (10 ml) were added to the stirred mixture. After 5 min, the separated organic phase was washed with brine (5 ml), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 8:2->7:3) to afford the title compounds A (267 mg, 68%, MNa+=766) and B (36 mg, 10%, MNa+=670).
    • Step B
  • The title compounds A (267 mg; MNa+=766) and B (36 mg, MNa+=670) from Step A above were dissolved in dioxane (11 ml) and water added (11 ml). The resulting suspension was treated with 1M NaOH (3.6 ml). After stirring at rt overnight, the reaction mixture was acidified with 1M HCl to pH 2-3, extracted with EtOAc (4×40 ml) and the combined organic phases dried over MgSO4, filtered and concentrated to afford the title compound (282 mg, quant., MNa+=642).
    • Preparative Example 69
  • Figure US20100009961A1-20100114-C00145
    • Step A
  • To the title compound of Preparative Example 61 Step A (500 mg) in anhydrous DMF (10 ml) was added K2CO3 (123 mg). After cooling down to 0° C., methyl iodide (75 μl) was added dropwise to the stirred mixture. After 10 min, the mixture was allowed to rt and stirred overnight. The reaction mixture was cooled down to 0° C., diluted with acidified saturated aq. NaCl solution (pH 2-3) and added to stirred EtOAc (150 ml). The separated organic phase was washed with brine (2×25 ml), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 8:2->7:3) to afford the title compounds: the 1-Me-tetrazole (170 mg, 33%, MH+=580) and the 2-Me-tetrazole (163 mg, 32%, MH+=580).
    • Step B
  • The title compounds from Step A above (170 mg of the 1-Me-tetrazole and 163 mg of the 2-Me-tetrazole) were separately dissolved in dioxane (5.5 ml) and treated with 1M KOH (1.5 ml) each. After stirring at rt for 3 h, the reaction mixtures were concentrated to ⅓ of their volumes and the pH adjusted to 3 with 1M HCl. The resulting aq. suspension was extracted with EtOAc (3×25 ml) and the combined organic phases dried over MgSO4, filtered and concentrated to afford the title compounds: the 1-Me-tetrazole (171 mg, quant., M+−27=524) and the 2-Me-tetrazole (172 mg, quant., M+−27=524).
    • Preparative Example 70
  • Figure US20100009961A1-20100114-C00146
    • Step A
  • The title compound from Preparative Example 61 (2 g) was dissolved in THF (75 ml) and CH3CN (75 ml) and triethylamine (4 ml) added. The mixture was cooled to −40° C. and ethylchloroformate (2.3 ml) was slowly added. The mixture was stirred at −25° C. for 1 h, filtered and the salts washed with 35 ml THF. The filtrate was placed in a cooling bath (−20° C.) and a 33%-solution of NH4OH (30 ml) was added. The mixture was stirred at −20° C. for 30 min and 15 min at rt. Since LC-MS indicated that the conversion was not complete, the mixture was concentrated. The reaction was repeated using the same reaction conditions. After the second run LC-MS indicated that the reaction was completed. The mixture was concentrated to afford the crude title compound together with salts from the reaction (MNa+=572).
    • Step B
  • The crude title compound from Step A above was suspended in CHCl3 (25 ml) and the mixture cooled to 0° C. At 0° C. TFA (25 ml) was added and stirring at 0° C. was continued for 2 h. The mixture was concentrated and the residue dissolved in H2O (15 ml). The pH was adjusted to pH=7.0 by adding 10% NaOH and the neutral solution loaded onto a RP-column (Merck; silica gel 60 RP-18, 40-63 μM). The column was washed with H2O to remove the salts, followed by CH3CN/H2O (1:1) to elute the title compound (1.3 g, 88%, MH+=406).
    • Preparative Example 71-87
  • Treating the compounds from the Preparative Examples with the amines as indicated in the Table below, according to a modified procedure as described in Preparative Example 70, the title compounds were obtained as HCl-salts.
  • Modifications:
    • Step A The crude mixture from Step A was dissolved in H2O and the pH adjusted to pH=4.0 by adding 1 M HCl. The mixture was then extracted with EtOAc, the organic phase separated, dried over MgSO4, filtered and the solvents removed.
    • Step B The residue after removal of the Teoc protecting group was diluted with 1M HCl and the aqueous phase washed with EtOAc. Concentration of the aqueous phase afforded the title compound as HCl-salt.
  • Preparative Preparative
    Example Example Amines Title compound MH+
    71 61
    Figure US20100009961A1-20100114-C00147
    Figure US20100009961A1-20100114-C00148
         		462
    72 61
    Figure US20100009961A1-20100114-C00149
    Figure US20100009961A1-20100114-C00150
         		434
    73 61
    Figure US20100009961A1-20100114-C00151
    Figure US20100009961A1-20100114-C00152
         		462
    74 61
    Figure US20100009961A1-20100114-C00153
    Figure US20100009961A1-20100114-C00154
         		490
    75 61
    Figure US20100009961A1-20100114-C00155
    Figure US20100009961A1-20100114-C00156
         		486
    76 61
    Figure US20100009961A1-20100114-C00157
    Figure US20100009961A1-20100114-C00158
         		546
    77 62
    Figure US20100009961A1-20100114-C00159
    Figure US20100009961A1-20100114-C00160
         		420
    78 62
    Figure US20100009961A1-20100114-C00161
    Figure US20100009961A1-20100114-C00162
         		447
    79 63 NH3
    Figure US20100009961A1-20100114-C00163
         		420
    80 66
    Figure US20100009961A1-20100114-C00164
    Figure US20100009961A1-20100114-C00165
         		478
    81 67
    Figure US20100009961A1-20100114-C00166
    Figure US20100009961A1-20100114-C00167
         		437
    82 68
    Figure US20100009961A1-20100114-C00168
    Figure US20100009961A1-20100114-C00169
         		530
    83 69 1-Me-tetrazole
    Figure US20100009961A1-20100114-C00170
    Figure US20100009961A1-20100114-C00171
         		406
    84 69 2-Me-tetrazole
    Figure US20100009961A1-20100114-C00172
    Figure US20100009961A1-20100114-C00173
         		406
    85 61 Step B none
    Figure US20100009961A1-20100114-C00174
         		436
    86 61 none
    Figure US20100009961A1-20100114-C00175
         		408
    87 64 none
    Figure US20100009961A1-20100114-C00176
         		374
    • Preparative Example 88
  • Figure US20100009961A1-20100114-C00177
    • Step A
  • Commercially available anthraquinone (8.0 g) was suspended in CHCl3 (100 ml) and conc. H2SO4 (20 ml) was added. The resulting biphasic system was rapidly stirred and NaN3 (3.1 g) was added in portions at rt. The mixture was stirred for 1 h at rt and at 30-40° C. (water bath) for another 3 h. After the addition of ice water (80 ml), the precipitate was collected by filtration and dried to afford the title compound (8.40 g; 97%; MH+=224).
    • Step B
  • The title compound from Step A above (8.0 g) was dissolved in DMSO (140 ml) under N2 at 10° C. After the addition of KOtBu (5.7 g), the mixture was stirred for 15 min at that temperature. After the addition of CH3I (4.2 ml), the mixture was allowed to warm to rt and stirred for 2 h. After the addition of 1 M HCl (130 ml) and EtOAc (100 ml), the organic phase was separated and the aqueous phase extracted with EtOAc (2×50 ml). The combined organic phase was washed with H2O (50 ml), brine (50 ml), dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (4.88 g; 61%; MH+=238).
    • Step C
  • Tosylmethyl isocyanide was dissolved in DMSO (10 ml) under N2 at 10° C. and KOtBu (1.36 g) was added. The mixture was stirred for 5 min and MeOH (0.173 ml) was added. The title compound from Step B above (0.8 g) was immediately added to the mixture. After 10 min dibromoethane (1.51 ml) was added and stirring was continued for 1 h at rt. The mixture was diluted with EtOAc (10 ml) and sat. NH4Cl (30 ml) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organic phase was washed with H2O (50 ml), brine (50 ml), dried over MgSO4 and concentrated. The residue was dissolved in DMF (40 ml) and potassium phthalimide (3.13 g) added. The resulting mixture was heated to 60° C. for 3 h and concentrated. The residue was suspended in CHCl3 and filtered. The filtrate was concentrated and the residue purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (612 mg; 43%; MH+=422).
    • Step D
  • The title compound from Step C above (0.6 g) was dissolved in toluene (30 ml) under N2 and dibutyltin oxide (1.68 g) and trimethylsilylazide (8.9 ml) were added. The mixture was then heated at 75° C. for 24 h. The mixture was concentrated, the residue suspended in EtOAc (40 ml) and 1 M HCl (40 ml) and stirred for 2 h at rt. MeOH (10 ml) was added and the organic phase was separated. The aqueous phase was extracted with EtOAc (3×20 ml) and the combined organic phase was washed with brine (20 ml), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica (MeOH/CH2Cl2) to afford the title compound (565 mg; 84%; MH+=465).
    • Step E
  • The title compound from Step D above (0.22 g) was dissolved in EtOH (7 ml) and CHCl3 (3 ml) and the mixture was heated to 80° C. Hydrazine monohydrate (0.108 g) was added and the mixture was stirred at 80° C. for 1 h. The mixture was allowed to cool to rt within 1 h. The precipitate was removed by filtration and washed with EtOH. The filtrate was concentrated and dissolved in CHCl3 (20 ml) and 1 M HCl (10 ml). The aqueous phase was separated, filtered and evaporated to afford the title compound (85 mg; 48%; MH+=335).
    • Preparative Example 89
  • Figure US20100009961A1-20100114-C00178
    • Step A
  • To a solution of the commercially available L-pyroglutamic acid ethylester (15.7 g) in methylene chloride (90 ml) was sequentially added at rt di-tert-butyldicarbonate (24 g) and a catalytic amount of DMAP (120 mg). After stirring for 6 h at rt the reaction mixture was quenched with saturated brine and extracted with methylene chloride. (3×30 ml). The organic phase was dried over MgSO4, concentrated and the residue purified by flash chromatography on silica (CH2Cl2) to afford the title compound (16.3 g, 63%, MNa+=280).
    • Step B
  • A solution of the title compound from Step A above (16.3 g) in toluene (100 ml) was cooled to −78° C. and triethylborohydride (67 ml of a 1.0 M solution in THF) was added dropwise over 90 minutes. After 3 h, 2,6 lutidine (43 ml) was added dropwise followed by DMAP(20 mg). To this mixture was added TFAA (11 ml) and the reaction was allowed to come to ambient temperature over 2 h. The mixture was diluted with ethyl acetate and water and the organics were washed with 3 N HCl, water, aqueous bicarbonate and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 5:1) to afford the title compound (10.9 g, 72%, MNa+=264).
    • Step C
  • A solution of the title compound from Step B above (3.5 g) in 1,2 dichloroethane (75 ml) was cooled to −15° C. and Et2Zn (25 mL of a 1.0 M solution in THF) was added dropwise. To this mixture was added drop wise ClCH2I (4.5 ml) over 30 minutes. After stirring for 18 h at −15° C. the mixture was quenched with saturated aqueous bicarbonate and the solvent was evaporated and the reaction was taken up in ethyl acetate and washed with brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 4:1) to afford the diastereomerically pure title compound (1.5 g, 41%, MNa+=278).
    • Step D
  • A solution of the title compound from Step C above (1.4 g) in MeOH (40 ml) and THF (20 ml) was treated with 1 N LiOH (10 ml) and stirred overnight at rt. The reaction mixture was acidified to pH 4.5 with 2 N HCl and stirred for 15 min at rt. The mixture was then extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and evaporated to afford the title compound (1.2 g, 96%, MNa+=250).
    • Step E
  • To a solution of the title compound from Step D above (1.2 g) in THF (20 ml) was added at −15° C. 4-methylmorpholine (710 μl) and then isobutyl chloroformate (780 μl) over 5 minutes and stirred then for 30 minutes. The reaction mixture was cooled to −30° C. and treated with a solution of NH3 in dioxane (25 ml, 0.5 M in dioxane). The reaction mixture was stirred for 30 minutes, warmed to rt and stirred overnight. The reaction mixture was acidified to pH 4.5 with 10% aqueous citric acid and extracted with ether (3×50 ml). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 1:10) to afford the title compound (1.0 g, 84%, MNa+=248).
    • Step F
  • To a stirred solution o of the title compound from Step E above (0.9 g) in methylene chloride (5 ml) was sequentially added at 0° C. TFA (5 ml). After stirring for 12 h at 0° C. the reaction mixture was concentrated under reduced pressure to afford the title compound (0.9 g, 100%, MH+=127).
    • Step G
  • The title compound from Step F above (450 mg) was dissolved in CH2Cl2 (12 ml) and triethylamine (0.4 ml). The mixture was cooled to 0° C. and DMAP (25 mg) was added followed by fumarylchloride (0.099 ml). The mixture was stirred at 0° C. and allowed to warm to rt overnight. The mixture was concentrated to afford the crude title compound (MH+=333).
    • Step H
  • To a cooled (0° C.) solution of DMF (4 ml) was carefully added oxalylchloride (0.32 ml). After the addition was completed, the mixture was stirred at 0° C. for 5 min. Then pyridine (0.6 ml) was added followed by a solution of the crude title compound from Step G above in DMF (2 ml) and CH2Cl2 (4 ml). The mixture was then stirred at 0° C. for 2 h. The mixture was concentrated and the residue partitioned between EtOAc (50 ml) and brine (25 ml). The organic phase was separated and the aqueous phase extracted with EtOAc (2×25 ml). The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 95:5) to afford the title compound (250 mg, 92%, MH+=297).
    • Step I
  • The title compound from Step H above (328 mg) was dissolved in CHCl3 (3 ml) and MeOH (3 ml). The mixture was then treated with ozone according to Preparative Example 2 Step C to afford the title compound (350 mg, 80%, MH+=165 (aldehyde); MH+=219 (hemiacetal)).
    • Preparative Example 90
  • Figure US20100009961A1-20100114-C00179
    • Step A
  • To a stirred solution of potassium hydroxide (1.2 g) in ethanol (10 mL) was sequentially added at rt the commercial available bis(tert.-butyldicarbonyl)amine (4.5 g). After stirring for 1 h at rt the reaction mixture was quenched with ether and the precipitate was filtered and washed with ether (3×10 mL) to afford the title compound (3.4 g)
    • Step B
  • The title compound from Step A above (95 mg) was dissolved in CHCl3 (2.25 ml) and 1,3-dimethoxybenzene (0.18 ml) added. To the mixture was then added TFA (0.75 ml) and the mixture was stirred at rt for 1 h 30 min. The mixture was concentrated, dissolved in CH3CN (3 ml) and concentrated again. The residue was dissolved in 100 mM HCl (3 ml) and EtOAc (3 ml). The aqueous phase was separated, washed with EtOAc (2 ml) and concentrated. The residue was suspended in CH3CN (1.5 ml), sonicated for 1 min and the CH3CN removed by syringe. The residue was then dried in HV to afford the title compound (42 mg, 84%, MH+=154).
    • Preparative Example 91
  • Figure US20100009961A1-20100114-C00180
    • Step A
  • To a solution of the commercial available Boc-Fmoc-protected amino acid (1.05 g) in methanol (25 ml) was added diethyl amine (1.5 ml). After stirring for 2.5 h at room temperature the reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and Et2O (50 ml). The organic phase was extracted with water (3×50 ml) and the combined aqueous extracts were concentrated. The residue was used for the next step without any further purification.
    • Step B
  • To a solution of the title compound from Step A above (530 mg) and 3-fluorobenzaldehyde (245 μl) in 15 ml of methanol was added NaBH3CN (150 mg), and the mixture was stirred at 25° C. overnight. The mixture was concentrated, and the residue was dissolved in EtOAc (50 ml). The organic layer was extracted with water (3×50 ml) and the combined aqueous extracts were concentrated. The residue was used for the next step without any further purification.
    • Step C
  • To a stirring solution of the title compound from Step B above (760 mg) in DMF (20 ml) was added HOBt (470 mg) followed by EDCI (670 mg) and DMAP (30 mg). N-methyl morpholine (440 μl) was added and stirring was continued at rt overnight. The solvent was removed in vacuo, the residue diluted with EtOAc and then washed with saturated aqueous NaHCO3. The organic phase was dried over MgSO4, concentrated and the residue purified by flash chromatography on silica (CH2Cl2/acetone, 9:1) to afford the title compound (430 mg, 60% over 3 steps, MH+=321).
    • Step D
  • The title compound from Step C above (760 mg) was dissolved in EtOAc (6 ml) and a solution of 4 M HCl in dioxane (6 ml) was added. After 2 h the mixture was triturated with aqueous NaHCO3 to pH 7.5 and stirred for 15 min at rt. After evaporation of the solvent, the crude product was purified by flash chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (420 mg, 80%, MH+=221).
    • Step E
  • To a solution of the title compound from Step D above (85 mg) in THF (5 ml) was added triethylamine (80 μl) and the mixture was stirred for 1 h at 50° C. Then the sulfamidate (240 mg.), prepared according to WO 03/037327, was added in one portion at −15° C. and the mixture was stirred at ambient temperature over 2 d. After the addition of 1 M NH4HCO3 solution (5 ml), the mixture was stirred for 30 min. Then an excess saturated NaHCO3 solution was added and stirring was continued for another 15 min. The mixture was then partitioned between EtOAc and water and the aqueous phase extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica (CH2Cl2/acetone, 9:1) to afford the title compound (135 mg, 79%, MH+=422).
    • Step F
  • A solution of the title compound from Step E above (135 mg) in MeOH (2.5 ml) and THF (5 ml) was treated with 1 N LiOH (1.5 ml) and stirred overnight at rt. The reaction mixture was acidified to pH 4.5 with 2 N HCl and stirred for 15 min at rt. The mixture was then extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and evaporated to afford the title compound (125 mg, 96%, MH+=408).
    • Preparative Example 92
  • Figure US20100009961A1-20100114-C00181
    • Step A
  • A solution of commercially available N-Boc-trans-4-hydroxyl-L-proline ester (2.93 g) in CH2Cl2 (20 ml) was cooled to −30° C. and treated with DIEA (4.8 ml). After the addition of triflic anhydride (2.2 ml), the mixture was stirred at −30° C. for 60 min and then treated with a solution of the commercially available amine in CH2Cl2 (20 ml). The mixture was allowed to warm to rt overnight. The mixture was diluted with CH2Cl2 (20 ml), washed with 0.5 M Na2CO3 (2×50 ml) and brine (50 ml). The organic phase was dried over MgSO4 and concentrated to leave a residue, which was purified by chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (2.22 g, 75%, MH+=367).
    • Step B
  • A solution of the title compound from Step A above (700 mg) in MeOH (24 ml) and THF (12 ml) was treated with 1 N LiOH (6 ml) and stirred overnight at rt. The reaction mixture was acidified to pH 4.5 with 1 N HCl and stirred for 15 min at rt. The mixture was then extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and evaporated to afford the title compound (665 mg, 95%, MH+=353).
    • Step C
  • To a stirring solution of the title compound from Step B above (665 mg) in DMF (15 ml) was added HOBt (390 mg) followed by EDCI (560 mg) and DMAP (30 mg). N-methyl morpholine (420 μl) was added and stirring was continued at rt overnight. The solvent was removed in vacuo, the residue diluted with EtOAc and then washed with saturated aqueous NaHCO3. The organic phase was dried over MgSO4, concentrated and the residue purified by flash chromatography on silica (CH2Cl2/acetone, 9:1) to afford the title compound (556 mg, 87%, MH+=335).
    • Step D
  • The title compound from Step C above (760 mg) was dissolved in EtOAc (4 ml) and a solution of 4 M HCl in dioxane (4 ml) was added. After 2 h the mixture was triturated with aqueous NaHCO3 to pH 7.5 and stirred for 15 min at rt. After evaporation of the solvent, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (300 mg, 77%, MH+=235).
    • Step E
  • To a solution of the title compound from Step D above (290 mg) in THF (5 ml) was added triethyl amine (280 μl) and the mixture was stirred for 1 h at 50° C. Then the sulfamidate (590 mg.), prepared according to WO 03/037327, was added in one portion at −15° C. and the mixture was stirred at ambient temperature over 2 d. After the addition of 1 M NH4HCO3 solution (5 ml), the mixture was stirred for 30 min. Then an excess saturated NaHCO3 solution was added and stirring was continued for another 15 min. The mixture was then partitioned between EtOAc and water and the aqueous phase extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (163 mg, 30%, MH+=436).
    • Step F
  • A solution of the title compound from Step E above (163 mg) in MeOH (2.5 ml) and THF (5 ml) was treated with 1 N LiOH (1.5 ml) and stirred overnight at rt. The reaction mixture was acidified to pH 4.5 with 2 N HCl and stirred for 15 min at rt. The mixture was then extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and evaporated to afford the title compound (140 mg, 96%, MH+=422).
    • Preparative Example 93
  • Figure US20100009961A1-20100114-C00182
    • Step A
  • To a stirring solution of the title compound from Preparative Example 91 (25 mg) in DMF (3 ml) was added HOBt (15 mg), followed by EDCI (20 mg) and DMAP (3 mg). Commercially available (S)-Pyrrolidine-2-carbonitrile hydrochloride (15 mg) was added after 1 h, followed by N-methyl morpholine (20 μl). The mixture was stirred at rt overnight, the solvent removed in vacuo, and the residue was diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO3, separated, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica (CH2Cl2/acetone, 9:1) to afford the title compound (17 mg, 59%, MH+=486).
    • Step B
  • To a stirring solution of the title compound Preparative Example 91 (125 mg) in DMF (5 ml) was HOBt (46 mg), followed by EDCI (65 mg) and DMAP (5 mg). After 1 h commercially available L-proline amide (68 mg) and N-methyl morpholine (100 μl) were added and stirring was continued at rt overnight. The solvent was removed in vacuo, the residue diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (137 mg; 88%; MH+=504).
    • Step C
  • To a solution of the title compound from Step B above (137 mg) in pyridine (7 ml) was added imidazole (41 mg). At −30° C. POCl3 (102 μl) was slowly added to the mixture and the mixture was allowed to reach rt over a period of 1 h. Then the solvent was removed and the residue diluted with 1 N HCl and Et2O. The organic phase was separated, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (72 mg, 55%, MH+=486).
    • Preparative Example 94-108
  • Following a similar procedure as that described in Preparative Examples 92 and 93, except using the amines and amides as indicated in the Table below, the following compound were prepared. For Preparative Examples 105 and 106 the conversion of the nitrile to the carboxamide with subsequent saponification of the ester moiety was done according to Preparative Example 91 Step F with 3M Na2CO3 and H2O2.
  • Preparative 1. Yield
    Example Amide Amine Product 2. MH+
     94
    Figure US20100009961A1-20100114-C00183
    Figure US20100009961A1-20100114-C00184
    Figure US20100009961A1-20100114-C00185
         		1. 55% 2. 498
     95
    Figure US20100009961A1-20100114-C00186
    Figure US20100009961A1-20100114-C00187
    Figure US20100009961A1-20100114-C00188
         		1. 90% 2. 537
     96
    Figure US20100009961A1-20100114-C00189
    Figure US20100009961A1-20100114-C00190
    Figure US20100009961A1-20100114-C00191
         		1. 71% 2. 493
     97
    Figure US20100009961A1-20100114-C00192
    Figure US20100009961A1-20100114-C00193
    Figure US20100009961A1-20100114-C00194
         		1. 70% 2. 504
     98
    Figure US20100009961A1-20100114-C00195
    Figure US20100009961A1-20100114-C00196
    Figure US20100009961A1-20100114-C00197
         		1. 73% 2. 516
     99
    Figure US20100009961A1-20100114-C00198
    Figure US20100009961A1-20100114-C00199
    Figure US20100009961A1-20100114-C00200
         		1. 65% 2. 493
    100
    Figure US20100009961A1-20100114-C00201
    Figure US20100009961A1-20100114-C00202
    Figure US20100009961A1-20100114-C00203
         		1. 54% 2. 505
    101
    Figure US20100009961A1-20100114-C00204
    Figure US20100009961A1-20100114-C00205
    Figure US20100009961A1-20100114-C00206
         		1. 78% 2. 493
    102
    Figure US20100009961A1-20100114-C00207
    Figure US20100009961A1-20100114-C00208
    Figure US20100009961A1-20100114-C00209
         		1. 56% 2. 500
    103
    Figure US20100009961A1-20100114-C00210
    Figure US20100009961A1-20100114-C00211
    Figure US20100009961A1-20100114-C00212
         		1. 65% 2. 512
    104
    Figure US20100009961A1-20100114-C00213
    Figure US20100009961A1-20100114-C00214
    Figure US20100009961A1-20100114-C00215
         		1. 71% 2. 514
    105
    Figure US20100009961A1-20100114-C00216
    Figure US20100009961A1-20100114-C00217
    Figure US20100009961A1-20100114-C00218
         		1. 68% 2. 511
    106
    Figure US20100009961A1-20100114-C00219
    Figure US20100009961A1-20100114-C00220
    Figure US20100009961A1-20100114-C00221
         		1. 56% 2. 511
    107
    Figure US20100009961A1-20100114-C00222
    Figure US20100009961A1-20100114-C00223
    Figure US20100009961A1-20100114-C00224
         		1. 62% 2. 526
    108
    Figure US20100009961A1-20100114-C00225
    Figure US20100009961A1-20100114-C00226
    Figure US20100009961A1-20100114-C00227
         		1. 2.
    • Preparative Example 109
  • Figure US20100009961A1-20100114-C00228
    • Step A
  • A solution of commercially available N-Boc-trans-4-hydroxyl-L-proline methyl ester (370 mg) in CH2Cl2 (2 ml) was cooled to −30° C. and treated with DIEA (600 μl). After the addition of triflic anhydride (280 μl), the mixture was stirred at −30° C. for 60 min and then treated with a solution of the title compound from Preparative Example 91 Step D in CH2Cl2 (2 ml). The mixture was allowed to warm to rt overnight. The mixture was diluted with CH2Cl2 (10 ml), washed with 0.5 M Na2CO3 (2×10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and concentrated to leave a residue, which was purified by chromatography on silica ((CH2Cl2/acetone, 4:1), 4:1) to afford the title compound (225 mg, 33%, MH+=448).
    • Step B
  • A solution of the title compound from Step A above (225 mg) in MeOH (4 ml) and THF (8 ml) was treated with 1 N LiOH (2 ml) and stirred overnight at rt. The reaction mixture was acidified to pH 4.5 with 1 N HCl and stirred for 15 min at rt. The mixture was then extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and evaporated to afford the title compound (91 mg, 40%, MH+=434).
    • Step C
  • To a stirring solution of the title compound from Step B above (91 mg) in DMF (3 ml) was added HOBt (40 mg), followed by EDCI (60 mg) and DMAP (10 mg). Commercially available (S)-Pyrrolidine-2-carbonitrile hydrochloride (35 mg) was added after 1 h, followed by N-methyl morpholine (66 μl). The mixture was stirred at rt overnight, the solvent removed in vacuo, and the residue was diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO3, separated, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica (CH2Cl2/acetone, 1:1) to afford the title compound (50 mg, 47%, MH+=512).
    • Preparative Example 110
  • Figure US20100009961A1-20100114-C00229
    • Step A
  • The title compound from Preparative Example 91 Step D (305 mg) was dissolved in THF (2 ml) was added triethyl amine (63 μl) and the mixture was stirred for 1 h at 50° C. Then the title compound from Preparative Example 19 (100 mg) was added in one portion at −15° C. and the mixture was stirred at ambient temperature overnight. After the addition of 1 M NH4HCO3 solution (5 ml), the mixture was stirred for 30 min. Then an excess saturated NaHCO3 solution was added and stirring was continued for another 15 min. The mixture was then partitioned between EtOAc and water and the aqueous phase extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (58 mg, 57%, MH+=378).
    • Step B
  • The title compound from Step A above (58 mg) was dissolved in EtOAc (2 ml) and a solution of 4 M HCl in dioxane (2 ml) was added. After 2 h the mixture was evaporated to afford the title compound (48 mg, quant., MH+=278).
    • Preparative Example 111
  • Figure US20100009961A1-20100114-C00230
    • Step A
  • Commercially available N-cyclohexylcarbodiimde-N′-methyl polystyrene resin (1.9 g) was suspended in 5 ml dichloromethane and agitated for 5 Min. The commercially available amino acid (468 mg) and amine (86 mg), prepared from the commercially available hydrochloride by adding 1 eq. pyridine, were dissolved in 1.5 ml dimethylformamide and added to the above resin. The mixture was agitated for 16 h, filtered and the resin washed with 2×5 ml dichloromethane and 5 ml methanol. The combined filtrates were concentrated and the residue purified by flash chromatography (silica, CH2Cl2/MeOH, 9:1) to afford the title compound (500 mg; 91%).
  • 1H-NMR (CDCl3): δ 1.45 (9H, s), 2.05-2.30 (4H, m), 3.25-3.40 (1H, m), 3.50-3.70 (2H, m), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 4.30-4.40 (2H, m), 4.55-4.65 (1H, m), 4.70-4.80 (1H, m), 5.50-5.60 (2H, m), 7.25-7.40 (4H, m), 7.55-7.65 (2H, m), 7.70-7.80 (2H, m).
    • Step B
  • The title compound from Step A above (500 mg) was dissolved in dichloromethane (10 ml) and treated with diethylamine (10 ml). After 2 h the mixture was concentrated and the residue was purified by flash chromatography (silica, CH2Cl2/MeOH, 4:1) to afford the title compound (224 mg; 80%).
  • 1H-NMR (CDCl3): δ 1.45 (9H, s), 1.70 (2H, s), 2.05-2.30 (4H, m), 2.95-3.05 (2H, m), 3.70-3.85 (2H, m), 4.35-4.50 (1H, m), 4.75-4.85 (1H, m), 5.50-5.60 (1H, m).
    • Preparative Example 112
  • Figure US20100009961A1-20100114-C00231
    • Step A
  • A solution of commercially available N-Fmoc-trans-4-hydroxyl-L-proline (4.5 g) in aqueous ethanol (80%, 45 ml) was titrated with a solution of Cs2CO3 (2.3 g) in water (18 ml) to pH 7. The solvents were evaporated and the residue dried in vacuo. The caesium salt was suspended in dry DMF (45 ml), cooled to 0° C. and treated with allyl bromide (11.5 ml) by dropwise addition over 10 min. After 30 min the solution was allowed to reach rt and stirring was continued for another 3 h. The reaction mixture was filtered and concentrated. The residue was purified by chromatography on silica (EtOAc/cyclohexane) to afford the title compound (4.5 g, 90%, MH+=394).
    • Step B
  • The title compound from Step A above (2.5 g) in CH2Cl2 (60 ml) was cooled to −30° C. and treated with DIEA (2.5 ml). After the addition of triflic anhydride (1.2 ml), the mixture was stirred at −30° C. for 60 min and then treated with a solution of Preparative Example 84 (1.17 g) in CH2Cl2 (15 ml). The mixture was allowed to warm to 0° C., stirred at 0° C. for 12 h and refluxed for additional 4 h. The mixture was diluted with CH2Cl2 (50 ml), washed with 0.5 M Na2CO3 (2×25 ml) and brine (25 ml). The organic phase was dried over MgSO4 and concentrated to leave a residue, which was purified by chromatography on silica (EtOAc/cyclohexane, 7:3) to afford the title compound (1.41 g, 50%, MH+=658).
    • Step C
  • To the title compound from Step B above (1.8 g) in THF (120 ml) was added dimedone (1.27 g) and Pd(PPh3)4 (422 mg). The reaction mixture was stirred at room temperature for 19 h. Following removal of the solvent under reduced pressure, chromatography on silica (CH2Cl2/MeOH 9:1) afforded the title compound (1.42 g, 84%, MH+=618).
    • Step D
  • To a solution of the title compound from Step C above (1.42 g) in CH2Cl2 (70 ml) was added HOBT (405 mg) followed by EDCI (575 mg) and N-methyl-morpholine (0.33 ml). After being stirred at ambient temperature for 24 h, the solvent was evaporated to give a viscous residue, which was partitioned between EtOAc and ammonium acetate buffer (pH 6). The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic phase dried over MgSO4 and concentrated to afford the title compound (1.35 g, MNH4 +=617).
    • Step E
  • To a solution of the title compound from Step D above (1.35 g) in acetonitrile (100 ml) was added diethyl amine (10 ml). After stirring for 2.5 h at rt, the reaction mixture was concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 9:1) to afford the title compound (712 mg; 85%, MH+=378).
    • Preparative Example 113
  • Figure US20100009961A1-20100114-C00232
  • To a solution of the title compound from Preparative Example 112 (13 mg) in CH2Cl2 (0.8 ml) was added piperidino methyl polystyrene resin (65 mg) and 3-fluorobenzene-1-sulfonyl chloride (5.5 μl). After shaking at rt for 3 h, tris-(2-aminoethyl)amine polystyrene resin (30 mg) was added and agitated for additional 1 h at rt. The mixture was filtered, the resin washed with CH2Cl2 (5 ml) and methanol (1 ml) and the combined filtrates evaporated. Purification by chromatography on silica (CH2Cl2/MeOH 9:1) afforded the title compound (13 mg, 71%, MNH4 +=553).
    • Preparative Example 114-116
  • Following a similar procedure as that described in Preparative Example 113, except using the sulfonic acid chlorides as indicated in the Table below, the following compounds were prepared.
  • Preparative Sulfonic 1. Yield
    Example acid chloride Product 2. MH+
    114
    Figure US20100009961A1-20100114-C00233
    Figure US20100009961A1-20100114-C00234
         		1. 69 2. 541 (MNH4 +)
    115
    Figure US20100009961A1-20100114-C00235
    Figure US20100009961A1-20100114-C00236
         		1. 92 2. 546 (MNa+)
    116
    Figure US20100009961A1-20100114-C00237
    Figure US20100009961A1-20100114-C00238
         		1. 89 2. 604 (MNa+)
    • Preparative Example 117-119
  • Following a similar procedure as that described in Preparative Example 113, except using the acid chlorides as indicated in the Table below, the following compounds were prepared.
  • Preparative Acid 1. Yield
    Example chloride Product 2. MH+
    117
    Figure US20100009961A1-20100114-C00239
    Figure US20100009961A1-20100114-C00240
         		1. 100 2. 488 (MH+)
    118
    Figure US20100009961A1-20100114-C00241
    Figure US20100009961A1-20100114-C00242
         		1. 49 2. 519 (MNH4 +)
    119
    Figure US20100009961A1-20100114-C00243
    Figure US20100009961A1-20100114-C00244
         		1. 70 2. 506 (MNa+)
    • Preparative Example 120
  • Figure US20100009961A1-20100114-C00245
  • To a solution of the title compound from Preparative Example 112 (20 mg) in CH2Cl2 (0.8 ml) was added tert.-butyl isocyanate (5.8 mg). After stirring at room temperature for 3 h the solvent was evaporated. Purification by chromatography (CH2Cl2/acetone 1:1) afford the title compound (16 mg, 63%, MH+=477).
    • Preparative Example 121
  • Following a similar procedure as that described in Preparative Example 120, except using the isocyanate as indicated in the Table below, the following compound was prepared.
  • Preparative 1. Yield
    Example Isocyanate Product 2. MH+
    121
    Figure US20100009961A1-20100114-C00246
    Figure US20100009961A1-20100114-C00247
         		1. 69 2. 592 (MNH4 +)
    • Preparative Example 122
  • Figure US20100009961A1-20100114-C00248
  • The title compound from Preparative Example 15 Step A (13 mg) was dissolved in CH2Cl2 (0.7 ml) and added to N-cyclohexylcarbodiimide, N′-methyl polystyrene resin (120 mg). The mixture was agitated for 15 min and then treated with a solution of the title compound from Preparative Example 112 (0.54 ml, 7.5 mM CH2Cl2). After shaking at rt for 12 h, the mixture was filtered and the resin washed with CH2Cl2 (5 ml). The filtrates were concentrated in vacuo to afford the title compound (30 mg, 95%, MNa+=632).
    • Preparative Example 123
  • Figure US20100009961A1-20100114-C00249
    • Step A
  • Commercially available 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (400 mg) and aziridine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (431 mg) were dissolved in toluene (5 ml). The mixture was stirred at rt overnight and then for 5 h at 80° C. The solvent was removed and the residue purified by chromatography on silica (CH2Cl2/acetone 9:1) to afford the title compound (468 mg, 58%, MH+=434).
    • Step B
  • The title compound from Step A above (245 mg) was dissolved in dioxane (5 ml) and a solution of 4 M HCl in dioxane (5 ml) was added. The mixture was stirred for 2 h at rt and the solvents removed to afford the title compound (208 mg, 100%, MH+=334).
    • Step C
  • To the title compound from Step B above (130 mg) were added CH2Cl2 (10 ml) and pyridine (1 ml). After the addition of commercially available thiophen-2-yl-acetyl chloride (61 mg) the reaction mixture was stirred at rt overnight. The solvent was removed and the residue purified by chromatography on silica (CH2Cl2/acetone 9:1) to afford the title compound (90 mg, 57%, MH+=458).
    • Step D
  • The title compound from Step C above (130 mg) was dissolved in THF (4 ml) and methanol (2 ml). After the addition of 1 M aqueous LiOH-solution (1 ml), the mixture was stirred for 4 h at rt. The solvents were removed and the residue dissolved in water and acidified with 1 M HCl to pH˜4. The mixture was extracted with EtOAc, the organic phase washed with brine, dried over MgSO4 and concentrated to yield the title compound (75 mg, 86%, MH+=444).
    • Step E
  • The title compound from Step D above (75 mg) was dissolved in DMF (5 ml). After the addition of EDCI (38 mg), HOBt (27 mg), N-methylmorpholine (0.15 ml) and DMAP (10 mol %), the mixture was stirred for 1 h at rt. Then commercially available 2-(S)-cyanopyrrolidine hydrochloride was added and the mixture was stirred overnight at rt. The solvent was removed and the residue dissolved in EtOAc, washed with brine, dried over MgSO4. and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc, 7:3) to afford the title compound (27 mg, 30%, MH+=522).
    • Preparative Example 124-125
  • Following a similar procedure as that described in Preparative Example 123, except using the piperazine derivatives and sulfonic acid chlorides as indicated in the Table below, the following compounds were prepared.
  • Piperazine Sulfonic 1. Yield
    Example derivative Acid chloride Product 2. MH+
    124
    Figure US20100009961A1-20100114-C00250
    Figure US20100009961A1-20100114-C00251
    Figure US20100009961A1-20100114-C00252
         		1. 73% 2. 556
    125
    Figure US20100009961A1-20100114-C00253
         		none
    Figure US20100009961A1-20100114-C00254
         		1. 27% 2. 492
  • Preparative Examples 126-129 have been intentionally excluded.
    • Preparative Example 130
  • Figure US20100009961A1-20100114-C00255
    • Step A
  • Commercially available 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (330 mg) in anhydrous THF (5 ml) was cooled to 0° C. and trimethyl-trifluoromethylsilane (300 μl) added, followed by addition of tetrabutylammoniumfluoride (60 μl; 1 M in THF). The reaction mixture was allowed to warm to rt and then stirred for 1 h. After dilution with diethyl ether, the organic phase was washed with brine and the aqueous phase extracted with diethyl ether. The combined organic phases were dried (MgSO4) and evaporated to afford the title compounds as a 1:1 mixture of alcohol and TMS ether (490 mg, 97%, [MH-Boc]+=242 (TMS ether); [MH-Boc]+=170 (alcohol)).
    • Step B
  • The title compounds from Step A above (721 mg) in dichloromethane (5 ml) were added to Dess Martin periodinane (2.32 g) in dichloromethane (15 ml) with stirring. Trifluoroacetic acid (410 μl) was added dropwise and the turbid reaction mixture stirred for 17 h at rt, after which it was directly coated on silica and purified by column chromatography (silica, cyclohexane/EtOAc 90:10->80:20) to afford the title compound (301 mg, 45%, [MH-Boc]+=168).
    • Step C
  • To the title compound from Step B above (106 mg) in dioxane (500 μl) was added 4 M HCl in dioxane (500 μl) and the resulting mixture stirred for 16 h at rt. Diethyl ether was added (2 ml) and the suspension filtered. The precipitate was dried and the title compound obtained as its HCl salt (81 mg, 91%, MH+=186).
  • Preparative Examples 131-199 have been intentionally excluded.
    • Preparative Example 200-294
  • If one were to follow a similar procedure as that described in Preparative Example 61 and in Preparative Example 44, except using the sulfamidates as indicated in the Table below in Step A of Preparative Example 61, one would obtain the title compounds, listed in the following Table in the “product” column.
  • Preparative
    Preparative Example
    Example Sulfamidate Product
    200 24
    Figure US20100009961A1-20100114-C00256
    201 25
    Figure US20100009961A1-20100114-C00257
    202 26
    Figure US20100009961A1-20100114-C00258
    203 27
    Figure US20100009961A1-20100114-C00259
    204 28
    Figure US20100009961A1-20100114-C00260
    205 29
    Figure US20100009961A1-20100114-C00261
    206 30
    Figure US20100009961A1-20100114-C00262
    207 31
    Figure US20100009961A1-20100114-C00263
    208 32
    Figure US20100009961A1-20100114-C00264
    209 33
    Figure US20100009961A1-20100114-C00265
    210 34
    Figure US20100009961A1-20100114-C00266
    211 35
    Figure US20100009961A1-20100114-C00267
    212 36
    Figure US20100009961A1-20100114-C00268
    213 37
    Figure US20100009961A1-20100114-C00269
    214 38
    Figure US20100009961A1-20100114-C00270
    215 39
    Figure US20100009961A1-20100114-C00271
    216 40
    Figure US20100009961A1-20100114-C00272
    217 41
    Figure US20100009961A1-20100114-C00273
    218 42
    Figure US20100009961A1-20100114-C00274
    219 43
    Figure US20100009961A1-20100114-C00275
    220 44
    Figure US20100009961A1-20100114-C00276
    221 45
    Figure US20100009961A1-20100114-C00277
    222 46
    Figure US20100009961A1-20100114-C00278
    223 24
    Figure US20100009961A1-20100114-C00279
    224 23
    Figure US20100009961A1-20100114-C00280
    225 25
    Figure US20100009961A1-20100114-C00281
    226 26
    Figure US20100009961A1-20100114-C00282
    227 27
    Figure US20100009961A1-20100114-C00283
    228 28
    Figure US20100009961A1-20100114-C00284
    229 29
    Figure US20100009961A1-20100114-C00285
    230 30
    Figure US20100009961A1-20100114-C00286
    231 31
    Figure US20100009961A1-20100114-C00287
    232 32
    Figure US20100009961A1-20100114-C00288
    233 33
    Figure US20100009961A1-20100114-C00289
    234 34
    Figure US20100009961A1-20100114-C00290
    235 35
    Figure US20100009961A1-20100114-C00291
    236 36
    Figure US20100009961A1-20100114-C00292
    237 37
    Figure US20100009961A1-20100114-C00293
    238 38
    Figure US20100009961A1-20100114-C00294
    239 39
    Figure US20100009961A1-20100114-C00295
    240 40
    Figure US20100009961A1-20100114-C00296
    241 41
    Figure US20100009961A1-20100114-C00297
    242 42
    Figure US20100009961A1-20100114-C00298
    243 43
    Figure US20100009961A1-20100114-C00299
    244 44
    Figure US20100009961A1-20100114-C00300
    245 45
    Figure US20100009961A1-20100114-C00301
    246 46
    Figure US20100009961A1-20100114-C00302
    247 24
    Figure US20100009961A1-20100114-C00303
    248 23
    Figure US20100009961A1-20100114-C00304
    249 25
    Figure US20100009961A1-20100114-C00305
    250 26
    Figure US20100009961A1-20100114-C00306
    251 27
    Figure US20100009961A1-20100114-C00307
    252 28
    Figure US20100009961A1-20100114-C00308
    253 29
    Figure US20100009961A1-20100114-C00309
    254 30
    Figure US20100009961A1-20100114-C00310
    255 31
    Figure US20100009961A1-20100114-C00311
    256 32
    Figure US20100009961A1-20100114-C00312
    257 33
    Figure US20100009961A1-20100114-C00313
    258 34
    Figure US20100009961A1-20100114-C00314
    259 35
    Figure US20100009961A1-20100114-C00315
    260 36
    Figure US20100009961A1-20100114-C00316
    261 37
    Figure US20100009961A1-20100114-C00317
    262 38
    Figure US20100009961A1-20100114-C00318
    263 39
    Figure US20100009961A1-20100114-C00319
    264 40
    Figure US20100009961A1-20100114-C00320
    265 41
    Figure US20100009961A1-20100114-C00321
    266 42
    Figure US20100009961A1-20100114-C00322
    267 43
    Figure US20100009961A1-20100114-C00323
    268 44
    Figure US20100009961A1-20100114-C00324
    269 45
    Figure US20100009961A1-20100114-C00325
    270 46
    Figure US20100009961A1-20100114-C00326
    271 24
    Figure US20100009961A1-20100114-C00327
    272 23
    Figure US20100009961A1-20100114-C00328
    273 25
    Figure US20100009961A1-20100114-C00329
    274 26
    Figure US20100009961A1-20100114-C00330
    275 27
    Figure US20100009961A1-20100114-C00331
    276 28
    Figure US20100009961A1-20100114-C00332
    277 29
    Figure US20100009961A1-20100114-C00333
    278 30
    Figure US20100009961A1-20100114-C00334
    279 31
    Figure US20100009961A1-20100114-C00335
    280 32
    Figure US20100009961A1-20100114-C00336
    281 33
    Figure US20100009961A1-20100114-C00337
    282 34
    Figure US20100009961A1-20100114-C00338
    283 35
    Figure US20100009961A1-20100114-C00339
    284 36
    Figure US20100009961A1-20100114-C00340
    285 37
    Figure US20100009961A1-20100114-C00341
    286 38
    Figure US20100009961A1-20100114-C00342
    287 39
    Figure US20100009961A1-20100114-C00343
    288 40
    Figure US20100009961A1-20100114-C00344
    289 41
    Figure US20100009961A1-20100114-C00345
    290 42
    Figure US20100009961A1-20100114-C00346
    291 43
    Figure US20100009961A1-20100114-C00347
    292 44
    Figure US20100009961A1-20100114-C00348
    293 45
    Figure US20100009961A1-20100114-C00349
    294 46
    Figure US20100009961A1-20100114-C00350
  • Examples 295-299 have been intentionally excluded.
    • Preparative Example 300
  • Figure US20100009961A1-20100114-C00351
    • Step A
  • If one were to treat the compound from Preparative Example 59 with the sulfimidate from Preparative Example 22 according to the procedure described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with NaN3 as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with acetic acid anhydride in pyridine at 100° C. for 2 h one would obtain, after the removal of the pyridine under reduced pressure and after column chromatography, the title compound.
    • Step D
  • If one were to treat the title compound from Step A above according to the procedures described in Preparative Example 70 one would obtain the title compound.
    • Preparative Example 301-335
  • If one were to follow a similar procedure as that described in Preparative Example 300, except using the appropriate intermediate from the Preparative Examples and anhydrides or acid chlorides and amines as indicated in the Table below, one would obtain the desired amine product.
  • Preparative Preparative Acid Chloride/
    Example Example Anhydride Amine Product
    301 300
    Figure US20100009961A1-20100114-C00352
         		NH3
    Figure US20100009961A1-20100114-C00353
    302 300
    Figure US20100009961A1-20100114-C00354
         		NH3
    Figure US20100009961A1-20100114-C00355
    303 300
    Figure US20100009961A1-20100114-C00356
         		NH3
    Figure US20100009961A1-20100114-C00357
    304  61
    Figure US20100009961A1-20100114-C00358
         		NH3
    Figure US20100009961A1-20100114-C00359
    305  61
    Figure US20100009961A1-20100114-C00360
         		NH3
    Figure US20100009961A1-20100114-C00361
    306  61
    Figure US20100009961A1-20100114-C00362
         		NH3
    Figure US20100009961A1-20100114-C00363
    307  61
    Figure US20100009961A1-20100114-C00364
         		NH3
    Figure US20100009961A1-20100114-C00365
    308  65
    Figure US20100009961A1-20100114-C00366
         		NH3
    Figure US20100009961A1-20100114-C00367
    309  65
    Figure US20100009961A1-20100114-C00368
         		NH3
    Figure US20100009961A1-20100114-C00369
    310  65
    Figure US20100009961A1-20100114-C00370
         		NH3
    Figure US20100009961A1-20100114-C00371
    311  65
    Figure US20100009961A1-20100114-C00372
         		NH3
    Figure US20100009961A1-20100114-C00373
    312 300
    Figure US20100009961A1-20100114-C00374
         		CH3NH2
    Figure US20100009961A1-20100114-C00375
    313 300
    Figure US20100009961A1-20100114-C00376
         		CH3NH2
    Figure US20100009961A1-20100114-C00377
    314 300
    Figure US20100009961A1-20100114-C00378
         		CH3NH2
    Figure US20100009961A1-20100114-C00379
    315 300
    Figure US20100009961A1-20100114-C00380
         		CH3NH2
    Figure US20100009961A1-20100114-C00381
    316  61
    Figure US20100009961A1-20100114-C00382
         		CH3NH2
    Figure US20100009961A1-20100114-C00383
    317  61
    Figure US20100009961A1-20100114-C00384
         		CH3NH2
    Figure US20100009961A1-20100114-C00385
    318  61
    Figure US20100009961A1-20100114-C00386
         		CH3NH2
    Figure US20100009961A1-20100114-C00387
    319  61
    Figure US20100009961A1-20100114-C00388
         		CH3NH2
    Figure US20100009961A1-20100114-C00389
    320  65
    Figure US20100009961A1-20100114-C00390
         		CH3NH2
    Figure US20100009961A1-20100114-C00391
    321  65
    Figure US20100009961A1-20100114-C00392
         		CH3NH2
    Figure US20100009961A1-20100114-C00393
    322  65
    Figure US20100009961A1-20100114-C00394
         		CH3NH2
    Figure US20100009961A1-20100114-C00395
    323  65
    Figure US20100009961A1-20100114-C00396
         		CH3NH2
    Figure US20100009961A1-20100114-C00397
    324 300
    Figure US20100009961A1-20100114-C00398
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00399
    325 300
    Figure US20100009961A1-20100114-C00400
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00401
    326 300
    Figure US20100009961A1-20100114-C00402
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00403
    327 300
    Figure US20100009961A1-20100114-C00404
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00405
    328  61
    Figure US20100009961A1-20100114-C00406
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00407
    329  61
    Figure US20100009961A1-20100114-C00408
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00409
    330  61
    Figure US20100009961A1-20100114-C00410
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00411
    331  61
    Figure US20100009961A1-20100114-C00412
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00413
    332  65
    Figure US20100009961A1-20100114-C00414
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00415
    333  65
    Figure US20100009961A1-20100114-C00416
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00417
    334  65
    Figure US20100009961A1-20100114-C00418
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00419
    335  65
    Figure US20100009961A1-20100114-C00420
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00421
  • Example numbers 336-399 were intentionally excluded.
    • Preparative Example 400-434
  • If one were to follow a similar procedure as that described in Preparative Example 66, except using the appropriate intermediate from the Preparative Examples and hydroxylamine hydrochlorides and amines as indicated in the Table below and treat the products according to Preparative Example 70, one would obtain the desired amine product.
  • Preparative Preparative Hydroxylamine
    Example Example hydrochloride Amine Product
    400 300
    Figure US20100009961A1-20100114-C00422
         		NH3
    Figure US20100009961A1-20100114-C00423
    401 300
    Figure US20100009961A1-20100114-C00424
         		NH3
    Figure US20100009961A1-20100114-C00425
    402 300
    Figure US20100009961A1-20100114-C00426
         		NH3
    Figure US20100009961A1-20100114-C00427
    403 300
    Figure US20100009961A1-20100114-C00428
         		NH3
    Figure US20100009961A1-20100114-C00429
    404  61
    Figure US20100009961A1-20100114-C00430
         		NH3
    Figure US20100009961A1-20100114-C00431
    405  61
    Figure US20100009961A1-20100114-C00432
         		NH3
    Figure US20100009961A1-20100114-C00433
    406  61
    Figure US20100009961A1-20100114-C00434
         		NH3
    Figure US20100009961A1-20100114-C00435
    407  61
    Figure US20100009961A1-20100114-C00436
         		NH3
    Figure US20100009961A1-20100114-C00437
    408  65
    Figure US20100009961A1-20100114-C00438
         		NH3
    Figure US20100009961A1-20100114-C00439
    409  65
    Figure US20100009961A1-20100114-C00440
         		NH3
    Figure US20100009961A1-20100114-C00441
    410  65
    Figure US20100009961A1-20100114-C00442
         		NH3
    Figure US20100009961A1-20100114-C00443
    411  65
    Figure US20100009961A1-20100114-C00444
         		NH3
    Figure US20100009961A1-20100114-C00445
    412 300
    Figure US20100009961A1-20100114-C00446
         		CH3NH2
    Figure US20100009961A1-20100114-C00447
    413 300
    Figure US20100009961A1-20100114-C00448
         		CH3NH2
    Figure US20100009961A1-20100114-C00449
    414 300
    Figure US20100009961A1-20100114-C00450
         		CH3NH2
    Figure US20100009961A1-20100114-C00451
    415 300
    Figure US20100009961A1-20100114-C00452
         		CH3NH2
    Figure US20100009961A1-20100114-C00453
    416  61
    Figure US20100009961A1-20100114-C00454
         		CH3NH2
    Figure US20100009961A1-20100114-C00455
    417  61
    Figure US20100009961A1-20100114-C00456
         		CH3NH2
    Figure US20100009961A1-20100114-C00457
    418  61
    Figure US20100009961A1-20100114-C00458
         		CH3NH2
    Figure US20100009961A1-20100114-C00459
    419  61
    Figure US20100009961A1-20100114-C00460
         		CH3NH2
    Figure US20100009961A1-20100114-C00461
    420  65
    Figure US20100009961A1-20100114-C00462
         		CH3NH2
    Figure US20100009961A1-20100114-C00463
    421  65
    Figure US20100009961A1-20100114-C00464
         		CH3NH2
    Figure US20100009961A1-20100114-C00465
    422  65
    Figure US20100009961A1-20100114-C00466
         		CH3NH2
    Figure US20100009961A1-20100114-C00467
    423  65
    Figure US20100009961A1-20100114-C00468
         		CH3NH2
    Figure US20100009961A1-20100114-C00469
    424 300
    Figure US20100009961A1-20100114-C00470
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00471
    425 300
    Figure US20100009961A1-20100114-C00472
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00473
    426 300
    Figure US20100009961A1-20100114-C00474
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00475
    427 300
    Figure US20100009961A1-20100114-C00476
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00477
    428  61
    Figure US20100009961A1-20100114-C00478
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00479
    429  61
    Figure US20100009961A1-20100114-C00480
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00481
    430  61
    Figure US20100009961A1-20100114-C00482
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00483
    431  65
    Figure US20100009961A1-20100114-C00484
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00485
    432  65
    Figure US20100009961A1-20100114-C00486
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00487
    433  65
    Figure US20100009961A1-20100114-C00488
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00489
    434  65
    Figure US20100009961A1-20100114-C00490
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00491
  • Example numbers 435-499 were intentionally excluded.
    • Preparative Example 500
  • Figure US20100009961A1-20100114-C00492
    • Step A
  • If one were to treat the compound from Preparative Example 300 Step A with conc. HCl in acetic acid according to the procedure described in Preparative Example 49 Step J, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above according to the procedure described in Preparative Example 70 Step A, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above according to the procedure described in Preparative Example 70 Step A but using hydrazine instead of an amine, one would obtain the title compound.
    • Step D
  • If one were to stir the title compound from Step C above with 1 eq. ethyl isocyanate in DMA one would obtain after removing of DMA and the title compound.
    • Step E
  • If one were to treat the title compound from Step D above with a 2% aqueous NaOH at 100° C. for several hours one would obtain after neutralisation, precipitation and recrystallisation from ethanol the title compound.
    • Step F
  • If one were to treat the title compound from Step E above according to the procedure described in Preparative Example 70 Step B, one would obtain the title compound.
    • Preparative Example 501-535
  • If one were to follow a similar procedure as that described in Preparative Example 500, except using the appropriate intermediate from the Preparative Examples and hydrazines and amines as indicated in the Table below, one would obtain the desired amine product.
  • Preparative Preparative
    Example Example Hydrazine Amine Product
    501 300
    Figure US20100009961A1-20100114-C00493
         		NH3
    Figure US20100009961A1-20100114-C00494
    502 300
    Figure US20100009961A1-20100114-C00495
         		NH3
    Figure US20100009961A1-20100114-C00496
    503 300
    Figure US20100009961A1-20100114-C00497
         		NH3
    Figure US20100009961A1-20100114-C00498
    504 61 N2H4 NH3
    Figure US20100009961A1-20100114-C00499
    505 61
    Figure US20100009961A1-20100114-C00500
         		NH3
    Figure US20100009961A1-20100114-C00501
    506 61
    Figure US20100009961A1-20100114-C00502
         		NH3
    Figure US20100009961A1-20100114-C00503
    507 61
    Figure US20100009961A1-20100114-C00504
         		NH3
    Figure US20100009961A1-20100114-C00505
    508 65 N2H4 NH3
    Figure US20100009961A1-20100114-C00506
    509 65
    Figure US20100009961A1-20100114-C00507
         		NH3
    Figure US20100009961A1-20100114-C00508
    510 65
    Figure US20100009961A1-20100114-C00509
         		NH3
    Figure US20100009961A1-20100114-C00510
    511 65 NH3
    Figure US20100009961A1-20100114-C00511
    512 300 N2H4 CH3NH2
    Figure US20100009961A1-20100114-C00512
    513 300
    Figure US20100009961A1-20100114-C00513
         		CH3NH2
    Figure US20100009961A1-20100114-C00514
    514 300
    Figure US20100009961A1-20100114-C00515
         		CH3NH2
    Figure US20100009961A1-20100114-C00516
    515 300
    Figure US20100009961A1-20100114-C00517
         		CH3NH2
    Figure US20100009961A1-20100114-C00518
    516 61 N2H4 CH3NH2
    Figure US20100009961A1-20100114-C00519
    517 61
    Figure US20100009961A1-20100114-C00520
         		CH3NH2
    Figure US20100009961A1-20100114-C00521
    518 61
    Figure US20100009961A1-20100114-C00522
         		CH3NH2
    Figure US20100009961A1-20100114-C00523
    519 61
    Figure US20100009961A1-20100114-C00524
         		CH3NH2
    Figure US20100009961A1-20100114-C00525
    520 65 N2H4 CH3NH2
    Figure US20100009961A1-20100114-C00526
    521 65
    Figure US20100009961A1-20100114-C00527
         		CH3NH2
    Figure US20100009961A1-20100114-C00528
    522 65
    Figure US20100009961A1-20100114-C00529
         		CH3NH2
    Figure US20100009961A1-20100114-C00530
    523 65
    Figure US20100009961A1-20100114-C00531
         		CH3NH2
    Figure US20100009961A1-20100114-C00532
    524 300 N2H4 (CH3)2NH
    Figure US20100009961A1-20100114-C00533
    525 300
    Figure US20100009961A1-20100114-C00534
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00535
    526 300
    Figure US20100009961A1-20100114-C00536
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00537
    527 300
    Figure US20100009961A1-20100114-C00538
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00539
    528 61 N2H4 (CH3)2NH
    Figure US20100009961A1-20100114-C00540
    529 61
    Figure US20100009961A1-20100114-C00541
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00542
    530 61
    Figure US20100009961A1-20100114-C00543
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00544
    531 61
    Figure US20100009961A1-20100114-C00545
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00546
    532 65 N2H4 (CH3)2NH
    Figure US20100009961A1-20100114-C00547
    533 65
    Figure US20100009961A1-20100114-C00548
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00549
    534 65
    Figure US20100009961A1-20100114-C00550
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00551
    535 65
    Figure US20100009961A1-20100114-C00552
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00553
  • Example numbers 536-599 were intentionally excluded.
    • Preparative Example 600
  • Figure US20100009961A1-20100114-C00554
    • Step A
  • If one were to treat the intermediate from Preparative Example 300 Step A with dry HCl gas in EtOH/CHCl3 at 0° C. and set aside for 10 days, one would obtain after removal of the solvents the imidate hydrochloride. If one were to treat the imidate hydrochloride with NH3 in dry EtOH and heat it to reflux for 7 h, one would obtain, after filtration and evaporation of the filtrate followed by recrystallization, the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with Boc2O according to the procedure described in Preparative Example 49 Step J but without the acid treatment, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above according to Preparative Example 61 Step C, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above according to the procedures described in Preparative Example 70, one would obtain the title compound.
    • Preparative Example 601-635
  • If one were to follow a similar procedure as that described in Preparative Example 600 except using the amines and appropriate intermediate from the Preparative Examples as indicated in the Table below, one would obtain the desired amine product.
  • Preparative Preparative Amine Amine
    Example Example Step A Step B Product
    601 300 CH3NH2 NH3
    Figure US20100009961A1-20100114-C00555
    602 300
    Figure US20100009961A1-20100114-C00556
         		NH3
    Figure US20100009961A1-20100114-C00557
    603 300
    Figure US20100009961A1-20100114-C00558
         		NH3
    Figure US20100009961A1-20100114-C00559
    604 61 NH3 NH3
    Figure US20100009961A1-20100114-C00560
    605 61 CH3NH2 NH3
    Figure US20100009961A1-20100114-C00561
    606 61
    Figure US20100009961A1-20100114-C00562
         		NH3
    Figure US20100009961A1-20100114-C00563
    607 61
    Figure US20100009961A1-20100114-C00564
         		NH3
    Figure US20100009961A1-20100114-C00565
    608 65 NH3 NH3
    Figure US20100009961A1-20100114-C00566
    609 65 CH3NH2 NH3
    Figure US20100009961A1-20100114-C00567
    610 65
    Figure US20100009961A1-20100114-C00568
         		NH3
    Figure US20100009961A1-20100114-C00569
    611 65
    Figure US20100009961A1-20100114-C00570
         		NH3
    Figure US20100009961A1-20100114-C00571
    612 300 NH3 CH3NH2
    Figure US20100009961A1-20100114-C00572
    613 300 CH3NH2 CH3NH2
    Figure US20100009961A1-20100114-C00573
    614 300
    Figure US20100009961A1-20100114-C00574
         		CH3NH2
    Figure US20100009961A1-20100114-C00575
    615 300
    Figure US20100009961A1-20100114-C00576
         		CH3NH2
    Figure US20100009961A1-20100114-C00577
    616 61 NH3 CH3NH2
    Figure US20100009961A1-20100114-C00578
    617 61 CH3NH2 CH3NH2
    Figure US20100009961A1-20100114-C00579
    618 61
    Figure US20100009961A1-20100114-C00580
         		CH3NH2
    Figure US20100009961A1-20100114-C00581
    619 61
    Figure US20100009961A1-20100114-C00582
         		CH3NH2
    Figure US20100009961A1-20100114-C00583
    620 65 NH3 CH3NH2
    Figure US20100009961A1-20100114-C00584
    621 65 CH3NH2 CH3NH2
    Figure US20100009961A1-20100114-C00585
    622 65
    Figure US20100009961A1-20100114-C00586
         		CH3NH2
    Figure US20100009961A1-20100114-C00587
    623 65
    Figure US20100009961A1-20100114-C00588
         		CH3NH2
    Figure US20100009961A1-20100114-C00589
    624 300 NH3 (CH3)2NH
    Figure US20100009961A1-20100114-C00590
    625 300 CH3NH2 (CH3)2NH
    Figure US20100009961A1-20100114-C00591
    626 300
    Figure US20100009961A1-20100114-C00592
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00593
    627 300
    Figure US20100009961A1-20100114-C00594
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00595
    628 61 NH3 (CH3)2NH
    Figure US20100009961A1-20100114-C00596
    629 61 CH3NH2 (CH3)2NH
    Figure US20100009961A1-20100114-C00597
    630 61
    Figure US20100009961A1-20100114-C00598
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00599
    631 61
    Figure US20100009961A1-20100114-C00600
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00601
    632 65 NH3 (CH3)2NH
    Figure US20100009961A1-20100114-C00602
    633 65 CH3NH2 (CH3)2NH
    Figure US20100009961A1-20100114-C00603
    634 65
    Figure US20100009961A1-20100114-C00604
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00605
    635 65
    Figure US20100009961A1-20100114-C00606
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00607
  • Example numbers 636-679 were intentionally excluded.
    • Preparative Example 680-687
  • If one were to follow a similar procedure as that described in Preparative Example 67 and 70, except using the appropriate intermediate from the Preparative Examples and amines as indicated in the Table below, one would obtain the desired amine product.
  • Prepa-
    rative Preparative
    Example Example Amine Product
    680 300 NH3
    Figure US20100009961A1-20100114-C00608
    681 61 NH3
    Figure US20100009961A1-20100114-C00609
    682 65 NH3
    Figure US20100009961A1-20100114-C00610
    683 300 CH3NH2
    Figure US20100009961A1-20100114-C00611
    684 61 CH3NH2
    Figure US20100009961A1-20100114-C00612
    685 65 CH3NH2
    Figure US20100009961A1-20100114-C00613
    686 300 (CH3)2NH
    Figure US20100009961A1-20100114-C00614
    687 65 (CH3)2NH
    Figure US20100009961A1-20100114-C00615
  • Example numbers 688-699 were intentionally excluded.
    • Preparative Example 700
  • Figure US20100009961A1-20100114-C00616
    • Step A
  • If one were to treat the compound from Preparative Example 300 Step A with hydroxylamine hydrochloride and base according to Preparative Example 67 Step A, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above according to Preparative Example 67 Step B, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from step B above with Lawesson's Reagent in toluene and heat the mixture to reflux for 4 h, one would obtain after column chromatography the title compound.
    • Step D
  • If one were to treat the title compound from Step C above with formic acid hydrazide (Pellizzari-Synthesis), one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above according to the procedures described in Preparative Example 70, one would obtain the title compound.
    • Preparative Example 701-735
  • If one were to follow a similar procedure as that described in Preparative Example 700, except using the appropriate intermediate from the Preparative Examples, acid hydrazides and amines as indicated in the Table below, one would obtain the desired amine product.
  • Preparative Preparative Acid
    Example Example hydrazide Amine Product
    701 300
    Figure US20100009961A1-20100114-C00617
         		NH3
    Figure US20100009961A1-20100114-C00618
    702 300
    Figure US20100009961A1-20100114-C00619
         		NH3
    Figure US20100009961A1-20100114-C00620
    703 300
    Figure US20100009961A1-20100114-C00621
         		NH3
    Figure US20100009961A1-20100114-C00622
    704 61
    Figure US20100009961A1-20100114-C00623
         		NH3
    Figure US20100009961A1-20100114-C00624
    705 61
    Figure US20100009961A1-20100114-C00625
         		NH3
    Figure US20100009961A1-20100114-C00626
    706 61
    Figure US20100009961A1-20100114-C00627
         		NH3
    Figure US20100009961A1-20100114-C00628
    707 61
    Figure US20100009961A1-20100114-C00629
         		NH3
    Figure US20100009961A1-20100114-C00630
    708 65
    Figure US20100009961A1-20100114-C00631
         		NH3
    Figure US20100009961A1-20100114-C00632
    709 65
    Figure US20100009961A1-20100114-C00633
         		NH3
    Figure US20100009961A1-20100114-C00634
    710 65
    Figure US20100009961A1-20100114-C00635
         		NH3
    Figure US20100009961A1-20100114-C00636
    711 65
    Figure US20100009961A1-20100114-C00637
         		NH3
    Figure US20100009961A1-20100114-C00638
    712 300
    Figure US20100009961A1-20100114-C00639
         		CH3NH2
    Figure US20100009961A1-20100114-C00640
    713 300
    Figure US20100009961A1-20100114-C00641
         		CH3NH2
    Figure US20100009961A1-20100114-C00642
    714 300
    Figure US20100009961A1-20100114-C00643
         		CH3NH2
    Figure US20100009961A1-20100114-C00644
    715 300
    Figure US20100009961A1-20100114-C00645
         		CH3NH2
    Figure US20100009961A1-20100114-C00646
    716 61
    Figure US20100009961A1-20100114-C00647
         		CH3NH2
    Figure US20100009961A1-20100114-C00648
    717 61
    Figure US20100009961A1-20100114-C00649
         		CH3NH2
    Figure US20100009961A1-20100114-C00650
    718 61
    Figure US20100009961A1-20100114-C00651
         		CH3NH2
    Figure US20100009961A1-20100114-C00652
    719 61
    Figure US20100009961A1-20100114-C00653
         		CH3NH2
    Figure US20100009961A1-20100114-C00654
    720 65
    Figure US20100009961A1-20100114-C00655
         		CH3NH2
    Figure US20100009961A1-20100114-C00656
    721 65
    Figure US20100009961A1-20100114-C00657
         		CH3NH2
    Figure US20100009961A1-20100114-C00658
    722 65
    Figure US20100009961A1-20100114-C00659
         		CH3NH2
    Figure US20100009961A1-20100114-C00660
    723 65
    Figure US20100009961A1-20100114-C00661
         		CH3NH2
    Figure US20100009961A1-20100114-C00662
    724 300
    Figure US20100009961A1-20100114-C00663
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00664
    725 300
    Figure US20100009961A1-20100114-C00665
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00666
    726 300
    Figure US20100009961A1-20100114-C00667
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00668
    727 300
    Figure US20100009961A1-20100114-C00669
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00670
    728 61
    Figure US20100009961A1-20100114-C00671
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00672
    729 61
    Figure US20100009961A1-20100114-C00673
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00674
    730 61
    Figure US20100009961A1-20100114-C00675
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00676
    731 61
    Figure US20100009961A1-20100114-C00677
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00678
    732 65
    Figure US20100009961A1-20100114-C00679
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00680
    733 65
    Figure US20100009961A1-20100114-C00681
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00682
    734 65
    Figure US20100009961A1-20100114-C00683
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00684
    735 65
    Figure US20100009961A1-20100114-C00685
         		(CH3)2NH
    Figure US20100009961A1-20100114-C00686
  • Example numbers 736-779 were intentionally excluded.
    • Preparative Example 780
  • Figure US20100009961A1-20100114-C00687
  • If one were to treat the starting material, which was obtained by treating the title compound from Preparative Example 300 Step A according to the procedures described in Preparative Example 500 Step A-C, according to the procedure described in Preparative Example 70 Step B, one would obtain the title compound.
    • Preparative Example 781-788
  • If one were to follow a similar procedure as that described in Preparative Example 780, except using the appropriate intermediate from the Preparative Examples and amines as indicated in the Table below, one would obtain the desired amine product.
  • Preparative Preparative
    Example Example Amine Product
    781 61 NH3
    Figure US20100009961A1-20100114-C00688
    782 65 NH3
    Figure US20100009961A1-20100114-C00689
    783 300 CH3NH2
    Figure US20100009961A1-20100114-C00690
    784 61 CH3NH2
    Figure US20100009961A1-20100114-C00691
    785 65 CH3NH2
    Figure US20100009961A1-20100114-C00692
    786 300 (CH3)2NH
    Figure US20100009961A1-20100114-C00693
    787 61 (CH3)2NH
    Figure US20100009961A1-20100114-C00694
    788 65 (CH3)2NH
    Figure US20100009961A1-20100114-C00695
  • Example numbers 789-799 were intentionally excluded.
    • Preparative Example 800
  • Figure US20100009961A1-20100114-C00696
    • Step A
  • If one were to treat commercial available N methyl anthranilic acid with 2 eq. of 2-bromo-5-chloronitrobenzene, 10 eq. of potassium carbonate and a catalytic amount of copper powder in 3-methylbutan-1-ol under reflux for several hours one would obtain, after removing of the volatile compound by steam distillation, acidification of the residue with 2 M HCl, precipitation and recrystallisation of the precipitate from ethanol, the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with 7 eq. of sodium dithionite in 2 M aqueous ammonia at 80° C. one would obtain, after filtration, acidification of the filtrate with glacial acetic acid to pH 4, precipitation and recrystallisation from methanol, the title compound.
    • Step C
  • If one were to reflux the title compound from Step B above in xylene under Dean Stark conditions one would obtain, after evaporation of the solvent, washing of the residue with 2 M aqueous ammonia and recrystallisation from acetone, the title compound.
    • Step D
  • If one were to treat the title compound from Step C above with the sulfamidate from Preparative Example 22 according to Preparative Example 61 Step A one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step A above with TFA as described in Preparative Example 70 Step B, one would obtain the title compound.
    • Preparative Example 801-805
  • If one were to follow a similar procedure as that described in Preparative Example 800, except using the diazepines and sulfamidates as indicated in the Table below, one would obtain the desired amine product.
  • Preparative
    Example Diazepine Sulfamidate Product
    801
    Figure US20100009961A1-20100114-C00697
         		22
    Figure US20100009961A1-20100114-C00698
    802
    Figure US20100009961A1-20100114-C00699
         		21
    Figure US20100009961A1-20100114-C00700
    803
    Figure US20100009961A1-20100114-C00701
         		24
    Figure US20100009961A1-20100114-C00702
    804
    Figure US20100009961A1-20100114-C00703
         		21
    Figure US20100009961A1-20100114-C00704
    805
    Figure US20100009961A1-20100114-C00705
         		24
    Figure US20100009961A1-20100114-C00706
  • Examples 806-809 have been intentionally excluded.
    • Preparative Example 810
  • Figure US20100009961A1-20100114-C00707
    • Step A
  • If one were to treat commercially available 10,10-dimethyl-10H-anthracen-9-one and concentrated sulphuric acid in chloroform in a flask equipped with reflux condenser with sodium azide at room temperature, followed by heating this mixture at 50° C. and subsequently pouring it on crushed ice followed by neutralization with conc. aqueous ammonia, separation and evaporation of the organic phase, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with the sulfamidate from Preparative Example 22 as described in Preparative Example 800, one would obtain the title compound.
    • Preparative Example 811-812
  • If one were to follow a similar procedure as described in Preparative Example 810, except using the azepines and sulfamidates as indicated in the able below, one would obtain the desired amine product.
  • Preparative
    Example Azepine Sulfamidate Product
    811
    Figure US20100009961A1-20100114-C00708
         		24
    Figure US20100009961A1-20100114-C00709
    812
    Figure US20100009961A1-20100114-C00710
         		21
    Figure US20100009961A1-20100114-C00711
  • Examples 813-829 have been intentionally excluded.
    • Preparative Example 830
  • Figure US20100009961A1-20100114-C00712
    Figure US20100009961A1-20100114-C00713
    • Step AA
  • If one were to add a solution of commercially available 2-amino-2-methyl-1-propanol in methylene chloride to a solution of commercially available 2-thiophenecarbonyl chloride in methylene chloride dropwise while maintaining the temperature below 20° C., subsequently stir the mixture at room temperature for 2 h and wash with water, dry the organic layer (MgSO4) and evaporate, suspend the residue in toluene and add thionyl chloride dropwise with stirring while maintaining the temperature below 30° C., subsequently continue the stirring overnight, evaporate the toluene, dissolve the residue in water, basify with 1 N aqueous NaOH and extract with ether, then, after drying (MgSO4) and evaporation of the solvent, followed by distillation, one would obtain the title compound.
    • Step BB
  • If one were to add commercial -nBuLi in hexane to the title compound from Step AA above in ether at −78° C., stir the mixture under argon for 0.25 h, add DMF, allow the mixture to slowly warm to room temperature and leave the mixture at this temperature for 18 h, subsequently add water and ether, separate the organic solution, wash with water, brine and dry the solution (MgSO4), then, after evaporation of the solvent, followed by chromatographic purification, one would obtain the title compound.
    • Step CC
  • If one were to boil the title compound from Step BB above under reflux with 4M aqueous hydrochloric acid under argon atmosphere for 14 h, saturate the cooled solution with NaCl, extract repeatedly with ethyl acetate, dry the combined organic extracts (MgSO4), then, after evaporation of the solvent, followed by recrystallization from ethyl acetate/hexane, one would obtain the title compound.
    • Step DD
  • If one were to treat the title compound from Step CC above in methanol dropwise with an ethereal solution of diazomethane at −15° C., followed by careful removal of all volatiles, then one would obtain the title compound.
    • Step A
  • If one were to add commercially available methyl 4-methylthiophene-2-carboxylate to N-bromosuccinimide, benzoyl peroxide and tetrachloromethane and would heat the mixture under reflux for 4 h followed by filtration and evaporation of the solvent, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with triphenylphosphine according to Preparative Example 51 Step C, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with the thiophene aldehyde from Step DD as described in Preparative Example 54 Step A, one would obtain the title compound.
    • Step D
  • If one were to treat a suspension of the title compound from Step C above, hydroiodic acid and red phosphorus at 140° C. for 18 h, followed by cooling and pouring the reaction mixture into an ice/water mixture, subsequent filtration, washing of the precipitate with water, dissolving the precipitate in refluxing conc. ammonia and subsequent filtration, acidification of the filtrate with conc. aqueous hydrochloric acid and extraction of the aqueous phase with dichloromethane, washing of the organic phase with water and drying (MgSO4) followed by evaporation of the solvent, one would obtain the title compound.
    • Step E
  • If one were to treat a suspension of the title compound from Step D above with polyphosphoric acid at 170° C., followed by cooling to 30° C., pouring into water, extraction with diethyl ether, washing with 1N aqueous sodium hydroxide solution and drying (MgSO4) followed by evaporation of the solvent, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 59 Step H and Step I, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above with the compound from Preparative Example 22 as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 831
  • Figure US20100009961A1-20100114-C00714
    • Step A
  • If one were to treat the title compound from Preparative Example 830 as described in Preparative Example 71 Step A, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 832-839
  • If one were to follow a similar procedure as that described in Preparative Example 830, except using the sulfamidates in Step H, and treat the product obtained according to Preparative Example 831 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salts.
  • Preparative
    Example Sulfamidate Amine Title compound
    831 21 NH3
    Figure US20100009961A1-20100114-C00715
    832 24 NH3
    Figure US20100009961A1-20100114-C00716
    833 22 NH3
    Figure US20100009961A1-20100114-C00717
    834 21 CH3NH2
    Figure US20100009961A1-20100114-C00718
    835 24 CH3NH2
    Figure US20100009961A1-20100114-C00719
    836 22 CH3NH2
    Figure US20100009961A1-20100114-C00720
    837 24 (CH3)2NH
    Figure US20100009961A1-20100114-C00721
    838 22 (CH3)2NH
    Figure US20100009961A1-20100114-C00722
  • Examples 839 to 849 have been intentionally excluded.
    • Preparative Example 850
  • Figure US20100009961A1-20100114-C00723
    Figure US20100009961A1-20100114-C00724
    • Step AA
  • If one were to treat commercially available thiophene-3-carbaldehyde with bromine and aluminium trichloride in dichloromethane and heat the reaction mixture for 2 h, subsequently pouring it into water, followed by extraction with ether, washing of the organic phase successively with aqueous 1N NaOH solution and water until neutral, then, after drying (MgSO4) and evaporation of the solvent, followed by distillation, one would obtain the title compound.
    • Step BB
  • If one were to treat a solution of the title compound from Step AA above in tetrahydrofuran with NaBH4 for 1 h and quench the reaction by the addition of saturated aqueous ammonium chloride solution followed by dilution with ethyl acetate, separation of the organic layer, washing with H2O and brine, then, after drying (MgSO4) and evaporation of the solvent, one would obtain the title compound.
    • Step CC
  • If one were to treat a solution of the title compound from Step BB above in chloroform with thionyl chloride at room temperature for 4 h, subsequently pouring it into water, followed by extraction with chloroform, washing of the organic phase with water, then, after drying (MgSO4) and evaporation of the solvent, one would obtain the title compound.
    • Step A
  • If one were to treat commercially available 2-bromo-3-methylthiophene in acetic acid with N-chlorosuccinimide and stir the reaction mixture for about 2 h, then refluxing it for 1 h, subsequently pouring it into water, followed by extraction with ether, washing of the organic phase successively with aqueous 1N NaOH solution and water until neutral, then, after drying (MgSO4) and evaporation of the solvent, followed by distillation, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 59 Step A, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with the title compound from Step CC above, as described in Preparative Example 59 Step B, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step C, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 59 Step D, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step E and Step F, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above as described in Preparative Example 59 Step H and Step I, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step K
  • If one were to treat the title compound from Step J above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 851
  • Figure US20100009961A1-20100114-C00725
    • Step A
  • If one were to treat the title compound from Preparative Example 851 as described in Preparative Example 71 Step A one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 852-859
  • If one were to follow a similar procedure as that described in Preparative Example 850, except using the sulfamidates in Step I, and treat the product obtained according to Preparative Example 851 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    852 21 NH3
    Figure US20100009961A1-20100114-C00726
    853 24 NH3
    Figure US20100009961A1-20100114-C00727
    854 22 NH3
    Figure US20100009961A1-20100114-C00728
    855 21 CH3NH2
    Figure US20100009961A1-20100114-C00729
    856 24 CH3NH2
    Figure US20100009961A1-20100114-C00730
    857 22 CH3NH2
    Figure US20100009961A1-20100114-C00731
    858 24 (CH3)2NH
    Figure US20100009961A1-20100114-C00732
    859 22 (CH3)2NH
    Figure US20100009961A1-20100114-C00733
  • Examples 860-899 have been intentionally excluded.
    • Preparative Example 900
  • Figure US20100009961A1-20100114-C00734
    • Step AA
  • If one were to add a solution of commercially available 2-(3bromo-2-thienyl)-1,3-dioxolane in dry diethylether with stirring to 1.05 N butyl lithium in diethylether at −70° C., followed by addition of the mixture to solid CO2 covered with diethylether. Hydrolysis, followed by extraction with diluted aqueous sodium hydroxide, acidification, then extraction with diethylether afford the title compound.
    • Step BB
  • If one were to add H2SO4 and methanol to a solution of the title compound from step AA above in dichloroethane, one would obtain the title compound.
    • Step A
  • If one were to treat a solution of commercially available 5-methylthiophene-2-carboxylic acid in benzene and methanol at 0° C. dropwise with 2.0 M trimethylsilyldiazo-methane in hexanes, one would obtain the methyl ester. If one were to treat a solution of that ester intermediate in CCl4 with NBS and 2,2′-azobisisobutyronitrile (AIBN) and heat the solution to reflux for 2 h, followed by cooling down to room temperature, filtration and concentration in vacuo one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with triphenylphosphine according to Preparative Example 49 Step C, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with the title compound from Step BB above as described in Preparative Example 54 Step A, one would obtain the title compound.
    • Step D
  • If one were to heat a mixture of the title compound from Step C, red phosphorous and hydroiodic acid in acetic acid at 110° C. for 1 h, one would obtain a solution after filtration of the hot mixture. After cooling to room temperature and pouring in ice water one would obtain the title compound by suction.
    • Step E
  • If one were to heat a mixture of the title compound from Step D above and polyphosphoric acid at 115° C. for 1.5 h one would obtain a mixture, which was poured on ice. After extraction with Ether washing the organic phases with water, drying (MgSO4) and removing of the solvent one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 59 Step H and Step I, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above with the compound from Preparative Example 22 as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 901
  • Figure US20100009961A1-20100114-C00735
    • Step A
  • If one were to treat the title compound from Preparative Example 900 as described in Preparative Example 71 Step A, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 902-909
  • If one were to follow a similar procedure as that described in Preparative Example 900, except using the sulfamidates in Step H, and treat the product obtained according to Preparative Example 901 with the amines as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    902 21 NH3
    Figure US20100009961A1-20100114-C00736
    903 24 NH3
    Figure US20100009961A1-20100114-C00737
    904 22 NH3
    Figure US20100009961A1-20100114-C00738
    905 21 CH3NH2
    Figure US20100009961A1-20100114-C00739
    906 24 CH3NH2
    Figure US20100009961A1-20100114-C00740
    907 22 CH3NH2
    Figure US20100009961A1-20100114-C00741
    908 24 (CH3)2NH
    Figure US20100009961A1-20100114-C00742
    909 22 (CH3)2NH
    Figure US20100009961A1-20100114-C00743
  • Examples 910-919 have been intentionally excluded.
    • Preparative Example 920
  • Figure US20100009961A1-20100114-C00744
    • Step A
  • If one were to add a solution of bromine in CHCl3 slowly to an ice-cooled solution of commercially available 2-chloro-5-methylthiophene in CHCl3 one would obtain a reaction mixture which was stirred for 2 h at room temperature, and subsequently poured into H2O. If one were to extract than the mixture with dichloromethane combine the organic extracts dry filter and evaporate the solvent, one would obtain a yellow/brown oil.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 59 Step A, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with commercially available 2-chloro-5-chloromethyl-thiophene as described in Preparative Example 59 Step B, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step C, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 59 Step D, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step E and Step F, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step G above as described in Preparative Example 59 Step H and Step I, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step K
  • If one were to treat the title compound from Step J above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 921
  • Figure US20100009961A1-20100114-C00745
    • Step A
  • If one were to treat the title compound from Preparative Example 920 as described in Preparative Example 71 Step A one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 922-929
  • If one were to follow a similar procedure as that described in Preparative Example 920, except using the sulfamidates in Step I, and treat the product obtained according to Preparative Example 921 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    922 21 NH3
    Figure US20100009961A1-20100114-C00746
    923 24 NH3
    Figure US20100009961A1-20100114-C00747
    924 22 NH3
    Figure US20100009961A1-20100114-C00748
    925 21 CH3NH2
    Figure US20100009961A1-20100114-C00749
    926 24 CH3NH2
    Figure US20100009961A1-20100114-C00750
    927 22 CH3NH2
    Figure US20100009961A1-20100114-C00751
    928 24 (CH3)2NH
    Figure US20100009961A1-20100114-C00752
    929 22 (CH3)2NH
    Figure US20100009961A1-20100114-C00753
  • Examples 930-999 have been intentionally excluded.
    • Preparative Example 1000-1209
  • If one were to follow similar procedure as described in Preparative Examples 92 and 93, except using the amides and amines as indicated in the Table below, the following title compound would be obtained.
  • Prep
    Example Amide Amines Title compound
    1000
    Figure US20100009961A1-20100114-C00754
    Figure US20100009961A1-20100114-C00755
    Figure US20100009961A1-20100114-C00756
    1001
    Figure US20100009961A1-20100114-C00757
    Figure US20100009961A1-20100114-C00758
    Figure US20100009961A1-20100114-C00759
    1002
    Figure US20100009961A1-20100114-C00760
    Figure US20100009961A1-20100114-C00761
    Figure US20100009961A1-20100114-C00762
    1003
    Figure US20100009961A1-20100114-C00763
    Figure US20100009961A1-20100114-C00764
    Figure US20100009961A1-20100114-C00765
    1004
    Figure US20100009961A1-20100114-C00766
    Figure US20100009961A1-20100114-C00767
    Figure US20100009961A1-20100114-C00768
    1005
    Figure US20100009961A1-20100114-C00769
    Figure US20100009961A1-20100114-C00770
    Figure US20100009961A1-20100114-C00771
    1006
    Figure US20100009961A1-20100114-C00772
    Figure US20100009961A1-20100114-C00773
    Figure US20100009961A1-20100114-C00774
    1007
    Figure US20100009961A1-20100114-C00775
    Figure US20100009961A1-20100114-C00776
    Figure US20100009961A1-20100114-C00777
    1008
    Figure US20100009961A1-20100114-C00778
    Figure US20100009961A1-20100114-C00779
    Figure US20100009961A1-20100114-C00780
    1009
    Figure US20100009961A1-20100114-C00781
    Figure US20100009961A1-20100114-C00782
    Figure US20100009961A1-20100114-C00783
    1010
    Figure US20100009961A1-20100114-C00784
    Figure US20100009961A1-20100114-C00785
    Figure US20100009961A1-20100114-C00786
    1011
    Figure US20100009961A1-20100114-C00787
    Figure US20100009961A1-20100114-C00788
    Figure US20100009961A1-20100114-C00789
    1012
    Figure US20100009961A1-20100114-C00790
    Figure US20100009961A1-20100114-C00791
    Figure US20100009961A1-20100114-C00792
    1013
    Figure US20100009961A1-20100114-C00793
    Figure US20100009961A1-20100114-C00794
    Figure US20100009961A1-20100114-C00795
    1014
    Figure US20100009961A1-20100114-C00796
    Figure US20100009961A1-20100114-C00797
    Figure US20100009961A1-20100114-C00798
    1015
    Figure US20100009961A1-20100114-C00799
    Figure US20100009961A1-20100114-C00800
    Figure US20100009961A1-20100114-C00801
    1016
    Figure US20100009961A1-20100114-C00802
    Figure US20100009961A1-20100114-C00803
    Figure US20100009961A1-20100114-C00804
    1017
    Figure US20100009961A1-20100114-C00805
    Figure US20100009961A1-20100114-C00806
    Figure US20100009961A1-20100114-C00807
    1018
    Figure US20100009961A1-20100114-C00808
    Figure US20100009961A1-20100114-C00809
    Figure US20100009961A1-20100114-C00810
    1019
    Figure US20100009961A1-20100114-C00811
    Figure US20100009961A1-20100114-C00812
    Figure US20100009961A1-20100114-C00813
    1020
    Figure US20100009961A1-20100114-C00814
    Figure US20100009961A1-20100114-C00815
    Figure US20100009961A1-20100114-C00816
    1021
    Figure US20100009961A1-20100114-C00817
    Figure US20100009961A1-20100114-C00818
    Figure US20100009961A1-20100114-C00819
    1022
    Figure US20100009961A1-20100114-C00820
    Figure US20100009961A1-20100114-C00821
    Figure US20100009961A1-20100114-C00822
    1023
    Figure US20100009961A1-20100114-C00823
    Figure US20100009961A1-20100114-C00824
    Figure US20100009961A1-20100114-C00825
    1024
    Figure US20100009961A1-20100114-C00826
    Figure US20100009961A1-20100114-C00827
    Figure US20100009961A1-20100114-C00828
    1025
    Figure US20100009961A1-20100114-C00829
    Figure US20100009961A1-20100114-C00830
    Figure US20100009961A1-20100114-C00831
    1026
    Figure US20100009961A1-20100114-C00832
    Figure US20100009961A1-20100114-C00833
    Figure US20100009961A1-20100114-C00834
    1027
    Figure US20100009961A1-20100114-C00835
    Figure US20100009961A1-20100114-C00836
    Figure US20100009961A1-20100114-C00837
    1028
    Figure US20100009961A1-20100114-C00838
    Figure US20100009961A1-20100114-C00839
    Figure US20100009961A1-20100114-C00840
    1029
    Figure US20100009961A1-20100114-C00841
    Figure US20100009961A1-20100114-C00842
    Figure US20100009961A1-20100114-C00843
    1030
    Figure US20100009961A1-20100114-C00844
    Figure US20100009961A1-20100114-C00845
    Figure US20100009961A1-20100114-C00846
    1031
    Figure US20100009961A1-20100114-C00847
    Figure US20100009961A1-20100114-C00848
    Figure US20100009961A1-20100114-C00849
    1032
    Figure US20100009961A1-20100114-C00850
    Figure US20100009961A1-20100114-C00851
    Figure US20100009961A1-20100114-C00852
    1033
    Figure US20100009961A1-20100114-C00853
    Figure US20100009961A1-20100114-C00854
    Figure US20100009961A1-20100114-C00855
    1034
    Figure US20100009961A1-20100114-C00856
    Figure US20100009961A1-20100114-C00857
    Figure US20100009961A1-20100114-C00858
    1035
    Figure US20100009961A1-20100114-C00859
    Figure US20100009961A1-20100114-C00860
    Figure US20100009961A1-20100114-C00861
    1036
    Figure US20100009961A1-20100114-C00862
    Figure US20100009961A1-20100114-C00863
    Figure US20100009961A1-20100114-C00864
    1037
    Figure US20100009961A1-20100114-C00865
    Figure US20100009961A1-20100114-C00866
    Figure US20100009961A1-20100114-C00867
    1038
    Figure US20100009961A1-20100114-C00868
    Figure US20100009961A1-20100114-C00869
    Figure US20100009961A1-20100114-C00870
    1039
    Figure US20100009961A1-20100114-C00871
    Figure US20100009961A1-20100114-C00872
    Figure US20100009961A1-20100114-C00873
    1040
    Figure US20100009961A1-20100114-C00874
    Figure US20100009961A1-20100114-C00875
    Figure US20100009961A1-20100114-C00876
    1041
    Figure US20100009961A1-20100114-C00877
    Figure US20100009961A1-20100114-C00878
    Figure US20100009961A1-20100114-C00879
    1042
    Figure US20100009961A1-20100114-C00880
    Figure US20100009961A1-20100114-C00881
    Figure US20100009961A1-20100114-C00882
    1043
    Figure US20100009961A1-20100114-C00883
    Figure US20100009961A1-20100114-C00884
    Figure US20100009961A1-20100114-C00885
    1044
    Figure US20100009961A1-20100114-C00886
    Figure US20100009961A1-20100114-C00887
    Figure US20100009961A1-20100114-C00888
    1045
    Figure US20100009961A1-20100114-C00889
    Figure US20100009961A1-20100114-C00890
    Figure US20100009961A1-20100114-C00891
    1046
    Figure US20100009961A1-20100114-C00892
    Figure US20100009961A1-20100114-C00893
    Figure US20100009961A1-20100114-C00894
    1047
    Figure US20100009961A1-20100114-C00895
    Figure US20100009961A1-20100114-C00896
    Figure US20100009961A1-20100114-C00897
    1048
    Figure US20100009961A1-20100114-C00898
    Figure US20100009961A1-20100114-C00899
    Figure US20100009961A1-20100114-C00900
    1049
    Figure US20100009961A1-20100114-C00901
    Figure US20100009961A1-20100114-C00902
    Figure US20100009961A1-20100114-C00903
    1050
    Figure US20100009961A1-20100114-C00904
    Figure US20100009961A1-20100114-C00905
    Figure US20100009961A1-20100114-C00906
    1051
    Figure US20100009961A1-20100114-C00907
    Figure US20100009961A1-20100114-C00908
    Figure US20100009961A1-20100114-C00909
    1052
    Figure US20100009961A1-20100114-C00910
    Figure US20100009961A1-20100114-C00911
    Figure US20100009961A1-20100114-C00912
    1053
    Figure US20100009961A1-20100114-C00913
    Figure US20100009961A1-20100114-C00914
    Figure US20100009961A1-20100114-C00915
    1054
    Figure US20100009961A1-20100114-C00916
    Figure US20100009961A1-20100114-C00917
    Figure US20100009961A1-20100114-C00918
    1055
    Figure US20100009961A1-20100114-C00919
    Figure US20100009961A1-20100114-C00920
    Figure US20100009961A1-20100114-C00921
    1056
    Figure US20100009961A1-20100114-C00922
    Figure US20100009961A1-20100114-C00923
    Figure US20100009961A1-20100114-C00924
    1057
    Figure US20100009961A1-20100114-C00925
    Figure US20100009961A1-20100114-C00926
    Figure US20100009961A1-20100114-C00927
    1058
    Figure US20100009961A1-20100114-C00928
    Figure US20100009961A1-20100114-C00929
    Figure US20100009961A1-20100114-C00930
    1059
    Figure US20100009961A1-20100114-C00931
    Figure US20100009961A1-20100114-C00932
    Figure US20100009961A1-20100114-C00933
    1060
    Figure US20100009961A1-20100114-C00934
    Figure US20100009961A1-20100114-C00935
    Figure US20100009961A1-20100114-C00936
    1061
    Figure US20100009961A1-20100114-C00937
    Figure US20100009961A1-20100114-C00938
    Figure US20100009961A1-20100114-C00939
    1062
    Figure US20100009961A1-20100114-C00940
    Figure US20100009961A1-20100114-C00941
    Figure US20100009961A1-20100114-C00942
    1063
    Figure US20100009961A1-20100114-C00943
    Figure US20100009961A1-20100114-C00944
    Figure US20100009961A1-20100114-C00945
    1064
    Figure US20100009961A1-20100114-C00946
    Figure US20100009961A1-20100114-C00947
    Figure US20100009961A1-20100114-C00948
    1065
    Figure US20100009961A1-20100114-C00949
    Figure US20100009961A1-20100114-C00950
    Figure US20100009961A1-20100114-C00951
    1066
    Figure US20100009961A1-20100114-C00952
    Figure US20100009961A1-20100114-C00953
    Figure US20100009961A1-20100114-C00954
    1067
    Figure US20100009961A1-20100114-C00955
    Figure US20100009961A1-20100114-C00956
    Figure US20100009961A1-20100114-C00957
    1068
    Figure US20100009961A1-20100114-C00958
    Figure US20100009961A1-20100114-C00959
    Figure US20100009961A1-20100114-C00960
    1069
    Figure US20100009961A1-20100114-C00961
    Figure US20100009961A1-20100114-C00962
    Figure US20100009961A1-20100114-C00963
    1070
    Figure US20100009961A1-20100114-C00964
    Figure US20100009961A1-20100114-C00965
    Figure US20100009961A1-20100114-C00966
    1071
    Figure US20100009961A1-20100114-C00967
    Figure US20100009961A1-20100114-C00968
    Figure US20100009961A1-20100114-C00969
    1072
    Figure US20100009961A1-20100114-C00970
    Figure US20100009961A1-20100114-C00971
    Figure US20100009961A1-20100114-C00972
    1073
    Figure US20100009961A1-20100114-C00973
    Figure US20100009961A1-20100114-C00974
    Figure US20100009961A1-20100114-C00975
    1074
    Figure US20100009961A1-20100114-C00976
    Figure US20100009961A1-20100114-C00977
    Figure US20100009961A1-20100114-C00978
    1075
    Figure US20100009961A1-20100114-C00979
    Figure US20100009961A1-20100114-C00980
    Figure US20100009961A1-20100114-C00981
    1076
    Figure US20100009961A1-20100114-C00982
    Figure US20100009961A1-20100114-C00983
    Figure US20100009961A1-20100114-C00984
    1077
    Figure US20100009961A1-20100114-C00985
    Figure US20100009961A1-20100114-C00986
    Figure US20100009961A1-20100114-C00987
    1078
    Figure US20100009961A1-20100114-C00988
    Figure US20100009961A1-20100114-C00989
    Figure US20100009961A1-20100114-C00990
    1079
    Figure US20100009961A1-20100114-C00991
    Figure US20100009961A1-20100114-C00992
    Figure US20100009961A1-20100114-C00993
    1080
    Figure US20100009961A1-20100114-C00994
    Figure US20100009961A1-20100114-C00995
    Figure US20100009961A1-20100114-C00996
    1081
    Figure US20100009961A1-20100114-C00997
    Figure US20100009961A1-20100114-C00998
    Figure US20100009961A1-20100114-C00999
    1082
    Figure US20100009961A1-20100114-C01000
    Figure US20100009961A1-20100114-C01001
    Figure US20100009961A1-20100114-C01002
    1083
    Figure US20100009961A1-20100114-C01003
    Figure US20100009961A1-20100114-C01004
    Figure US20100009961A1-20100114-C01005
    1084
    Figure US20100009961A1-20100114-C01006
    Figure US20100009961A1-20100114-C01007
    Figure US20100009961A1-20100114-C01008
    1085
    Figure US20100009961A1-20100114-C01009
    Figure US20100009961A1-20100114-C01010
    Figure US20100009961A1-20100114-C01011
    1086
    Figure US20100009961A1-20100114-C01012
    Figure US20100009961A1-20100114-C01013
    Figure US20100009961A1-20100114-C01014
    1087
    Figure US20100009961A1-20100114-C01015
    Figure US20100009961A1-20100114-C01016
    Figure US20100009961A1-20100114-C01017
    1088
    Figure US20100009961A1-20100114-C01018
    Figure US20100009961A1-20100114-C01019
    Figure US20100009961A1-20100114-C01020
    1089
    Figure US20100009961A1-20100114-C01021
    Figure US20100009961A1-20100114-C01022
    Figure US20100009961A1-20100114-C01023
    1090
    Figure US20100009961A1-20100114-C01024
    Figure US20100009961A1-20100114-C01025
    Figure US20100009961A1-20100114-C01026
    1091
    Figure US20100009961A1-20100114-C01027
    Figure US20100009961A1-20100114-C01028
    Figure US20100009961A1-20100114-C01029
    1092
    Figure US20100009961A1-20100114-C01030
    Figure US20100009961A1-20100114-C01031
    Figure US20100009961A1-20100114-C01032
    1093
    Figure US20100009961A1-20100114-C01033
    Figure US20100009961A1-20100114-C01034
    Figure US20100009961A1-20100114-C01035
    1094
    Figure US20100009961A1-20100114-C01036
    Figure US20100009961A1-20100114-C01037
    Figure US20100009961A1-20100114-C01038
    1095
    Figure US20100009961A1-20100114-C01039
    Figure US20100009961A1-20100114-C01040
    Figure US20100009961A1-20100114-C01041
    1096
    Figure US20100009961A1-20100114-C01042
    Figure US20100009961A1-20100114-C01043
    Figure US20100009961A1-20100114-C01044
    1097
    Figure US20100009961A1-20100114-C01045
    Figure US20100009961A1-20100114-C01046
    Figure US20100009961A1-20100114-C01047
    1098
    Figure US20100009961A1-20100114-C01048
    Figure US20100009961A1-20100114-C01049
    Figure US20100009961A1-20100114-C01050
    1099
    Figure US20100009961A1-20100114-C01051
    Figure US20100009961A1-20100114-C01052
    Figure US20100009961A1-20100114-C01053
    1100
    Figure US20100009961A1-20100114-C01054
    Figure US20100009961A1-20100114-C01055
    Figure US20100009961A1-20100114-C01056
    1101
    Figure US20100009961A1-20100114-C01057
    Figure US20100009961A1-20100114-C01058
    Figure US20100009961A1-20100114-C01059
    1102
    Figure US20100009961A1-20100114-C01060
    Figure US20100009961A1-20100114-C01061
    Figure US20100009961A1-20100114-C01062
    1103
    Figure US20100009961A1-20100114-C01063
    Figure US20100009961A1-20100114-C01064
    Figure US20100009961A1-20100114-C01065
    1104
    Figure US20100009961A1-20100114-C01066
    Figure US20100009961A1-20100114-C01067
    Figure US20100009961A1-20100114-C01068
    1105
    Figure US20100009961A1-20100114-C01069
    Figure US20100009961A1-20100114-C01070
    Figure US20100009961A1-20100114-C01071
    1106
    Figure US20100009961A1-20100114-C01072
    Figure US20100009961A1-20100114-C01073
    Figure US20100009961A1-20100114-C01074
    1107
    Figure US20100009961A1-20100114-C01075
    Figure US20100009961A1-20100114-C01076
    Figure US20100009961A1-20100114-C01077
    1108
    Figure US20100009961A1-20100114-C01078
    Figure US20100009961A1-20100114-C01079
    Figure US20100009961A1-20100114-C01080
    1109
    Figure US20100009961A1-20100114-C01081
    Figure US20100009961A1-20100114-C01082
    Figure US20100009961A1-20100114-C01083
    1110
    Figure US20100009961A1-20100114-C01084
    Figure US20100009961A1-20100114-C01085
    Figure US20100009961A1-20100114-C01086
    1111
    Figure US20100009961A1-20100114-C01087
    Figure US20100009961A1-20100114-C01088
    Figure US20100009961A1-20100114-C01089
    1112
    Figure US20100009961A1-20100114-C01090
    Figure US20100009961A1-20100114-C01091
    Figure US20100009961A1-20100114-C01092
    1113
    Figure US20100009961A1-20100114-C01093
    Figure US20100009961A1-20100114-C01094
    Figure US20100009961A1-20100114-C01095
    1114
    Figure US20100009961A1-20100114-C01096
    Figure US20100009961A1-20100114-C01097
    Figure US20100009961A1-20100114-C01098
    1115
    Figure US20100009961A1-20100114-C01099
    Figure US20100009961A1-20100114-C01100
    Figure US20100009961A1-20100114-C01101
    1116
    Figure US20100009961A1-20100114-C01102
    Figure US20100009961A1-20100114-C01103
    Figure US20100009961A1-20100114-C01104
    1117
    Figure US20100009961A1-20100114-C01105
    Figure US20100009961A1-20100114-C01106
    Figure US20100009961A1-20100114-C01107
    1118
    Figure US20100009961A1-20100114-C01108
    Figure US20100009961A1-20100114-C01109
    Figure US20100009961A1-20100114-C01110
    1119
    Figure US20100009961A1-20100114-C01111
    Figure US20100009961A1-20100114-C01112
    Figure US20100009961A1-20100114-C01113
    1120
    Figure US20100009961A1-20100114-C01114
    Figure US20100009961A1-20100114-C01115
    Figure US20100009961A1-20100114-C01116
    1121
    Figure US20100009961A1-20100114-C01117
    Figure US20100009961A1-20100114-C01118
    Figure US20100009961A1-20100114-C01119
    1122
    Figure US20100009961A1-20100114-C01120
    Figure US20100009961A1-20100114-C01121
    Figure US20100009961A1-20100114-C01122
    1123
    Figure US20100009961A1-20100114-C01123
    Figure US20100009961A1-20100114-C01124
    Figure US20100009961A1-20100114-C01125
    1124
    Figure US20100009961A1-20100114-C01126
    Figure US20100009961A1-20100114-C01127
    Figure US20100009961A1-20100114-C01128
    1125
    Figure US20100009961A1-20100114-C01129
    Figure US20100009961A1-20100114-C01130
    Figure US20100009961A1-20100114-C01131
    1126
    Figure US20100009961A1-20100114-C01132
    Figure US20100009961A1-20100114-C01133
    Figure US20100009961A1-20100114-C01134
    1127
    Figure US20100009961A1-20100114-C01135
    Figure US20100009961A1-20100114-C01136
    Figure US20100009961A1-20100114-C01137
    1128
    Figure US20100009961A1-20100114-C01138
    Figure US20100009961A1-20100114-C01139
    Figure US20100009961A1-20100114-C01140
    1129
    Figure US20100009961A1-20100114-C01141
    Figure US20100009961A1-20100114-C01142
    Figure US20100009961A1-20100114-C01143
    1130
    Figure US20100009961A1-20100114-C01144
    Figure US20100009961A1-20100114-C01145
    Figure US20100009961A1-20100114-C01146
    1131
    Figure US20100009961A1-20100114-C01147
    Figure US20100009961A1-20100114-C01148
    Figure US20100009961A1-20100114-C01149
    1132
    Figure US20100009961A1-20100114-C01150
    Figure US20100009961A1-20100114-C01151
    Figure US20100009961A1-20100114-C01152
    1133
    Figure US20100009961A1-20100114-C01153
    Figure US20100009961A1-20100114-C01154
    Figure US20100009961A1-20100114-C01155
    1134
    Figure US20100009961A1-20100114-C01156
    Figure US20100009961A1-20100114-C01157
    Figure US20100009961A1-20100114-C01158
    1135
    Figure US20100009961A1-20100114-C01159
    Figure US20100009961A1-20100114-C01160
    Figure US20100009961A1-20100114-C01161
    1136
    Figure US20100009961A1-20100114-C01162
    Figure US20100009961A1-20100114-C01163
    Figure US20100009961A1-20100114-C01164
    1137
    Figure US20100009961A1-20100114-C01165
    Figure US20100009961A1-20100114-C01166
    Figure US20100009961A1-20100114-C01167
    1138
    Figure US20100009961A1-20100114-C01168
    Figure US20100009961A1-20100114-C01169
    Figure US20100009961A1-20100114-C01170
    1139
    Figure US20100009961A1-20100114-C01171
    Figure US20100009961A1-20100114-C01172
    Figure US20100009961A1-20100114-C01173
    1140
    Figure US20100009961A1-20100114-C01174
    Figure US20100009961A1-20100114-C01175
    Figure US20100009961A1-20100114-C01176
    1141
    Figure US20100009961A1-20100114-C01177
    Figure US20100009961A1-20100114-C01178
    Figure US20100009961A1-20100114-C01179
    1142
    Figure US20100009961A1-20100114-C01180
    Figure US20100009961A1-20100114-C01181
    Figure US20100009961A1-20100114-C01182
    1143
    Figure US20100009961A1-20100114-C01183
    Figure US20100009961A1-20100114-C01184
    Figure US20100009961A1-20100114-C01185
    1144
    Figure US20100009961A1-20100114-C01186
    Figure US20100009961A1-20100114-C01187
    Figure US20100009961A1-20100114-C01188
    1145
    Figure US20100009961A1-20100114-C01189
    Figure US20100009961A1-20100114-C01190
    Figure US20100009961A1-20100114-C01191
    1146
    Figure US20100009961A1-20100114-C01192
    Figure US20100009961A1-20100114-C01193
    Figure US20100009961A1-20100114-C01194
    1147
    Figure US20100009961A1-20100114-C01195
    Figure US20100009961A1-20100114-C01196
    Figure US20100009961A1-20100114-C01197
    1148
    Figure US20100009961A1-20100114-C01198
    Figure US20100009961A1-20100114-C01199
    Figure US20100009961A1-20100114-C01200
    1149
    Figure US20100009961A1-20100114-C01201
    Figure US20100009961A1-20100114-C01202
    Figure US20100009961A1-20100114-C01203
    1150
    Figure US20100009961A1-20100114-C01204
    Figure US20100009961A1-20100114-C01205
    Figure US20100009961A1-20100114-C01206
    1151
    Figure US20100009961A1-20100114-C01207
    Figure US20100009961A1-20100114-C01208
    Figure US20100009961A1-20100114-C01209
    1152
    Figure US20100009961A1-20100114-C01210
    Figure US20100009961A1-20100114-C01211
    Figure US20100009961A1-20100114-C01212
    1153
    Figure US20100009961A1-20100114-C01213
    Figure US20100009961A1-20100114-C01214
    Figure US20100009961A1-20100114-C01215
    1154
    Figure US20100009961A1-20100114-C01216
    Figure US20100009961A1-20100114-C01217
    Figure US20100009961A1-20100114-C01218
    1155
    Figure US20100009961A1-20100114-C01219
    Figure US20100009961A1-20100114-C01220
    Figure US20100009961A1-20100114-C01221
    1156
    Figure US20100009961A1-20100114-C01222
    Figure US20100009961A1-20100114-C01223
    Figure US20100009961A1-20100114-C01224
    1157
    Figure US20100009961A1-20100114-C01225
    Figure US20100009961A1-20100114-C01226
    Figure US20100009961A1-20100114-C01227
    1158
    Figure US20100009961A1-20100114-C01228
    Figure US20100009961A1-20100114-C01229
    Figure US20100009961A1-20100114-C01230
    1159
    Figure US20100009961A1-20100114-C01231
    Figure US20100009961A1-20100114-C01232
    Figure US20100009961A1-20100114-C01233
    1160
    Figure US20100009961A1-20100114-C01234
    Figure US20100009961A1-20100114-C01235
    Figure US20100009961A1-20100114-C01236
    1161
    Figure US20100009961A1-20100114-C01237
    Figure US20100009961A1-20100114-C01238
    Figure US20100009961A1-20100114-C01239
    1162
    Figure US20100009961A1-20100114-C01240
    Figure US20100009961A1-20100114-C01241
    Figure US20100009961A1-20100114-C01242
    1163
    Figure US20100009961A1-20100114-C01243
    Figure US20100009961A1-20100114-C01244
    Figure US20100009961A1-20100114-C01245
    1164
    Figure US20100009961A1-20100114-C01246
    Figure US20100009961A1-20100114-C01247
    Figure US20100009961A1-20100114-C01248
    1165
    Figure US20100009961A1-20100114-C01249
    Figure US20100009961A1-20100114-C01250
    Figure US20100009961A1-20100114-C01251
    1166
    Figure US20100009961A1-20100114-C01252
    Figure US20100009961A1-20100114-C01253
    Figure US20100009961A1-20100114-C01254
    1167
    Figure US20100009961A1-20100114-C01255
    Figure US20100009961A1-20100114-C01256
    Figure US20100009961A1-20100114-C01257
    1168
    Figure US20100009961A1-20100114-C01258
    Figure US20100009961A1-20100114-C01259
    Figure US20100009961A1-20100114-C01260
    1169
    Figure US20100009961A1-20100114-C01261
    Figure US20100009961A1-20100114-C01262
    Figure US20100009961A1-20100114-C01263
    1170
    Figure US20100009961A1-20100114-C01264
    Figure US20100009961A1-20100114-C01265
    Figure US20100009961A1-20100114-C01266
    1171
    Figure US20100009961A1-20100114-C01267
    Figure US20100009961A1-20100114-C01268
    Figure US20100009961A1-20100114-C01269
    1172
    Figure US20100009961A1-20100114-C01270
    Figure US20100009961A1-20100114-C01271
    Figure US20100009961A1-20100114-C01272
    1173
    Figure US20100009961A1-20100114-C01273
    Figure US20100009961A1-20100114-C01274
    Figure US20100009961A1-20100114-C01275
    1174
    Figure US20100009961A1-20100114-C01276
    Figure US20100009961A1-20100114-C01277
    Figure US20100009961A1-20100114-C01278
    1175
    Figure US20100009961A1-20100114-C01279
    Figure US20100009961A1-20100114-C01280
    Figure US20100009961A1-20100114-C01281
    1176
    Figure US20100009961A1-20100114-C01282
    Figure US20100009961A1-20100114-C01283
    Figure US20100009961A1-20100114-C01284
    1177
    Figure US20100009961A1-20100114-C01285
    Figure US20100009961A1-20100114-C01286
    Figure US20100009961A1-20100114-C01287
    1178
    Figure US20100009961A1-20100114-C01288
    Figure US20100009961A1-20100114-C01289
    Figure US20100009961A1-20100114-C01290
    1179
    Figure US20100009961A1-20100114-C01291
    Figure US20100009961A1-20100114-C01292
    Figure US20100009961A1-20100114-C01293
    1180
    Figure US20100009961A1-20100114-C01294
    Figure US20100009961A1-20100114-C01295
    Figure US20100009961A1-20100114-C01296
    1181
    Figure US20100009961A1-20100114-C01297
    Figure US20100009961A1-20100114-C01298
    Figure US20100009961A1-20100114-C01299
    1182
    Figure US20100009961A1-20100114-C01300
    Figure US20100009961A1-20100114-C01301
    Figure US20100009961A1-20100114-C01302
    1183
    Figure US20100009961A1-20100114-C01303
    Figure US20100009961A1-20100114-C01304
    Figure US20100009961A1-20100114-C01305
    1184
    Figure US20100009961A1-20100114-C01306
    Figure US20100009961A1-20100114-C01307
    Figure US20100009961A1-20100114-C01308
    1185
    Figure US20100009961A1-20100114-C01309
    Figure US20100009961A1-20100114-C01310
    Figure US20100009961A1-20100114-C01311
    1186
    Figure US20100009961A1-20100114-C01312
    Figure US20100009961A1-20100114-C01313
    Figure US20100009961A1-20100114-C01314
    1187
    Figure US20100009961A1-20100114-C01315
    Figure US20100009961A1-20100114-C01316
    Figure US20100009961A1-20100114-C01317
    1188
    Figure US20100009961A1-20100114-C01318
    Figure US20100009961A1-20100114-C01319
    Figure US20100009961A1-20100114-C01320
    1189
    Figure US20100009961A1-20100114-C01321
    Figure US20100009961A1-20100114-C01322
    Figure US20100009961A1-20100114-C01323
    1190
    Figure US20100009961A1-20100114-C01324
    Figure US20100009961A1-20100114-C01325
    Figure US20100009961A1-20100114-C01326
    1191
    Figure US20100009961A1-20100114-C01327
    Figure US20100009961A1-20100114-C01328
    Figure US20100009961A1-20100114-C01329
    1192
    Figure US20100009961A1-20100114-C01330
    Figure US20100009961A1-20100114-C01331
    Figure US20100009961A1-20100114-C01332
    1193
    Figure US20100009961A1-20100114-C01333
    Figure US20100009961A1-20100114-C01334
    Figure US20100009961A1-20100114-C01335
    1194
    Figure US20100009961A1-20100114-C01336
    Figure US20100009961A1-20100114-C01337
    Figure US20100009961A1-20100114-C01338
    1195
    Figure US20100009961A1-20100114-C01339
    Figure US20100009961A1-20100114-C01340
    Figure US20100009961A1-20100114-C01341
    1196
    Figure US20100009961A1-20100114-C01342
    Figure US20100009961A1-20100114-C01343
    Figure US20100009961A1-20100114-C01344
    1197
    Figure US20100009961A1-20100114-C01345
    Figure US20100009961A1-20100114-C01346
    Figure US20100009961A1-20100114-C01347
    1198
    Figure US20100009961A1-20100114-C01348
    Figure US20100009961A1-20100114-C01349
    Figure US20100009961A1-20100114-C01350
    1199
    Figure US20100009961A1-20100114-C01351
    Figure US20100009961A1-20100114-C01352
    Figure US20100009961A1-20100114-C01353
    1200
    Figure US20100009961A1-20100114-C01354
    Figure US20100009961A1-20100114-C01355
    Figure US20100009961A1-20100114-C01356
    1201
    Figure US20100009961A1-20100114-C01357
    Figure US20100009961A1-20100114-C01358
    Figure US20100009961A1-20100114-C01359
    1202
    Figure US20100009961A1-20100114-C01360
    Figure US20100009961A1-20100114-C01361
    Figure US20100009961A1-20100114-C01362
    1203
    Figure US20100009961A1-20100114-C01363
    Figure US20100009961A1-20100114-C01364
    Figure US20100009961A1-20100114-C01365
    1204
    Figure US20100009961A1-20100114-C01366
    Figure US20100009961A1-20100114-C01367
    Figure US20100009961A1-20100114-C01368
    1205
    Figure US20100009961A1-20100114-C01369
    Figure US20100009961A1-20100114-C01370
    Figure US20100009961A1-20100114-C01371
    1206
    Figure US20100009961A1-20100114-C01372
    Figure US20100009961A1-20100114-C01373
    Figure US20100009961A1-20100114-C01374
    1207
    Figure US20100009961A1-20100114-C01375
    Figure US20100009961A1-20100114-C01376
    Figure US20100009961A1-20100114-C01377
    1208
    Figure US20100009961A1-20100114-C01378
    Figure US20100009961A1-20100114-C01379
    Figure US20100009961A1-20100114-C01380
    1209
    Figure US20100009961A1-20100114-C01381
    Figure US20100009961A1-20100114-C01382
    Figure US20100009961A1-20100114-C01383
  • Examples 1210-1299 have been intentionally excluded.
    • Preparative Example 1300
  • Figure US20100009961A1-20100114-C01384
    • Step A
  • If one were to treat commercially available anthraquinone with 1.5-2 equivalents of bromine and some iodine at 160° C., and then treat the mixture with aqueous sodium hydroxide at reflux, one would obtain the title compound, after crystallisation from glacial acetic acid.
    • Step B
  • If one were to treat the title compound from Step A above with hot concentrated H2SO4, treat the obtained solution with Al powder at rt and stir the mixture at rt for 3 h, one would obtain the title compound, after aqueous workup and chromatography on silica gel.
    • Step C
  • If one were to treat the title compound from Step B above as described in Preparative Example 59 Step D, Step E and Step F, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 59 Step H, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step I, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 1301
  • Figure US20100009961A1-20100114-C01385
    • Step A
  • If one were to treat the title compound from Preparative Example 1300 as described in Preparative Example 71 Step A one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 1302-1309
  • If one were to follow a similar procedure as that described in Preparative Example 1300, except using the sulfamidates in Step G, and treat the product obtained according to Preparative Example 1301 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    1302 21 NH3
    Figure US20100009961A1-20100114-C01386
    1303 24 NH3
    Figure US20100009961A1-20100114-C01387
    1304 22 NH3
    Figure US20100009961A1-20100114-C01388
    1305 21 CH3NH2
    Figure US20100009961A1-20100114-C01389
    1306 24 CH3NH2
    Figure US20100009961A1-20100114-C01390
    1307 22 CH3NH2
    Figure US20100009961A1-20100114-C01391
    1308 24 (CH3)2NH
    Figure US20100009961A1-20100114-C01392
    1309 22 (CH3)2NH
    Figure US20100009961A1-20100114-C01393
  • Examples 1310-1349 have been intentionally excluded.
    • Preparative Example 1350
  • Figure US20100009961A1-20100114-C01394
    • Step A
  • If one were to treat a solution of commercially available 4-chloroanthranilic acid in water and concentrated hydrochloric acid at 0° C. with a solution of sodium nitrate in water over 45 min and stir the resulting mixture at 0° C. for 1 h, one would obtain the diazonium salt solution after filtration. If one were to treat a solution of commercially available hydroxylamine hydrochloride in water at 10° C. with an aqueous solution of sodium hydroxide and carefully pour the mixture into an aqueous solution of hydrated copper(II) sulfate and concentrated ammonia solution, one would obtain a blue solution after filtration. If one were to carefully add the diazonium salt solution from above to the blue solution over a period of 1 h and then heat the mixture at reflux, followed by the addition of concentrated hydrochloric acid, one would obtain a precipitate after 3 h. If one were to collect the precipitate by filtration, wash it with water and dissolved it in a solution of sodium bicarbonate, one would obtain a clear solution after treatment with charcoal and filtration. If one were to add an excess of 6 M aqueous hydrochloric acid and collect the precipitate, one would obtain the title compound after crystallisation from EtOH.
    • Step B
  • If one were to treat the title compound of Step A above at 400° C. for twenty-five minutes and then sublime the mixture at 250° C. under a pressure of 2 mm, one would obtain the title compound after crystallization from benzene.
    • Step C
  • If one were to treat the title compound from Step B above as described in Preparative Example 59 Step D, Step E and Step F, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 59 Step H, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 59 Step I, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 1351
  • Figure US20100009961A1-20100114-C01395
    • Step A
  • If one were to treat the title compound from Preparative Example 1350 as described in Preparative Example 71 Step A one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 1352-1359
  • If one were to follow a similar procedure as that described in Preparative Example 1350, except using the sulfamidates in Step G, and treat the product obtained according to Preparative Example 1351 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    1352 21 NH3
    Figure US20100009961A1-20100114-C01396
    1353 24 NH3
    Figure US20100009961A1-20100114-C01397
    1354 22 NH3
    Figure US20100009961A1-20100114-C01398
    1355 21 CH3NH2
    Figure US20100009961A1-20100114-C01399
    1356 24 CH3NH2
    Figure US20100009961A1-20100114-C01400
    1357 22 CH3NH2
    Figure US20100009961A1-20100114-C01401
    1358 24 (CH3)2NH
    Figure US20100009961A1-20100114-C01402
    1359 22 (CH3)2NH
    Figure US20100009961A1-20100114-C01403
  • Examples 1360-1399 have been intentionally excluded.
    • Preparative Example 1400
  • Figure US20100009961A1-20100114-C01404
    • Step A
  • If one were to treat commercially available 4-bromo benzaldehyde dissolved in ether at 0° C. over a period of two hours portion-wise with KCN and concentrated HCl and maintain the temperature of the reaction below 10° C., followed by stirring for 1 h after complete addition, while permitting the temperature to rise to 15° C., subsequently the resultant two-phase system is filtered off and washed with ether, separating the combined organic solutions one would obtain the intermediate after washing with saturated aqueous sodium bisulfide, drying over MgSO4, and concentrating in vacuo. If one were to dilute the residue with benzene and slowly add this mixture over a period of one hour to concentrated H2SO4, which would maintained under stirring in an ice bath at a temperature below 15° C. until completion of the addition, followed by stirring for an additional hour, allowing the mixture to warm to room temperature one would obtain after pouring the reaction mixture onto ice and the mixture is being extracted with benzene, the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step D, Step E and Step F, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 61 Step C, one would obtain the title compound.
    • Preparative Example 1401
  • Figure US20100009961A1-20100114-C01405
    • Step A
  • If one were to treat the title compound from Preparative Example 1400 as described in Preparative Example 71 Step A one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Preparative Example 71 Step B, one would obtain the title compound.
    • Preparative Example 1402-1409
  • If one were to follow a similar procedure as that described in Preparative Example 1400, except using the sulfamidates in Step B, and treat the product obtained according to Preparative Example 1401 with the amine as indicated in the table below, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Amine Title compound
    1402 21 NH3
    Figure US20100009961A1-20100114-C01406
    1403 24 NH3
    Figure US20100009961A1-20100114-C01407
    1404 22 NH3
    Figure US20100009961A1-20100114-C01408
    1405 21 CH3NH2
    Figure US20100009961A1-20100114-C01409
    1406 24 CH3NH2
    Figure US20100009961A1-20100114-C01410
    1407 22 CH3NH2
    Figure US20100009961A1-20100114-C01411
    1408 24 (CH3)2NH
    Figure US20100009961A1-20100114-C01412
    1409 22 (CH3)2NH
    Figure US20100009961A1-20100114-C01413
  • Examples 1410-1449 have been intentionally excluded.
    • Preparative Example 1450
  • Figure US20100009961A1-20100114-C01414
    • Step A
  • If one were to add commercially available diethylmethylmalonate to a solution of sodium ethoxide in EtOH, and then add a solution of α,α′-dibromo-m-xylene in benzene to the above solution and boil the mixture at reflux for 1 h, one would obtain the title compound after distillation and crystallisation.
    • Step B
  • If one were to treat the title compound from Step A above with aqueous-ethanolic potassium hydroxide, one would obtain the crude tetracarboxylic acid. If one were to decarboxylate the crude tetracarboxylic acid at 210° C., one would obtain the title compound.
    • Step C
  • If one were to convert the title compound from Step B above to its bis-acid chloride with thionyl chloride in benzene and treat the bis-acid chloride with a solution of diazomethane in ether, one would obtain the diazoketone intermediate after 12 h and evaporation of the solvents. If one were to treat the diazoketone with benzyl alcohol-γ-collidine (1:1) in an oil-bath maintained at 180° C. for 10 Min, one would obtain the crude title compound. If one were to treat the crude title compound with MeOH and HCl, one would obtain the dimethylester. If one were to treat the diemthylester with KOH in EtOH, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above with phosphorus pentachloride in benzene for 1 h and warm the mixture on a steam-bath for 5 min, one would obtain the crude bis-acid chloride. If one were to dissolve the bis-acid chloride in nitrobenzene, add a solution of aluminium chloride in nitrobenzene at 0° C. and then allow the mixture to stand at rt for 6 h, one would obtain the title compound, after removal of the nitrobenzene by steam distillation and crystallisation of the residue with EtOH.
    • Step E
  • If one were to treat the title compound from Step D above with hydrazine hydrate and potassium hydroxide in diethylene glycol for 4 h at 180° C., followed by purification by chromatography on alumina one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E with 10 eq. of aluminium chloride by adding the compound to the reagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. of acetic anhydride to the mixture, pour onto ice and hydrochloric acid and extract with an appropriate solvent, wash with water, evaporate, recrystallize from methanol, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above with selenium dioxide in water and dioxane and refluxed for 4 h, followed by removal of precipitated selenium one would obtain after recrystallizaiton the title compound.
    • Step H
  • If one were to treat the title compound from Step G above with hydrogen peroxide and drop wise with 10% NaOH in ethanol at 80° C., followed by dilution with water, treatment with norite, filtration and acidifying with HCl, one would obtain after recrystallization the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 70 Step A, one would obtain the title compound
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 93 Step C, one would obtain the title compound.
    • Step K
  • If one were to treat the title compound from Step J above as described in Preparative Example 13 Step B, one would obtain the title compound.
    • Step L
  • If one were to treat the title compound from Step K above with diisobutylaluminum hydride in CH2Cl2 at −78° C., add 10% aq AcOH, extract with ether:hexane, wash with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step M
  • If one were to treat the title compound from Step L above with 1.2 eq. commercially available methylmagnesium bromide in Et2O at room temperature, heat the mixture to reflux, add ice and half concentrated hydrochlorid acid, extract with Et2O, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step N
  • If one were to treat the title compound from Step M above with methylsulfonyl chloride and triethylamine in CH2Cl2 at 0° C., evaporate, add water and ethyl acetate to the residue, extract with ethyl acetate, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate and then the obtained intermediate with NaN3 in DMA as described in Preparative Example 17 Step C, one would obtain the title compound.
    • Step O
  • If one were to treat the title compound from Step N above as described in Preparative Example 17 Step D, one would obtain the title compound.
    • Preparative Example 1451
  • Figure US20100009961A1-20100114-C01415
    • Step A
  • If one were to treat the title compound from Preparative Example 1450 Step E with 10 eq. of aluminium chloride by adding the compound to the reagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. of acetic anhydride to the mixture, pour onto ice and hydrochloric acid and extract with an appropriate solvent, wash with water, evaporate, recrystallize from methanol, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step F above with selenium dioxide in water and dioxane and refluxed for 4 h, followed by removal of precipitated selenium one would obtain after recrystallizaiton the title compound.
    • Step C
  • If one were to treat the title compound from Step G above with hydrogen peroxide and drop wise with 10% NaOH in ethanol at 80° C., followed by dilution with water, treatment with norite, filtration and acidifying with HCl, one would obtain after recrystallization the title compound.
    • Step D
  • If one were to treat the title compound from Step H above as described in Preparative Example 70 Step A, one would obtain the title compound
    • Step E
  • If one were to treat the title compound from Step Iabove as described in Preparative Example 93 Step C, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step J above as described in Preparative Example 13 Step B, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step K above with diisobutylaluminium hydride in CH2Cl2 at −78° C., add 10% aq AcOH, extract with ether:hexane, wash with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step L above with 1.2 eq. commercially available methylmagnesium bromide in Et2O at room temperature, heat the mixture to reflux, add ice and half concentrated hydrochlorid acid, extract with Et2O, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step M above with methylsulfonyl chloride and triethylamine in CH2Cl2 at 0° C., evaporate, add water and ethyl acetate to the residue, extract with ethyl acetate, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate and then the obtained intermediate with NaN3 in DMA as described in Preparative Example 17 Step C, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step N above as described in Preparative Example 17 Step D, one would obtain the title compound.
    • Preparative Example 1452
  • Figure US20100009961A1-20100114-C01416
    • Step A
  • If one were to treat commercially available 1,2,3,4,5,6,7,8-octahydro-anthracene with 10 eq. of aluminium chloride by adding the compound to the reagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. of acetic anhydride to the mixture, pour onto ice and hydrochloric acid and extract with an appropriate solvent, wash with water, evaporate, recrystallize from methanol, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with selenium dioxide in water and dioxane and refluxed for 4 h, followed by removal of precipitated selenium one would obtain after recrystallization the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with hydrogen peroxide and drop wise with 10% NaOH in ethanol at 80° C., followed by dilution with water, treatment with norite, filtration and acidifying with HCl, one would obtain after recrystallization the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 70 Step A, one would obtain the title compound
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 93 Step C, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 13 Step B, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above with diisobutylaluminium hydride in CH2Cl2 at −78° C., add 10% aq AcOH, extract with ether:hexane, wash with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above with 1.2 eq. commercially available methylmagnesium bromide in Et2O at room temperature, heat the mixture to reflux, add ice and half concentrated hydrochlorid acid, extract with Et2O, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above with methylsulfonyl chloride and triethylamine in CH2Cl2 at 0° C., evaporate, add water and ethyl acetate to the residue, extract with ethyl acetate, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate and then the obtained intermediate with NaN3 in DMA as described in Preparative Example 17 Step C, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step I above as described in Preparative Example 17 Step D, one would obtain the title compound.
    • Preparative Example 1453
  • Figure US20100009961A1-20100114-C01417
    • Step A
  • If one were to treat commercially available 2-methyl-1H-indene and with 0.01 eq of platinum oxide in tetrahydrofuran and hydrogenate at 20-30 psi for 10-15 h at room temperature, filter the mixture through a pad of Celite, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with 1.0 eq. of 3-chloro-2-methyl-propionyl chloride and 3.0 eq. of aluminum chloride in nitromethane at room temperature, decompose the mixture with ice and hydrochloric acid, dilute with water, filter, dissolve the solid in benzene and wash with dilute hydrochloric acid, evaporate, purify with a Soxhlet extractor, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with concentrated sulphuric acid by adding the compound in small portions to the acid at low temperature, heat on the steam-bath, pour onto ice and extract with benzene and water, evaporate, distillate at reduced pressure, recrystallize from petroleum ether, sublimate, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above with amalgamated zinc, water, acetic acid, toluene, hydrochloric acid, separate the organic layer, evaporate, distillate at reduced pressure, recrystallize, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D with 10 eq. of aluminium chloride by adding the compound to the reagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. of acetic anhydride to the mixture, pour onto ice and hydrochloric acid and extract with an appropriate solvent, wash with water, evaporate, recrystallize from methanol, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E with an aqueous solution of potassium hypochlorite prepared from bleaching powder in methanol, separate the precipitate formed by filtration, acidify the filtrate, separate the precipitate formed by filtration, recrystallize from methanol, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 70 Step A, one would obtain the title compound
    • Step H
  • If one were to treat the title compound from Step G above as described in Preparative Example 93 Step C, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above with diisobutylaluminium hydride in CH2Cl2 at −78° C., add 10% aq AcOH, extract with ether:hexane, wash with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step H above as described in Preparative Example 13 Step B, one would obtain the title compound.
    • Step K
  • If one were to treat the title compound from Step I above with 1.2 eq. commercially available methylmagnesium bromide in Et2O at room temperature, heat the mixture to reflux, add ice and half concentrated hydrochlorid acid, extract with Et2O, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step L
  • If one were to treat the title compound from Step K above with methylsulfonyl chloride and triethylamine in CH2Cl2 at 0° C., evaporate, add water and ethyl acetate to the residue, extract with ethyl acetate, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate and then the obtained intermediate with NaN3 in DMA as described in Preparative Example 17 Step C, one would obtain the title compound.
    • Step M
  • If one were to treat the title compound from Step L above as described in Preparative Example 17 Step D, one would obtain the title compound.
    • Preparative Example 1454
  • Figure US20100009961A1-20100114-C01418
    • Step A
  • If one were to treat commercially available indane with 1.0 eq. of 3-chloro-propionyl chloride and 3.0 eq. of aluminum chloride in nitromethane at room temperature, decompose the mixture with ice and hydrochloric acid, dilute with water, filter, dissolve the solid in benzene and wash with dilute hydrochloric acid, evaporate, purify with a Soxhlet extractor, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with concentrated sulphuric acid by adding the compound in small portions to the acid at low temperature, heat on the steam-bath, pour onto ice and extract with benzene and water, evaporate, distillate at reduced pressure, recrystallize from petroleum ether, sublimate, one would obtain the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with amalgamated zinc, water, acetic acid, toluene, hydrochloric acid, separate the organic layer, evaporate, distillate at reduced pressure, recrystallize, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step D with 10 eq. of aluminium chloride by adding the compound to the reagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. of acetic anhydride to the mixture, pour onto ice and hydrochloric acid and extract with an appropriate solvent, wash with water, evaporate, recrystallize from methanol, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D with an aqueous solution of potassium hypochlorite prepared from bleaching powder in methanol, separate the precipitate formed by filtration, acidify the filtrate, separate the precipitate formed by filtration, recrystallize from methanol, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above as described in Preparative Example 70 Step A, one would obtain the title compound
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 93 Step C, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above with diisobutylaluminium hydride in CH2Cl2 at −78° C., add 10% aq AcOH, extract with ether:hexane, wash with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step G above as described in Preparative Example 13 Step B, one would obtain the title compound.
    • Step J
  • If one were to treat the title compound from Step H above with 1.2 eq. commercially available methylmagnesium bromide in Et2O at room temperature, heat the mixture to reflux, add ice and half concentrated hydrochloride acid, extract with Et2O, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate, purify the crude product through chromatography on silica gel, one would obtain the title compound.
    • Step K
  • If one were to treat the title compound from Step J above with methylsulfonyl chloride and triethylamine in CH2Cl2 at 0° C., evaporate, add water and ethyl acetate to the residue, extract with ethyl acetate, wash the organic layer with H2O, sat. aq NaHCO3, and brine, dry over Na2SO4, evaporate and then the obtained intermediate with NaN3 in DMA as described in Preparative Example 17 Step C, one would obtain the title compound.
    • Step L
  • If one were to treat the title compound from Step K above as described in Preparative Example 17 Step D, one would obtain the title compound.
  • Examples 1455-1499 have been intentionally excluded.
    • Preparative Example 1500
  • Figure US20100009961A1-20100114-C01419
    • Step A
  • If one were to treat commercially available 1,4-benzoquinone with buta-1,3-diene in benzene at 100° C. in an autoclave, separate the precipitate, wash it with methanol, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with LiAlH4 in THF at rt for 15 min and then heat to reflux for 50 min, one would obtain after removal of the solvent, followed by aqueous workup and column chromatography the title compound.
    • Step C
  • If one were to treat the title compound from Step B above with methanesulfonyl chloride in pyridine at 0° C. for 24 h, one would obtain after pouring into an ice/water mixture followed by extraction with benzene and subsequently washing the organic phase with water, cold 5% sulphuric acid, water, 2% sodium bicarbonate solution, brine and finally evaporation to dryness, the methansulfonate intermediate. If one were to treat the methansulfonate intermediate with LiAlH4 in THF and heat to reflux for 24 h, one would obtain after removal of the solvent, followed by aqueous workup the alcohol intermediate.
  • If one were to treat the alcohol intermediate with CrO3 in pyridine at 40° C. for 9 h, one would obtain after pouring into water, followed by extraction with CCl4 and subsequently drying the organic phase and evaporating to dryness, followed by column chromatography and crystallization the alkene intermediate. If one were to treat the alkene intermediate with Pd/C in ethanol at 10 bar H2 and room temperature, separate the crude product from the reaction mixture and then the obtained intermediate with CrO3 in aqueous acetic acid and water, neutralize the mixture, extract with Et2O, recrystallize from THF/CH2Cl2, one would obtain the title compound.
    • Step D
  • If one were to treat the title compound from Step C above as described in Preparative Example 59 Step G, one would obtain the title compound.
    • Step E
  • If one were to treat the title compound from Step D above as described in Preparative Example 59 Step H, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E with NaCN in 90% ethanol under reflux, add water, extract with CHCl3, wash the organic layer with 5% sulphuric acid, sat. aq NaHCO3, water, brine, dry over Na2SO4, distillate, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above as described in Preparative Example 61 Step A, one would obtain the title compound.
    • Step H
  • If one were to treat the title compound from Step G above as described in Preparative Example 61 Step B, one would obtain the title compound.
    • Step I
  • If one were to treat the title compound from Step H above as described in Preparative Example 70 Step B, one would obtain the title compound.
    • Preparative Example 1501-1502
  • If one were to follow a similar procedure as that described in Preparative Example 1500, except using the sulfamidates in Step G, one would obtain the desired title compound as HCl salt.
  • Preparative
    Example Sulfamidate Title compound
    1501 22
    Figure US20100009961A1-20100114-C01420
    1502 24
    Figure US20100009961A1-20100114-C01421
    • Example 1
  • Figure US20100009961A1-20100114-C01422
  • The title compound from Preparative Example 5 (378 mg) and 419 mg K2CO3 were suspended in 3 ml THF and cooled to 0° C. A solution of Preparative Example 1 (109 mg) in 1 ml THF was slowly added and the reaction mixture stirred at 0° C. for 2 h and then at rt overnight. The mixture was diluted with 30 ml EtOAc and 10 ml H2O, the organic phase separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica (CH2Cl2/MeOH, 4:1) to afford the title compound (66 mg; 39%; MH+=389).
    • Example 2-14
  • Following a similar procedure as that described in Example 1, except using the compounds from the Preparative Examples indicated in the Table below, the following compounds were prepared.
  • Compound Compound
    Preparative Preparative 1. Yield
    Example Example Example Product 2. MH+
    2 1  6
    Figure US20100009961A1-20100114-C01423
         		1. 17% 2. 346
    3 1  7
    Figure US20100009961A1-20100114-C01424
         		1. 8% 2. 417
    4 1 13
    Figure US20100009961A1-20100114-C01425
         		1. 19% 2. 360
    5 1 14 Step B
    Figure US20100009961A1-20100114-C01426
         		1. 18% 2. 389
    6 1 14
    Figure US20100009961A1-20100114-C01427
         		1. 15% 2. 375
    7 1 15 Step C
    Figure US20100009961A1-20100114-C01428
         		1. 8% 2. 372
    8 1 15
    Figure US20100009961A1-20100114-C01429
         		1. 8% 2. 374
    9 1 16
    Figure US20100009961A1-20100114-C01430
         		1. 16% 2. 389
    10 1 17 Step D
    Figure US20100009961A1-20100114-C01431
         		1. 7% 2. 390
    11 1 17
    Figure US20100009961A1-20100114-C01432
         		1. 8% 2. 372
    12 1 10
    Figure US20100009961A1-20100114-C01433
         		1. 16% 2. 429
    13 1 11
    Figure US20100009961A1-20100114-C01434
         		1. 19% 2. 415
    14 1 12
    Figure US20100009961A1-20100114-C01435
         		1. 19% 2. 401
    • Example 15
  • Figure US20100009961A1-20100114-C01436
  • An aliquot of the title compound of Preparative Example 3 was taken and the solvent removed. The residue (67 mg) was dissolved in DMF (2 ml) and triethylamine (0.1 ml). The title compound from Preparative Example 90 (71 mg) was added and the mixture was stirred at 60° C. for 2 h. The solvent was removed and the residue was purified by preparative TLC (CHCl3/MeOH (+0.1% Triethylamine), 4:1) to afford the title compound (12 mg; 13%; MH+=381).
    • Example 16
  • Figure US20100009961A1-20100114-C01437
  • The title compound from Preparative Example 18 Step B (100 mg) and Preparative Example 2 (68 mg) were dissolved in 2 ml EtOH and 1 ml H2O. The pH of the solution was adjusted to pH˜6 by adding 0.1 M HCl-solution and the mixture was stirred at rt for 10 min. After the addition of NaCNBH3 (24 mg) the pH was maintained at pH˜6 by the addition of 0.1 M HCl and the mixture was stirred at rt overnight. The mixture was diluted with 30 ml EtOAc and 15 ml sat. NaHCO3/brine (1:1), the organic phase separated, dried over MgSO4 and concentrated. The residue was purified by Prep TLC(CH2Cl2/MeOH, 95:5) to afford the title compound (25.9 mg; 17%; MH+=399).
    • Example 17-47
  • Following a similar procedure as described in Example 16 by dissolving the amine in a EtOH/H2O— or MeOH/H2O-mixture and adjusting the pH to pH˜6-8 by either 0.1 M HCl, 3 M NaOAc or 1 M NaOH, except using the compounds from the Preparative Examples indicated in the Table below, the following compounds were prepared. In case the reaction was not completed after 24 h as judged by HPLC, additional aldehyde from Preparative Example 2 or 89 and NaCNBH3 were added, and the reaction was continued for another 1-3 days.
  • For the products obtained, the following purification methods were employed:
    • Method A: chromatography on silica using CH2Cl2/MeOH-mixtures; or
    • Method B: product was precipitated from the reaction mixture by adding 1 M HCl to pH 1-3 and the precipitate washed with MeOH; or
    • Method C: reaction mixture was concentrated to half its volume and the crude product purified by reverse phase HPLC (21.5×250 mm, Phenomenex, Luna C-18 (2), 5 μM; flow=15 ml/min or 10×250 mm, Phenomenex, Luna C-18 (2), 5 μM; flow=3 ml/min) using acetonitrile (solvent B; 0.1% formic acid) and H2O (solvent A; 0.1% formic acid) as eluents and a suitable gradient, ramping solvent B from 0% to 100% over a period of 18 min.
  • Compound Compound
    Preparative Preparative Purification 1. Yield
    Example Example Example Method Product 2. MH+
    17 2 18 A
    Figure US20100009961A1-20100114-C01438
         		1. 17% 2. 417
    18 2 47 A
    Figure US20100009961A1-20100114-C01439
         		1. 41% 2. 431
    19 2 48 A
    Figure US20100009961A1-20100114-C01440
         		1. 18% 2. 431
    20 2 8 A
    Figure US20100009961A1-20100114-C01441
         		1. 25% 2. 424
    21 2 9 A
    Figure US20100009961A1-20100114-C01442
         		1. 18% 2. 390
    22 2 49 A
    Figure US20100009961A1-20100114-C01443
         		1. 21% 2. 478
    23 2 50 B
    Figure US20100009961A1-20100114-C01444
         		1. 30% 2. 442
    24 2 51 B
    Figure US20100009961A1-20100114-C01445
         		1. 5% 2. 478
    25 2 87 B
    Figure US20100009961A1-20100114-C01446
         		1. 46% 2. 510
    26 2 110 A
    Figure US20100009961A1-20100114-C01447
         		1. 15% 2. 414
    27 2 70 C
    Figure US20100009961A1-20100114-C01448
         		1. 36% 2. 542
    28 2 72 C
    Figure US20100009961A1-20100114-C01449
         		1. 14% 2. 570
    29 2 71 C
    Figure US20100009961A1-20100114-C01450
         		1. 38% 2. 598
    30 2 73 C
    Figure US20100009961A1-20100114-C01451
         		1. 21% 2. 598
    31 2 74 C
    Figure US20100009961A1-20100114-C01452
         		1. 8% 2. 626
    32 2 75 C
    Figure US20100009961A1-20100114-C01453
         		1. 58% 2. 622
    33 2 76 C
    Figure US20100009961A1-20100114-C01454
         		1. 9% 2. 682
    34 2 56 C
    Figure US20100009961A1-20100114-C01455
         		1. 11% 2. 528
    35 2 77 C
    Figure US20100009961A1-20100114-C01456
         		1. 7% 2. 556
    36 2 78 C
    Figure US20100009961A1-20100114-C01457
         		1. 10% 2. 584
    37 2 79 C
    Figure US20100009961A1-20100114-C01458
         		1. 12% 2. 556
    38 2 80 C
    Figure US20100009961A1-20100114-C01459
         		1. 43% 2. 614
    39 2 81 C
    Figure US20100009961A1-20100114-C01460
         		1. 2% 2. 573
    40 2 82 C
    Figure US20100009961A1-20100114-C01461
         		1. 26% 2. 666
    41 2 83 C
    Figure US20100009961A1-20100114-C01462
         		1. 12% 2. 542
    42 2 84 C
    Figure US20100009961A1-20100114-C01463
         		1. 10% 2. 542
    43 2 85 C
    Figure US20100009961A1-20100114-C01464
         		1. 60% 2. 572
    44 2 86 C
    Figure US20100009961A1-20100114-C01465
         		1. 28% 2. 544
    45 2 52 C
    Figure US20100009961A1-20100114-C01466
         		1. 14% 2. 503
    46 2 88 C
    Figure US20100009961A1-20100114-C01467
         		1. 2% 2. 471
    47 89 56 C
    Figure US20100009961A1-20100114-C01468
         		1. 9% 2. 540
    • Example 48
  • Figure US20100009961A1-20100114-C01469
  • The title compound from Preparative Example 93 (16 mg) was dissolved in a mixture of H2O (3 ml) and a solution of 4 M HCl in dioxane (3 ml). After 20 h the reaction mixture was diluted with toluene. The organic layer was evaporated to afford the title compound (14 mg; 99%; MH+=386).
    • Example 49-64
  • Following a similar procedure as that described in Example 48, except using the compounds from the Preparative Examples indicated in the Table below, the following compound was prepared.
  • Compound
    Preparative 1. Yield
    Example Example Product 2. MH+
    49 95
    Figure US20100009961A1-20100114-C01470
         		1. 77% 2. 436
    50 96
    Figure US20100009961A1-20100114-C01471
         		1. 92% 2. 393
    51 97
    Figure US20100009961A1-20100114-C01472
         		1. 89% 2. 404
    52 98
    Figure US20100009961A1-20100114-C01473
         		1. 96% 2. 416
    53 99
    Figure US20100009961A1-20100114-C01474
         		1. 57% 2. 393
    54 100
    Figure US20100009961A1-20100114-C01475
         		1. 95% 2. 404
    55 101
    Figure US20100009961A1-20100114-C01476
         		1. 93% 2. 393
    56 102
    Figure US20100009961A1-20100114-C01477
         		1. 98% 2. 400
    57 108
    Figure US20100009961A1-20100114-C01478
         		1. 96% 2. 400
    58 103
    Figure US20100009961A1-20100114-C01479
         		1. 95% 2. 412
    59 104
    Figure US20100009961A1-20100114-C01480
         		1. 95% 2. 414
    60 105
    Figure US20100009961A1-20100114-C01481
         		1. 92% 2. 411
    61 106
    Figure US20100009961A1-20100114-C01482
         		1. 95% 2. 411
    62 107
    Figure US20100009961A1-20100114-C01483
         		1. 81% 2. 426
    63 109
    Figure US20100009961A1-20100114-C01484
         		1. 85% 2. 412
    64 94
    Figure US20100009961A1-20100114-C01485
         		1. 95% 2. 398
    • Example 65
  • Figure US20100009961A1-20100114-C01486
  • The title compound from Preparative Example 113 (13 mg) was treated with 4 M HCl in dioxane as described in Example 47 to afford the title compound (11.2 mg, 98%, MH+=436).
    • Example 66-75
  • Following a similar procedure as that described in Example 65, except using the compounds from the Preparative Examples indicated in the Table below, the following compounds were prepared.
  • Compound
    Preparative 1. Yield
    Example Example Product 2. MH+
    66 114
    Figure US20100009961A1-20100114-C01487
         		1. 100 2. 424
    67 115
    Figure US20100009961A1-20100114-C01488
         		1. 33 2. 424
    68 116
    Figure US20100009961A1-20100114-C01489
         		1. 40 2. 482
    69 117
    Figure US20100009961A1-20100114-C01490
         		1. 85 2. 388
    70 118
    Figure US20100009961A1-20100114-C01491
         		1. 96 2. 402
    71 119
    Figure US20100009961A1-20100114-C01492
         		1. 84 2. 384
    72 122
    Figure US20100009961A1-20100114-C01493
         		1. 30 2. 510
    73 112 Step D
    Figure US20100009961A1-20100114-C01494
         		1. 50 2. 500
    74 121
    Figure US20100009961A1-20100114-C01495
         		1. 97 2. 475
    75 120
    Figure US20100009961A1-20100114-C01496
         		1. 100 2. 377
    • Example 76
  • Figure US20100009961A1-20100114-C01497
  • The title compound from Preparative Example 123 (27 mg) was dissolved in dichloromethane (2 ml) and trimethylsilyl iodine (21 mg) was added. The mixture was stirred for 1 h at room temperature. After removal of the solvent the residue was purified by preparative TLC to afford the desired compound (CHCl3/MeOH, 4 mg, 20%, MH+=388).
    • Examples 77-78
  • Following a similar procedure as that described in Example 76, except using the compounds from the Preparative Examples as indicated in the Table below, the following compounds were prepared.
  • Preparative 1. Yield
    Example Example Product 2. MH+
    77 124
    Figure US20100009961A1-20100114-C01498
         		1. 10% 2. 422
    78 125
    Figure US20100009961A1-20100114-C01499
         		1. 11% 2. 358
  • Examples 79-99 have been intentionally excluded.
    • Example 100-184
  • If one were to follow the procedures outlined in Preparative Example 71 and Examples 28 or 29 but using the amines, carboxylic acids and aldehydes from the Preparative Examples as indicated in the Table below, one would obtain the indicated Product.
  • Example Carboxylic
    # Amine Acid Aldehyde Product
    100
    Figure US20100009961A1-20100114-C01500
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01501
    101
    Figure US20100009961A1-20100114-C01502
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01503
    102
    Figure US20100009961A1-20100114-C01504
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01505
    103
    Figure US20100009961A1-20100114-C01506
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01507
    104
    Figure US20100009961A1-20100114-C01508
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01509
    105
    Figure US20100009961A1-20100114-C01510
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01511
    106
    Figure US20100009961A1-20100114-C01512
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01513
    107
    Figure US20100009961A1-20100114-C01514
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01515
    108
    Figure US20100009961A1-20100114-C01516
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01517
    109
    Figure US20100009961A1-20100114-C01518
         		Prep Ex 62 Prep Ex 2 
    Figure US20100009961A1-20100114-C01519
    110 NH3 Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01520
    111 MeNH2 Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01521
    112 (Me)2NH Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01522
    113
    Figure US20100009961A1-20100114-C01523
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01524
    114
    Figure US20100009961A1-20100114-C01525
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01526
    115
    Figure US20100009961A1-20100114-C01527
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01528
    116
    Figure US20100009961A1-20100114-C01529
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01530
    117
    Figure US20100009961A1-20100114-C01531
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01532
    118
    Figure US20100009961A1-20100114-C01533
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01534
    119
    Figure US20100009961A1-20100114-C01535
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01536
    120
    Figure US20100009961A1-20100114-C01537
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01538
    121
    Figure US20100009961A1-20100114-C01539
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01540
    122
    Figure US20100009961A1-20100114-C01541
         		Prep Ex 55 Prep Ex 2 
    Figure US20100009961A1-20100114-C01542
    123
    Figure US20100009961A1-20100114-C01543
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01544
    124
    Figure US20100009961A1-20100114-C01545
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01546
    125
    Figure US20100009961A1-20100114-C01547
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01548
    126
    Figure US20100009961A1-20100114-C01549
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01550
    127
    Figure US20100009961A1-20100114-C01551
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01552
    128
    Figure US20100009961A1-20100114-C01553
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01554
    129
    Figure US20100009961A1-20100114-C01555
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01556
    130
    Figure US20100009961A1-20100114-C01557
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01558
    131
    Figure US20100009961A1-20100114-C01559
         		Prep Ex 65 Prep Ex 2 
    Figure US20100009961A1-20100114-C01560
    132
    Figure US20100009961A1-20100114-C01561
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01562
    133
    Figure US20100009961A1-20100114-C01563
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01564
    134
    Figure US20100009961A1-20100114-C01565
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01566
    135
    Figure US20100009961A1-20100114-C01567
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01568
    136
    Figure US20100009961A1-20100114-C01569
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01570
    137
    Figure US20100009961A1-20100114-C01571
         		Prep Ex 61 Prep Ex 2 
    Figure US20100009961A1-20100114-C01572
    138 MeNH2 Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01573
    139 (Me)2NH Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01574
    140
    Figure US20100009961A1-20100114-C01575
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01576
    141
    Figure US20100009961A1-20100114-C01577
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01578
    142
    Figure US20100009961A1-20100114-C01579
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01580
    143
    Figure US20100009961A1-20100114-C01581
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01582
    144
    Figure US20100009961A1-20100114-C01583
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01584
    145
    Figure US20100009961A1-20100114-C01585
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01586
    146
    Figure US20100009961A1-20100114-C01587
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01588
    147
    Figure US20100009961A1-20100114-C01589
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01590
    148
    Figure US20100009961A1-20100114-C01591
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01592
    149
    Figure US20100009961A1-20100114-C01593
         		Prep Ex 62 Prep Ex 89
    Figure US20100009961A1-20100114-C01594
    150 NH3 Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01595
    151 MeNH2 Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01596
    152 (Me)2NH Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01597
    153
    Figure US20100009961A1-20100114-C01598
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01599
    154
    Figure US20100009961A1-20100114-C01600
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01601
    155
    Figure US20100009961A1-20100114-C01602
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01603
    156
    Figure US20100009961A1-20100114-C01604
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01605
    157
    Figure US20100009961A1-20100114-C01606
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01607
    158
    Figure US20100009961A1-20100114-C01608
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01609
    159
    Figure US20100009961A1-20100114-C01610
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01611
    160
    Figure US20100009961A1-20100114-C01612
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01613
    161
    Figure US20100009961A1-20100114-C01614
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01615
    162
    Figure US20100009961A1-20100114-C01616
         		Prep Ex 55 Prep Ex 89
    Figure US20100009961A1-20100114-C01617
    163
    Figure US20100009961A1-20100114-C01618
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01619
    164
    Figure US20100009961A1-20100114-C01620
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01621
    165
    Figure US20100009961A1-20100114-C01622
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01623
    166
    Figure US20100009961A1-20100114-C01624
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01625
    167
    Figure US20100009961A1-20100114-C01626
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01627
    168
    Figure US20100009961A1-20100114-C01628
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01629
    169
    Figure US20100009961A1-20100114-C01630
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01631
    170
    Figure US20100009961A1-20100114-C01632
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01633
    171
    Figure US20100009961A1-20100114-C01634
         		Prep Ex 65 Prep Ex 89
    Figure US20100009961A1-20100114-C01635
    172 NH3 Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01636
    173 MeNH2 Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01637
    174 (Me)2NH Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01638
    175
    Figure US20100009961A1-20100114-C01639
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01640
    176
    Figure US20100009961A1-20100114-C01641
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01642
    177
    Figure US20100009961A1-20100114-C01643
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01644
    178
    Figure US20100009961A1-20100114-C01645
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01646
    179
    Figure US20100009961A1-20100114-C01647
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01648
    180
    Figure US20100009961A1-20100114-C01649
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01650
    181
    Figure US20100009961A1-20100114-C01651
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01652
    182
    Figure US20100009961A1-20100114-C01653
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01654
    183
    Figure US20100009961A1-20100114-C01655
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01656
    184
    Figure US20100009961A1-20100114-C01657
         		Prep Ex 61 Prep Ex 89
    Figure US20100009961A1-20100114-C01658
  • Examples 185-199 have been intentionally excluded.
    • Example 200-389
  • If one were to follow the procedures outlined in Examples 28 or 29 except using the compounds from the Preparative Examples as indicated in the Table below, one would obtain the indicated Product.
  • Preparative Preparative
    Example Example Example Product
    200 200 2
    Figure US20100009961A1-20100114-C01659
    201 201 2
    Figure US20100009961A1-20100114-C01660
    202 202 2
    Figure US20100009961A1-20100114-C01661
    203 203 2
    Figure US20100009961A1-20100114-C01662
    204 204 2
    Figure US20100009961A1-20100114-C01663
    205 205 2
    Figure US20100009961A1-20100114-C01664
    206 206 2
    Figure US20100009961A1-20100114-C01665
    207 207 2
    Figure US20100009961A1-20100114-C01666
    208 208 2
    Figure US20100009961A1-20100114-C01667
    209 209 2
    Figure US20100009961A1-20100114-C01668
    210 210 2
    Figure US20100009961A1-20100114-C01669
    211 211 2
    Figure US20100009961A1-20100114-C01670
    212 212 2
    Figure US20100009961A1-20100114-C01671
    213 213 2
    Figure US20100009961A1-20100114-C01672
    214 214 2
    Figure US20100009961A1-20100114-C01673
    215 215 2
    Figure US20100009961A1-20100114-C01674
    216 216 2
    Figure US20100009961A1-20100114-C01675
    217 217 2
    Figure US20100009961A1-20100114-C01676
    218 218 2
    Figure US20100009961A1-20100114-C01677
    219 219 2
    Figure US20100009961A1-20100114-C01678
    220 220 2
    Figure US20100009961A1-20100114-C01679
    221 221 2
    Figure US20100009961A1-20100114-C01680
    222 222 2
    Figure US20100009961A1-20100114-C01681
    223 223 2
    Figure US20100009961A1-20100114-C01682
    224 224 2
    Figure US20100009961A1-20100114-C01683
    225 225 2
    Figure US20100009961A1-20100114-C01684
    226 226 2
    Figure US20100009961A1-20100114-C01685
    227 227 2
    Figure US20100009961A1-20100114-C01686
    228 228 2
    Figure US20100009961A1-20100114-C01687
    229 229 2
    Figure US20100009961A1-20100114-C01688
    230 230 2
    Figure US20100009961A1-20100114-C01689
    231 231 2
    Figure US20100009961A1-20100114-C01690
    232 232 2
    Figure US20100009961A1-20100114-C01691
    233 233 2
    Figure US20100009961A1-20100114-C01692
    234 234 2
    Figure US20100009961A1-20100114-C01693
    235 235 2
    Figure US20100009961A1-20100114-C01694
    236 236 2
    Figure US20100009961A1-20100114-C01695
    237 237 2
    Figure US20100009961A1-20100114-C01696
    238 238 2
    Figure US20100009961A1-20100114-C01697
    239 239 2
    Figure US20100009961A1-20100114-C01698
    240 240 2
    Figure US20100009961A1-20100114-C01699
    241 241 2
    Figure US20100009961A1-20100114-C01700
    242 242 2
    Figure US20100009961A1-20100114-C01701
    243 243 2
    Figure US20100009961A1-20100114-C01702
    244 244 2
    Figure US20100009961A1-20100114-C01703
    245 245 2
    Figure US20100009961A1-20100114-C01704
    246 246 2
    Figure US20100009961A1-20100114-C01705
    247 247 2
    Figure US20100009961A1-20100114-C01706
    248 248 2
    Figure US20100009961A1-20100114-C01707
    249 249 2
    Figure US20100009961A1-20100114-C01708
    250 250 2
    Figure US20100009961A1-20100114-C01709
    251 251 2
    Figure US20100009961A1-20100114-C01710
    252 252 2
    Figure US20100009961A1-20100114-C01711
    253 253 2
    Figure US20100009961A1-20100114-C01712
    254 254 2
    Figure US20100009961A1-20100114-C01713
    255 255 2
    Figure US20100009961A1-20100114-C01714
    256 256 2
    Figure US20100009961A1-20100114-C01715
    257 257 2
    Figure US20100009961A1-20100114-C01716
    258 258 2
    Figure US20100009961A1-20100114-C01717
    259 259 2
    Figure US20100009961A1-20100114-C01718
    260 260 2
    Figure US20100009961A1-20100114-C01719
    261 261 2
    Figure US20100009961A1-20100114-C01720
    262 262 2
    Figure US20100009961A1-20100114-C01721
    263 263 2
    Figure US20100009961A1-20100114-C01722
    264 264 2
    Figure US20100009961A1-20100114-C01723
    265 265 2
    Figure US20100009961A1-20100114-C01724
    266 266 2
    Figure US20100009961A1-20100114-C01725
    267 267 2
    Figure US20100009961A1-20100114-C01726
    268 268 2
    Figure US20100009961A1-20100114-C01727
    269 269 2
    Figure US20100009961A1-20100114-C01728
    270 270 2
    Figure US20100009961A1-20100114-C01729
    271 271 2
    Figure US20100009961A1-20100114-C01730
    272 272 2
    Figure US20100009961A1-20100114-C01731
    273 273 2
    Figure US20100009961A1-20100114-C01732
    274 274 2
    Figure US20100009961A1-20100114-C01733
    275 275 2
    Figure US20100009961A1-20100114-C01734
    276 276 2
    Figure US20100009961A1-20100114-C01735
    277 277 2
    Figure US20100009961A1-20100114-C01736
    278 278 2
    Figure US20100009961A1-20100114-C01737
    279 279 2
    Figure US20100009961A1-20100114-C01738
    280 280 2
    Figure US20100009961A1-20100114-C01739
    281 281 2
    Figure US20100009961A1-20100114-C01740
    282 282 2
    Figure US20100009961A1-20100114-C01741
    283 283 2
    Figure US20100009961A1-20100114-C01742
    284 284 2
    Figure US20100009961A1-20100114-C01743
    285 285 2
    Figure US20100009961A1-20100114-C01744
    286 286 2
    Figure US20100009961A1-20100114-C01745
    287 287 2
    Figure US20100009961A1-20100114-C01746
    288 288 2
    Figure US20100009961A1-20100114-C01747
    289 289 2
    Figure US20100009961A1-20100114-C01748
    290 290 2
    Figure US20100009961A1-20100114-C01749
    291 291 2
    Figure US20100009961A1-20100114-C01750
    292 292 2
    Figure US20100009961A1-20100114-C01751
    293 293 2
    Figure US20100009961A1-20100114-C01752
    294 294 2
    Figure US20100009961A1-20100114-C01753
    295 200 89
    Figure US20100009961A1-20100114-C01754
    296 201 89
    Figure US20100009961A1-20100114-C01755
    297 202 89
    Figure US20100009961A1-20100114-C01756
    298 203 89
    Figure US20100009961A1-20100114-C01757
    299 204 89
    Figure US20100009961A1-20100114-C01758
    300 205 89
    Figure US20100009961A1-20100114-C01759
    301 206 89
    Figure US20100009961A1-20100114-C01760
    302 207 89
    Figure US20100009961A1-20100114-C01761
    303 208 89
    Figure US20100009961A1-20100114-C01762
    304 209 89
    Figure US20100009961A1-20100114-C01763
    305 210 89
    Figure US20100009961A1-20100114-C01764
    306 211 89
    Figure US20100009961A1-20100114-C01765
    307 212 89
    Figure US20100009961A1-20100114-C01766
    308 213 89
    Figure US20100009961A1-20100114-C01767
    309 214 89
    Figure US20100009961A1-20100114-C01768
    310 215 89
    Figure US20100009961A1-20100114-C01769
    311 216 89
    Figure US20100009961A1-20100114-C01770
    312 217 89
    Figure US20100009961A1-20100114-C01771
    313 218 89
    Figure US20100009961A1-20100114-C01772
    314 219 89
    Figure US20100009961A1-20100114-C01773
    315 220 89
    Figure US20100009961A1-20100114-C01774
    316 221 89
    Figure US20100009961A1-20100114-C01775
    317 222 89
    Figure US20100009961A1-20100114-C01776
    318 223 89
    Figure US20100009961A1-20100114-C01777
    319 224 89
    Figure US20100009961A1-20100114-C01778
    320 225 89
    Figure US20100009961A1-20100114-C01779
    321 226 89
    Figure US20100009961A1-20100114-C01780
    322 227 89
    Figure US20100009961A1-20100114-C01781
    323 228 89
    Figure US20100009961A1-20100114-C01782
    324 229 89
    Figure US20100009961A1-20100114-C01783
    325 230 89
    Figure US20100009961A1-20100114-C01784
    326 231 89
    Figure US20100009961A1-20100114-C01785
    327 232 89
    Figure US20100009961A1-20100114-C01786
    328 233 89
    Figure US20100009961A1-20100114-C01787
    329 234 89
    Figure US20100009961A1-20100114-C01788
    330 235 89
    Figure US20100009961A1-20100114-C01789
    331 236 89
    Figure US20100009961A1-20100114-C01790
    332 237 89
    Figure US20100009961A1-20100114-C01791
    333 238 89
    Figure US20100009961A1-20100114-C01792
    334 239 89
    Figure US20100009961A1-20100114-C01793
    335 240 89
    Figure US20100009961A1-20100114-C01794
    336 241 89
    Figure US20100009961A1-20100114-C01795
    337 242 89
    Figure US20100009961A1-20100114-C01796
    338 243 89
    Figure US20100009961A1-20100114-C01797
    339 244 89
    Figure US20100009961A1-20100114-C01798
    340 245 89
    Figure US20100009961A1-20100114-C01799
    341 246 89
    Figure US20100009961A1-20100114-C01800
    342 247 89
    Figure US20100009961A1-20100114-C01801
    343 248 89
    Figure US20100009961A1-20100114-C01802
    344 249 89
    Figure US20100009961A1-20100114-C01803
    345 250 89
    Figure US20100009961A1-20100114-C01804
    346 251 89
    Figure US20100009961A1-20100114-C01805
    347 252 89
    Figure US20100009961A1-20100114-C01806
    348 253 89
    Figure US20100009961A1-20100114-C01807
    349 254 89
    Figure US20100009961A1-20100114-C01808
    350 255 89
    Figure US20100009961A1-20100114-C01809
    351 256 89
    Figure US20100009961A1-20100114-C01810
    352 257 89
    Figure US20100009961A1-20100114-C01811
    353 258 89
    Figure US20100009961A1-20100114-C01812
    354 259 89
    Figure US20100009961A1-20100114-C01813
    355 260 89
    Figure US20100009961A1-20100114-C01814
    356 261 89
    Figure US20100009961A1-20100114-C01815
    357 262 89
    Figure US20100009961A1-20100114-C01816
    358 263 89
    Figure US20100009961A1-20100114-C01817
    359 264 89
    Figure US20100009961A1-20100114-C01818
    360 265 89
    Figure US20100009961A1-20100114-C01819
    361 266 89
    Figure US20100009961A1-20100114-C01820
    362 267 89
    Figure US20100009961A1-20100114-C01821
    363 268 89
    Figure US20100009961A1-20100114-C01822
    364 269 89
    Figure US20100009961A1-20100114-C01823
    365 270 89
    Figure US20100009961A1-20100114-C01824
    366 271 89
    Figure US20100009961A1-20100114-C01825
    367 272 89
    Figure US20100009961A1-20100114-C01826
    368 273 89
    Figure US20100009961A1-20100114-C01827
    369 274 89
    Figure US20100009961A1-20100114-C01828
    370 275 89
    Figure US20100009961A1-20100114-C01829
    371 276 89
    Figure US20100009961A1-20100114-C01830
    372 277 89
    Figure US20100009961A1-20100114-C01831
    373 278 89
    Figure US20100009961A1-20100114-C01832
    374 279 89
    Figure US20100009961A1-20100114-C01833
    375 280 89
    Figure US20100009961A1-20100114-C01834
    376 281 89
    Figure US20100009961A1-20100114-C01835
    377 282 89
    Figure US20100009961A1-20100114-C01836
    378 283 89
    Figure US20100009961A1-20100114-C01837
    379 284 89
    Figure US20100009961A1-20100114-C01838
    380 285 89
    Figure US20100009961A1-20100114-C01839
    381 286 89
    Figure US20100009961A1-20100114-C01840
    382 287 89
    Figure US20100009961A1-20100114-C01841
    383 288 89
    Figure US20100009961A1-20100114-C01842
    384 289 89
    Figure US20100009961A1-20100114-C01843
    385 290 89
    Figure US20100009961A1-20100114-C01844
    386 291 89
    Figure US20100009961A1-20100114-C01845
    387 292 89
    Figure US20100009961A1-20100114-C01846
    388 293 89
    Figure US20100009961A1-20100114-C01847
    389 294 89
    Figure US20100009961A1-20100114-C01848
  • Examples 390-399 have been intentionally excluded.
    • Example 400-595
  • If one were to follow the procedures outlined in Examples 28 or 29 except using the compounds from the Preparative Examples as indicated in the Table below, one would obtain the indicated Product.
  • Preparative Preparative
    Example Example Example Product
    400 300 2
    Figure US20100009961A1-20100114-C01849
    401 301 2
    Figure US20100009961A1-20100114-C01850
    402 302 2
    Figure US20100009961A1-20100114-C01851
    403 303 2
    Figure US20100009961A1-20100114-C01852
    404 304 2
    Figure US20100009961A1-20100114-C01853
    405 305 2
    Figure US20100009961A1-20100114-C01854
    406 306 2
    Figure US20100009961A1-20100114-C01855
    407 307 2
    Figure US20100009961A1-20100114-C01856
    408 308 2
    Figure US20100009961A1-20100114-C01857
    409 309 2
    Figure US20100009961A1-20100114-C01858
    410 310 2
    Figure US20100009961A1-20100114-C01859
    411 311 2
    Figure US20100009961A1-20100114-C01860
    412 312 2
    Figure US20100009961A1-20100114-C01861
    413 313 2
    Figure US20100009961A1-20100114-C01862
    414 314 2
    Figure US20100009961A1-20100114-C01863
    415 315 2
    Figure US20100009961A1-20100114-C01864
    416 316 2
    Figure US20100009961A1-20100114-C01865
    417 317 2
    Figure US20100009961A1-20100114-C01866
    418 318 2
    Figure US20100009961A1-20100114-C01867
    419 319 2
    Figure US20100009961A1-20100114-C01868
    420 320 2
    Figure US20100009961A1-20100114-C01869
    421 321 2
    Figure US20100009961A1-20100114-C01870
    422 322 2
    Figure US20100009961A1-20100114-C01871
    423 323 2
    Figure US20100009961A1-20100114-C01872
    424 324 2
    Figure US20100009961A1-20100114-C01873
    425 325 2
    Figure US20100009961A1-20100114-C01874
    426 326 2
    Figure US20100009961A1-20100114-C01875
    427 327 2
    Figure US20100009961A1-20100114-C01876
    428 328 2
    Figure US20100009961A1-20100114-C01877
    429 329 2
    Figure US20100009961A1-20100114-C01878
    430 330 2
    Figure US20100009961A1-20100114-C01879
    431 331 2
    Figure US20100009961A1-20100114-C01880
    432 332 2
    Figure US20100009961A1-20100114-C01881
    433 333 2
    Figure US20100009961A1-20100114-C01882
    434 334 2
    Figure US20100009961A1-20100114-C01883
    435 335 2
    Figure US20100009961A1-20100114-C01884
    436 400 2
    Figure US20100009961A1-20100114-C01885
    437 401 2
    Figure US20100009961A1-20100114-C01886
    438 402 2
    Figure US20100009961A1-20100114-C01887
    439 403 2
    Figure US20100009961A1-20100114-C01888
    440 404 2
    Figure US20100009961A1-20100114-C01889
    441 405 2
    Figure US20100009961A1-20100114-C01890
    442 406 2
    Figure US20100009961A1-20100114-C01891
    443 407 2
    Figure US20100009961A1-20100114-C01892
    444 408 2
    Figure US20100009961A1-20100114-C01893
    445 409 2
    Figure US20100009961A1-20100114-C01894
    446 410 2
    Figure US20100009961A1-20100114-C01895
    447 411 2
    Figure US20100009961A1-20100114-C01896
    448 412 2
    Figure US20100009961A1-20100114-C01897
    449 413 2
    Figure US20100009961A1-20100114-C01898
    450 414 2
    Figure US20100009961A1-20100114-C01899
    451 415 2
    Figure US20100009961A1-20100114-C01900
    452 416 2
    Figure US20100009961A1-20100114-C01901
    453 417 2
    Figure US20100009961A1-20100114-C01902
    454 418 2
    Figure US20100009961A1-20100114-C01903
    455 419 2
    Figure US20100009961A1-20100114-C01904
    456 420 2
    Figure US20100009961A1-20100114-C01905
    457 421 2
    Figure US20100009961A1-20100114-C01906
    458 422 2
    Figure US20100009961A1-20100114-C01907
    459 423 2
    Figure US20100009961A1-20100114-C01908
    460 424 2
    Figure US20100009961A1-20100114-C01909
    461 425 2
    Figure US20100009961A1-20100114-C01910
    462 426 2
    Figure US20100009961A1-20100114-C01911
    463 427 2
    Figure US20100009961A1-20100114-C01912
    464 428 2
    Figure US20100009961A1-20100114-C01913
    465 429 2
    Figure US20100009961A1-20100114-C01914
    466 430 2
    Figure US20100009961A1-20100114-C01915
    467 431 2
    Figure US20100009961A1-20100114-C01916
    468 432 2
    Figure US20100009961A1-20100114-C01917
    469 433 2
    Figure US20100009961A1-20100114-C01918
    470 434 2
    Figure US20100009961A1-20100114-C01919
    471 500 2
    Figure US20100009961A1-20100114-C01920
    472 501 2
    Figure US20100009961A1-20100114-C01921
    473 502 2
    Figure US20100009961A1-20100114-C01922
    474 503 2
    Figure US20100009961A1-20100114-C01923
    475 504 2
    Figure US20100009961A1-20100114-C01924
    476 505 2
    Figure US20100009961A1-20100114-C01925
    477 506 2
    Figure US20100009961A1-20100114-C01926
    478 507 2
    Figure US20100009961A1-20100114-C01927
    479 508 2
    Figure US20100009961A1-20100114-C01928
    480 509 2
    Figure US20100009961A1-20100114-C01929
    481 510 2
    Figure US20100009961A1-20100114-C01930
    482 511 2
    Figure US20100009961A1-20100114-C01931
    483 512 2
    Figure US20100009961A1-20100114-C01932
    484 513 2
    Figure US20100009961A1-20100114-C01933
    485 514 2
    Figure US20100009961A1-20100114-C01934
    486 515 2
    Figure US20100009961A1-20100114-C01935
    487 516 2
    Figure US20100009961A1-20100114-C01936
    488 517 2
    Figure US20100009961A1-20100114-C01937
    489 518 2
    Figure US20100009961A1-20100114-C01938
    490 519 2
    Figure US20100009961A1-20100114-C01939
    491 520 2
    Figure US20100009961A1-20100114-C01940
    492 521 2
    Figure US20100009961A1-20100114-C01941
    493 522 2
    Figure US20100009961A1-20100114-C01942
    494 523 2
    Figure US20100009961A1-20100114-C01943
    495 524 2
    Figure US20100009961A1-20100114-C01944
    496 525 2
    Figure US20100009961A1-20100114-C01945
    497 526 2
    Figure US20100009961A1-20100114-C01946
    498 527 2
    Figure US20100009961A1-20100114-C01947
    499 528 2
    Figure US20100009961A1-20100114-C01948
    500 529 2
    Figure US20100009961A1-20100114-C01949
    501 530 2
    Figure US20100009961A1-20100114-C01950
    502 531 2
    Figure US20100009961A1-20100114-C01951
    503 532 2
    Figure US20100009961A1-20100114-C01952
    504 533 2
    Figure US20100009961A1-20100114-C01953
    505 534 2
    Figure US20100009961A1-20100114-C01954
    506 535 2
    Figure US20100009961A1-20100114-C01955
    507 600 2
    Figure US20100009961A1-20100114-C01956
    508 601 2
    Figure US20100009961A1-20100114-C01957
    509 602 2
    Figure US20100009961A1-20100114-C01958
    510 603 2
    Figure US20100009961A1-20100114-C01959
    511 604 2
    Figure US20100009961A1-20100114-C01960
    512 605 2
    Figure US20100009961A1-20100114-C01961
    513 606 2
    Figure US20100009961A1-20100114-C01962
    514 607 2
    Figure US20100009961A1-20100114-C01963
    515 608 2
    Figure US20100009961A1-20100114-C01964
    516 609 2
    Figure US20100009961A1-20100114-C01965
    517 610 2
    Figure US20100009961A1-20100114-C01966
    518 611 2
    Figure US20100009961A1-20100114-C01967
    519 612 2
    Figure US20100009961A1-20100114-C01968
    520 613 2
    Figure US20100009961A1-20100114-C01969
    521 614 2
    Figure US20100009961A1-20100114-C01970
    522 615 2
    Figure US20100009961A1-20100114-C01971
    523 616 2
    Figure US20100009961A1-20100114-C01972
    524 617 2
    Figure US20100009961A1-20100114-C01973
    525 618 2
    Figure US20100009961A1-20100114-C01974
    526 619 2
    Figure US20100009961A1-20100114-C01975
    527 620 2
    Figure US20100009961A1-20100114-C01976
    528 621 2
    Figure US20100009961A1-20100114-C01977
    529 622 2
    Figure US20100009961A1-20100114-C01978
    530 623 2
    Figure US20100009961A1-20100114-C01979
    531 624 2
    Figure US20100009961A1-20100114-C01980
    532 625 2
    Figure US20100009961A1-20100114-C01981
    533 626 2
    Figure US20100009961A1-20100114-C01982
    534 627 2
    Figure US20100009961A1-20100114-C01983
    535 628 2
    Figure US20100009961A1-20100114-C01984
    536 629 2
    Figure US20100009961A1-20100114-C01985
    537 630 2
    Figure US20100009961A1-20100114-C01986
    538 631 2
    Figure US20100009961A1-20100114-C01987
    539 632 2
    Figure US20100009961A1-20100114-C01988
    540 633 2
    Figure US20100009961A1-20100114-C01989
    541 634 2
    Figure US20100009961A1-20100114-C01990
    542 635 2
    Figure US20100009961A1-20100114-C01991
    543 680 2
    Figure US20100009961A1-20100114-C01992
    544 681 2
    Figure US20100009961A1-20100114-C01993
    545 682 2
    Figure US20100009961A1-20100114-C01994
    546 683 2
    Figure US20100009961A1-20100114-C01995
    547 684 2
    Figure US20100009961A1-20100114-C01996
    548 685 2
    Figure US20100009961A1-20100114-C01997
    549 686 2
    Figure US20100009961A1-20100114-C01998
    550 687 2
    Figure US20100009961A1-20100114-C01999
    551 700 2
    Figure US20100009961A1-20100114-C02000
    552 701 2
    Figure US20100009961A1-20100114-C02001
    553 702 2
    Figure US20100009961A1-20100114-C02002
    554 703 2
    Figure US20100009961A1-20100114-C02003
    555 704 2
    Figure US20100009961A1-20100114-C02004
    556 705 2
    Figure US20100009961A1-20100114-C02005
    557 706 2
    Figure US20100009961A1-20100114-C02006
    558 707 2
    Figure US20100009961A1-20100114-C02007
    559 708 2
    Figure US20100009961A1-20100114-C02008
    560 709 2
    Figure US20100009961A1-20100114-C02009
    561 710 2
    Figure US20100009961A1-20100114-C02010
    562 711 2
    Figure US20100009961A1-20100114-C02011
    563 712 2
    Figure US20100009961A1-20100114-C02012
    564 713 2
    Figure US20100009961A1-20100114-C02013
    565 714 2
    Figure US20100009961A1-20100114-C02014
    566 715 2
    Figure US20100009961A1-20100114-C02015
    567 716 2
    Figure US20100009961A1-20100114-C02016
    568 717 2
    Figure US20100009961A1-20100114-C02017
    569 718 2
    Figure US20100009961A1-20100114-C02018
    570 719 2
    Figure US20100009961A1-20100114-C02019
    571 720 2
    Figure US20100009961A1-20100114-C02020
    572 721 2
    Figure US20100009961A1-20100114-C02021
    573 722 2
    Figure US20100009961A1-20100114-C02022
    574 723 2
    Figure US20100009961A1-20100114-C02023
    575 724 2
    Figure US20100009961A1-20100114-C02024
    576 725 2
    Figure US20100009961A1-20100114-C02025
    577 726 2
    Figure US20100009961A1-20100114-C02026
    578 727 2
    Figure US20100009961A1-20100114-C02027
    579 728 2
    Figure US20100009961A1-20100114-C02028
    580 729 2
    Figure US20100009961A1-20100114-C02029
    581 730 2
    Figure US20100009961A1-20100114-C02030
    582 731 2
    Figure US20100009961A1-20100114-C02031
    583 732 2
    Figure US20100009961A1-20100114-C02032
    584 733 2
    Figure US20100009961A1-20100114-C02033
    585 734 2
    Figure US20100009961A1-20100114-C02034
    586 735 2
    Figure US20100009961A1-20100114-C02035
    587 780 2
    Figure US20100009961A1-20100114-C02036
    588 781 2
    Figure US20100009961A1-20100114-C02037
    589 782 2
    Figure US20100009961A1-20100114-C02038
    590 783 2
    Figure US20100009961A1-20100114-C02039
    591 784 2
    Figure US20100009961A1-20100114-C02040
    592 785 2
    Figure US20100009961A1-20100114-C02041
    593 786 2
    Figure US20100009961A1-20100114-C02042
    594 787 2
    Figure US20100009961A1-20100114-C02043
    595 788 2
    Figure US20100009961A1-20100114-C02044
  • Examples 596-599 have been intentionally excluded.
    • Example 600-795
  • If one were to follow the procedures outlined in Examples 28 or 29 except using the compounds from the Preparative Examples as indicated in the Table below, one would obtain the indicated Product.
  • Preparative Preparative
    Example Example Example Product
    600 336 89
    Figure US20100009961A1-20100114-C02045
    601 337 89
    Figure US20100009961A1-20100114-C02046
    602 338 89
    Figure US20100009961A1-20100114-C02047
    603 339 89
    Figure US20100009961A1-20100114-C02048
    604 340 89
    Figure US20100009961A1-20100114-C02049
    605 341 89
    Figure US20100009961A1-20100114-C02050
    606 342 89
    Figure US20100009961A1-20100114-C02051
    607 343 89
    Figure US20100009961A1-20100114-C02052
    608 344 89
    Figure US20100009961A1-20100114-C02053
    609 345 89
    Figure US20100009961A1-20100114-C02054
    610 346 89
    Figure US20100009961A1-20100114-C02055
    611 347 89
    Figure US20100009961A1-20100114-C02056
    612 348 89
    Figure US20100009961A1-20100114-C02057
    613 349 89
    Figure US20100009961A1-20100114-C02058
    614 350 89
    Figure US20100009961A1-20100114-C02059
    615 351 89
    Figure US20100009961A1-20100114-C02060
    616 352 89
    Figure US20100009961A1-20100114-C02061
    617 353 89
    Figure US20100009961A1-20100114-C02062
    618 354 89
    Figure US20100009961A1-20100114-C02063
    619 355 89
    Figure US20100009961A1-20100114-C02064
    620 356 89
    Figure US20100009961A1-20100114-C02065
    621 357 89
    Figure US20100009961A1-20100114-C02066
    622 358 89
    Figure US20100009961A1-20100114-C02067
    623 359 89
    Figure US20100009961A1-20100114-C02068
    624 360 89
    Figure US20100009961A1-20100114-C02069
    625 361 89
    Figure US20100009961A1-20100114-C02070
    626 362 89
    Figure US20100009961A1-20100114-C02071
    627 363 89
    Figure US20100009961A1-20100114-C02072
    628 364 89
    Figure US20100009961A1-20100114-C02073
    629 365 89
    Figure US20100009961A1-20100114-C02074
    630 366 89
    Figure US20100009961A1-20100114-C02075
    631 367 89
    Figure US20100009961A1-20100114-C02076
    632 368 89
    Figure US20100009961A1-20100114-C02077
    633 369 89
    Figure US20100009961A1-20100114-C02078
    634 370 89
    Figure US20100009961A1-20100114-C02079
    635 371 89
    Figure US20100009961A1-20100114-C02080
    636 435 89
    Figure US20100009961A1-20100114-C02081
    637 436 89
    Figure US20100009961A1-20100114-C02082
    638 437 89
    Figure US20100009961A1-20100114-C02083
    639 438 89
    Figure US20100009961A1-20100114-C02084
    640 439 89
    Figure US20100009961A1-20100114-C02085
    641 440 89
    Figure US20100009961A1-20100114-C02086
    642 441 89
    Figure US20100009961A1-20100114-C02087
    643 442 89
    Figure US20100009961A1-20100114-C02088
    644 443 89
    Figure US20100009961A1-20100114-C02089
    645 444 89
    Figure US20100009961A1-20100114-C02090
    646 445 89
    Figure US20100009961A1-20100114-C02091
    647 446 89
    Figure US20100009961A1-20100114-C02092
    648 447 89
    Figure US20100009961A1-20100114-C02093
    649 448 89
    Figure US20100009961A1-20100114-C02094
    650 449 89
    Figure US20100009961A1-20100114-C02095
    651 450 89
    Figure US20100009961A1-20100114-C02096
    652 451 89
    Figure US20100009961A1-20100114-C02097
    653 452 89
    Figure US20100009961A1-20100114-C02098
    654 453 89
    Figure US20100009961A1-20100114-C02099
    655 454 89
    Figure US20100009961A1-20100114-C02100
    656 455 89
    Figure US20100009961A1-20100114-C02101
    657 456 89
    Figure US20100009961A1-20100114-C02102
    658 457 89
    Figure US20100009961A1-20100114-C02103
    659 458 89
    Figure US20100009961A1-20100114-C02104
    660 459 89
    Figure US20100009961A1-20100114-C02105
    661 460 89
    Figure US20100009961A1-20100114-C02106
    662 461 89
    Figure US20100009961A1-20100114-C02107
    663 462 89
    Figure US20100009961A1-20100114-C02108
    664 463 89
    Figure US20100009961A1-20100114-C02109
    665 464 89
    Figure US20100009961A1-20100114-C02110
    666 465 89
    Figure US20100009961A1-20100114-C02111
    667 466 89
    Figure US20100009961A1-20100114-C02112
    668 467 89
    Figure US20100009961A1-20100114-C02113
    669 468 89
    Figure US20100009961A1-20100114-C02114
    670 469 89
    Figure US20100009961A1-20100114-C02115
    671 536 89
    Figure US20100009961A1-20100114-C02116
    672 537 89
    Figure US20100009961A1-20100114-C02117
    673 538 89
    Figure US20100009961A1-20100114-C02118
    674 539 89
    Figure US20100009961A1-20100114-C02119
    675 540 89
    Figure US20100009961A1-20100114-C02120
    676 541 89
    Figure US20100009961A1-20100114-C02121
    677 542 89
    Figure US20100009961A1-20100114-C02122
    678 543 89
    Figure US20100009961A1-20100114-C02123
    679 544 89
    Figure US20100009961A1-20100114-C02124
    680 545 89
    Figure US20100009961A1-20100114-C02125
    681 546 89
    Figure US20100009961A1-20100114-C02126
    682 547 89
    Figure US20100009961A1-20100114-C02127
    683 548 89
    Figure US20100009961A1-20100114-C02128
    684 549 89
    Figure US20100009961A1-20100114-C02129
    685 550 89
    Figure US20100009961A1-20100114-C02130
    686 551 89
    Figure US20100009961A1-20100114-C02131
    687 552 89
    Figure US20100009961A1-20100114-C02132
    688 553 89
    Figure US20100009961A1-20100114-C02133
    689 554 89
    Figure US20100009961A1-20100114-C02134
    690 555 89
    Figure US20100009961A1-20100114-C02135
    691 556 89
    Figure US20100009961A1-20100114-C02136
    692 557 89
    Figure US20100009961A1-20100114-C02137
    693 558 89
    Figure US20100009961A1-20100114-C02138
    694 559 89
    Figure US20100009961A1-20100114-C02139
    695 560 89
    Figure US20100009961A1-20100114-C02140
    696 561 89
    Figure US20100009961A1-20100114-C02141
    697 562 89
    Figure US20100009961A1-20100114-C02142
    698 563 89
    Figure US20100009961A1-20100114-C02143
    699 564 89
    Figure US20100009961A1-20100114-C02144
    700 565 89
    Figure US20100009961A1-20100114-C02145
    701 566 89
    Figure US20100009961A1-20100114-C02146
    702 567 89
    Figure US20100009961A1-20100114-C02147
    703 568 89
    Figure US20100009961A1-20100114-C02148
    704 569 89
    Figure US20100009961A1-20100114-C02149
    705 570 89
    Figure US20100009961A1-20100114-C02150
    706 571 89
    Figure US20100009961A1-20100114-C02151
    707 636 89
    Figure US20100009961A1-20100114-C02152
    708 637 89
    Figure US20100009961A1-20100114-C02153
    709 638 89
    Figure US20100009961A1-20100114-C02154
    710 639 89
    Figure US20100009961A1-20100114-C02155
    711 640 89
    Figure US20100009961A1-20100114-C02156
    712 641 89
    Figure US20100009961A1-20100114-C02157
    713 642 89
    Figure US20100009961A1-20100114-C02158
    714 643 89
    Figure US20100009961A1-20100114-C02159
    715 644 89
    Figure US20100009961A1-20100114-C02160
    716 645 89
    Figure US20100009961A1-20100114-C02161
    717 646 89
    Figure US20100009961A1-20100114-C02162
    718 647 89
    Figure US20100009961A1-20100114-C02163
    719 648 89
    Figure US20100009961A1-20100114-C02164
    720 649 89
    Figure US20100009961A1-20100114-C02165
    721 650 89
    Figure US20100009961A1-20100114-C02166
    722 651 89
    Figure US20100009961A1-20100114-C02167
    723 652 89
    Figure US20100009961A1-20100114-C02168
    724 653 89
    Figure US20100009961A1-20100114-C02169
    725 654 89
    Figure US20100009961A1-20100114-C02170
    726 655 89
    Figure US20100009961A1-20100114-C02171
    727 656 89
    Figure US20100009961A1-20100114-C02172
    728 657 89
    Figure US20100009961A1-20100114-C02173
    729 658 89
    Figure US20100009961A1-20100114-C02174
    730 659 89
    Figure US20100009961A1-20100114-C02175
    731 660 89
    Figure US20100009961A1-20100114-C02176
    732 661 89
    Figure US20100009961A1-20100114-C02177
    733 662 89
    Figure US20100009961A1-20100114-C02178
    734 663 89
    Figure US20100009961A1-20100114-C02179
    735 664 89
    Figure US20100009961A1-20100114-C02180
    736 665 89
    Figure US20100009961A1-20100114-C02181
    737 666 89
    Figure US20100009961A1-20100114-C02182
    738 667 89
    Figure US20100009961A1-20100114-C02183
    739 668 89
    Figure US20100009961A1-20100114-C02184
    740 669 89
    Figure US20100009961A1-20100114-C02185
    741 670 89
    Figure US20100009961A1-20100114-C02186
    742 671 89
    Figure US20100009961A1-20100114-C02187
    743 688 89
    Figure US20100009961A1-20100114-C02188
    744 689 89
    Figure US20100009961A1-20100114-C02189
    745 690 89
    Figure US20100009961A1-20100114-C02190
    746 691 89
    Figure US20100009961A1-20100114-C02191
    747 692 89
    Figure US20100009961A1-20100114-C02192
    748 693 89
    Figure US20100009961A1-20100114-C02193
    749 694 89
    Figure US20100009961A1-20100114-C02194
    750 695 89
    Figure US20100009961A1-20100114-C02195
    751 736 89
    Figure US20100009961A1-20100114-C02196
    752 737 89
    Figure US20100009961A1-20100114-C02197
    753 738 89
    Figure US20100009961A1-20100114-C02198
    754 739 89
    Figure US20100009961A1-20100114-C02199
    755 740 89
    Figure US20100009961A1-20100114-C02200
    756 741 89
    Figure US20100009961A1-20100114-C02201
    757 742 89
    Figure US20100009961A1-20100114-C02202
    758 743 89
    Figure US20100009961A1-20100114-C02203
    759 744 89
    Figure US20100009961A1-20100114-C02204
    760 745 89
    Figure US20100009961A1-20100114-C02205
    761 746 89
    Figure US20100009961A1-20100114-C02206
    762 747 89
    Figure US20100009961A1-20100114-C02207
    763 748 89
    Figure US20100009961A1-20100114-C02208
    764 749 89
    Figure US20100009961A1-20100114-C02209
    765 750 89
    Figure US20100009961A1-20100114-C02210
    766 751 89
    Figure US20100009961A1-20100114-C02211
    767 752 89
    Figure US20100009961A1-20100114-C02212
    768 753 89
    Figure US20100009961A1-20100114-C02213
    769 754 89
    Figure US20100009961A1-20100114-C02214
    770 755 89
    Figure US20100009961A1-20100114-C02215
    771 756 89
    Figure US20100009961A1-20100114-C02216
    772 757 89
    Figure US20100009961A1-20100114-C02217
    773 758 89
    Figure US20100009961A1-20100114-C02218
    774 759 89
    Figure US20100009961A1-20100114-C02219
    775 760 89
    Figure US20100009961A1-20100114-C02220
    776 761 89
    Figure US20100009961A1-20100114-C02221
    777 762 89
    Figure US20100009961A1-20100114-C02222
    778 763 89
    Figure US20100009961A1-20100114-C02223
    779 764 89
    Figure US20100009961A1-20100114-C02224
    780 765 89
    Figure US20100009961A1-20100114-C02225
    781 766 89
    Figure US20100009961A1-20100114-C02226
    782 767 89
    Figure US20100009961A1-20100114-C02227
    783 768 89
    Figure US20100009961A1-20100114-C02228
    784 769 89
    Figure US20100009961A1-20100114-C02229
    785 770 89
    Figure US20100009961A1-20100114-C02230
    786 771 89
    Figure US20100009961A1-20100114-C02231
    787 789 89
    Figure US20100009961A1-20100114-C02232
    788 790 89
    Figure US20100009961A1-20100114-C02233
    789 791 89
    Figure US20100009961A1-20100114-C02234
    790 792 89
    Figure US20100009961A1-20100114-C02235
    791 793 89
    Figure US20100009961A1-20100114-C02236
    792 794 89
    Figure US20100009961A1-20100114-C02237
    793 795 89
    Figure US20100009961A1-20100114-C02238
    794 796 89
    Figure US20100009961A1-20100114-C02239
    795 797 89
    Figure US20100009961A1-20100114-C02240
  • Examples 796-799 have been intentionally excluded.
    • Example 800-833
  • If one were to follow a similar procedure as that described in Examples 27 or 28, and treat the title compounds from the Preparative Examples in the table below as described in Preparative Example 69 and 71, except using the amines as indicated in the Table below, one would obtain the desired product.
  • Preparative Preparative
    Example Example Example Amine Product
    800 61 Step B  2 NH3
    Figure US20100009961A1-20100114-C02241
    801 62  2 NH3
    Figure US20100009961A1-20100114-C02242
    802 65  2 NH3
    Figure US20100009961A1-20100114-C02243
    803 61 Step B  2 NH3
    Figure US20100009961A1-20100114-C02244
    804 62  2 NH3
    Figure US20100009961A1-20100114-C02245
    805 65  2 NH3
    Figure US20100009961A1-20100114-C02246
    806 61 Step B  2 CH3NH2
    Figure US20100009961A1-20100114-C02247
    807 62  2 CH3NH2
    Figure US20100009961A1-20100114-C02248
    808 65  2 CH3NH2
    Figure US20100009961A1-20100114-C02249
    809 61 Step B  2 CH3NH2
    Figure US20100009961A1-20100114-C02250
    810 62  2 CH3NH2
    Figure US20100009961A1-20100114-C02251
    811 65  2 CH3NH2
    Figure US20100009961A1-20100114-C02252
    812 61 Step B  2 (CH3)2NH
    Figure US20100009961A1-20100114-C02253
    813 65  2 (CH3)2NH
    Figure US20100009961A1-20100114-C02254
    814 61 Step B  2 (CH3)2NH
    Figure US20100009961A1-20100114-C02255
    815 65  2 (CH3)2NH
    Figure US20100009961A1-20100114-C02256
    816 61 Step B 89 NH3
    Figure US20100009961A1-20100114-C02257
    817 62 89 NH3
    Figure US20100009961A1-20100114-C02258
    818 65 89 NH3
    Figure US20100009961A1-20100114-C02259
    819 61 Step B 89 NH3
    Figure US20100009961A1-20100114-C02260
    820 62 89 NH3
    Figure US20100009961A1-20100114-C02261
    821 65 89 NH3
    Figure US20100009961A1-20100114-C02262
    822 61 Step B 89 CH3NH2
    Figure US20100009961A1-20100114-C02263
    823 62 89 CH3NH2
    Figure US20100009961A1-20100114-C02264
    824 65 89 CH3NH2
    Figure US20100009961A1-20100114-C02265
    825 61 Step B 89 CH3NH2
    Figure US20100009961A1-20100114-C02266
    826 62 89 CH3NH2
    Figure US20100009961A1-20100114-C02267
    827 65 89 CH3NH2
    Figure US20100009961A1-20100114-C02268
    828 61 Step B 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02269
    829 62 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02270
    830 65 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02271
    831 61 Step B 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02272
    832 62 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02273
    833 65 89 (CH3)2NH
    Figure US20100009961A1-20100114-C02274
  • Examples 834-999 have been intentionally excluded.
    • Example 1000-1168
  • If one were to follow the procedures outlined in Examples 28 or 29 except using the compounds from the Preparative Examples as indicated in the Table below, one would obtain the indicated Product.
  • Preparative Preparative
    Example Example Example Product
    1000  801  2
    Figure US20100009961A1-20100114-C02275
    1001  804  2
    Figure US20100009961A1-20100114-C02276
    1002  805  2
    Figure US20100009961A1-20100114-C02277
    1003  800  2
    Figure US20100009961A1-20100114-C02278
    1004  802  2
    Figure US20100009961A1-20100114-C02279
    1005  803  2
    Figure US20100009961A1-20100114-C02280
    1006  801 89
    Figure US20100009961A1-20100114-C02281
    1007  804 89
    Figure US20100009961A1-20100114-C02282
    1008  805 89
    Figure US20100009961A1-20100114-C02283
    1009  800 89
    Figure US20100009961A1-20100114-C02284
    1010  802 89
    Figure US20100009961A1-20100114-C02285
    1011  803 89
    Figure US20100009961A1-20100114-C02286
    1012  810  2
    Figure US20100009961A1-20100114-C02287
    1013  812  2
    Figure US20100009961A1-20100114-C02288
    1014  811  2
    Figure US20100009961A1-20100114-C02289
    1015  810 89
    Figure US20100009961A1-20100114-C02290
    1016  812 89
    Figure US20100009961A1-20100114-C02291
    1017  811 89
    Figure US20100009961A1-20100114-C02292
    1018  831  2
    Figure US20100009961A1-20100114-C02293
    1019  832  2
    Figure US20100009961A1-20100114-C02294
    1020  833  2
    Figure US20100009961A1-20100114-C02295
    1021  834  2
    Figure US20100009961A1-20100114-C02296
    1022  835  2
    Figure US20100009961A1-20100114-C02297
    1023  836  2
    Figure US20100009961A1-20100114-C02298
    1024  837  2
    Figure US20100009961A1-20100114-C02299
    1025  838  2
    Figure US20100009961A1-20100114-C02300
    1026  839  2
    Figure US20100009961A1-20100114-C02301
    1027  851  2
    Figure US20100009961A1-20100114-C02302
    1028  852  2
    Figure US20100009961A1-20100114-C02303
    1029  853  2
    Figure US20100009961A1-20100114-C02304
    1030  854  2
    Figure US20100009961A1-20100114-C02305
    1031  855  2
    Figure US20100009961A1-20100114-C02306
    1032  856  2
    Figure US20100009961A1-20100114-C02307
    1033  857  2
    Figure US20100009961A1-20100114-C02308
    1034  858  2
    Figure US20100009961A1-20100114-C02309
    1035  859  2
    Figure US20100009961A1-20100114-C02310
    1036  901  2
    Figure US20100009961A1-20100114-C02311
    1037  902  2
    Figure US20100009961A1-20100114-C02312
    1038  903  2
    Figure US20100009961A1-20100114-C02313
    1039  904  2
    Figure US20100009961A1-20100114-C02314
    1040  905  2
    Figure US20100009961A1-20100114-C02315
    1041  906  2
    Figure US20100009961A1-20100114-C02316
    1042  907  2
    Figure US20100009961A1-20100114-C02317
    1043  908  2
    Figure US20100009961A1-20100114-C02318
    1044  909  2
    Figure US20100009961A1-20100114-C02319
    1045  921  2
    Figure US20100009961A1-20100114-C02320
    1046  922  2
    Figure US20100009961A1-20100114-C02321
    1047  923  2
    Figure US20100009961A1-20100114-C02322
    1048  924  2
    Figure US20100009961A1-20100114-C02323
    1049  925  2
    Figure US20100009961A1-20100114-C02324
    1050  926  2
    Figure US20100009961A1-20100114-C02325
    1051  927  2
    Figure US20100009961A1-20100114-C02326
    1052  928  2
    Figure US20100009961A1-20100114-C02327
    1053  929  2
    Figure US20100009961A1-20100114-C02328
    1054  831 89
    Figure US20100009961A1-20100114-C02329
    1055  832 89
    Figure US20100009961A1-20100114-C02330
    1056  833 89
    Figure US20100009961A1-20100114-C02331
    1057  834 89
    Figure US20100009961A1-20100114-C02332
    1058  835 89
    Figure US20100009961A1-20100114-C02333
    1059  836 89
    Figure US20100009961A1-20100114-C02334
    1060  837 89
    Figure US20100009961A1-20100114-C02335
    1061  838 89
    Figure US20100009961A1-20100114-C02336
    1062  839 89
    Figure US20100009961A1-20100114-C02337
    1063  851 89
    Figure US20100009961A1-20100114-C02338
    1064  852 89
    Figure US20100009961A1-20100114-C02339
    1065  853 89
    Figure US20100009961A1-20100114-C02340
    1066  854 89
    Figure US20100009961A1-20100114-C02341
    1067  855 89
    Figure US20100009961A1-20100114-C02342
    1068  856 89
    Figure US20100009961A1-20100114-C02343
    1069  857 89
    Figure US20100009961A1-20100114-C02344
    1070  858 89
    Figure US20100009961A1-20100114-C02345
    1071  859 89
    Figure US20100009961A1-20100114-C02346
    1072  901 89
    Figure US20100009961A1-20100114-C02347
    1073  902 89
    Figure US20100009961A1-20100114-C02348
    1074  903 89
    Figure US20100009961A1-20100114-C02349
    1075  904 89
    Figure US20100009961A1-20100114-C02350
    1076  905 89
    Figure US20100009961A1-20100114-C02351
    1077  906 89
    Figure US20100009961A1-20100114-C02352
    1078  907 89
    Figure US20100009961A1-20100114-C02353
    1079  908 89
    Figure US20100009961A1-20100114-C02354
    1080  909 89
    Figure US20100009961A1-20100114-C02355
    1081  921 89
    Figure US20100009961A1-20100114-C02356
    1082  922 89
    Figure US20100009961A1-20100114-C02357
    1083  923 89
    Figure US20100009961A1-20100114-C02358
    1084  924 89
    Figure US20100009961A1-20100114-C02359
    1085  925 89
    Figure US20100009961A1-20100114-C02360
    1086  926 89
    Figure US20100009961A1-20100114-C02361
    1087  927 89
    Figure US20100009961A1-20100114-C02362
    1088  928 89
    Figure US20100009961A1-20100114-C02363
    1089  929 89
    Figure US20100009961A1-20100114-C02364
    1090 1301  2
    Figure US20100009961A1-20100114-C02365
    1091 1302  2
    Figure US20100009961A1-20100114-C02366
    1092 1303  2
    Figure US20100009961A1-20100114-C02367
    1093 1304  2
    Figure US20100009961A1-20100114-C02368
    1094 1305  2
    Figure US20100009961A1-20100114-C02369
    1095 1306  2
    Figure US20100009961A1-20100114-C02370
    1096 1307  2
    Figure US20100009961A1-20100114-C02371
    1097 1308  2
    Figure US20100009961A1-20100114-C02372
    1098 1309  2
    Figure US20100009961A1-20100114-C02373
    1099 1351  2
    Figure US20100009961A1-20100114-C02374
    1100 1352  2
    Figure US20100009961A1-20100114-C02375
    1101 1353  2
    Figure US20100009961A1-20100114-C02376
    1102 1354  2
    Figure US20100009961A1-20100114-C02377
    1103 1355  2
    Figure US20100009961A1-20100114-C02378
    1104 1356  2
    Figure US20100009961A1-20100114-C02379
    1105 1357  2
    Figure US20100009961A1-20100114-C02380
    1106 1358  2
    Figure US20100009961A1-20100114-C02381
    1107 1359  2
    Figure US20100009961A1-20100114-C02382
    1108 1401  2
    Figure US20100009961A1-20100114-C02383
    1109 1402  2
    Figure US20100009961A1-20100114-C02384
    1110 1403  2
    Figure US20100009961A1-20100114-C02385
    1111 1404  2
    Figure US20100009961A1-20100114-C02386
    1112 1405  2
    Figure US20100009961A1-20100114-C02387
    1113 1406  2
    Figure US20100009961A1-20100114-C02388
    1114 1407  2
    Figure US20100009961A1-20100114-C02389
    1115 1408  2
    Figure US20100009961A1-20100114-C02390
    1116 1409  2
    Figure US20100009961A1-20100114-C02391
    1117 1301 89
    Figure US20100009961A1-20100114-C02392
    1118 1302 89
    Figure US20100009961A1-20100114-C02393
    1119 1303 89
    Figure US20100009961A1-20100114-C02394
    1120 1304 89
    Figure US20100009961A1-20100114-C02395
    1121 1305 89
    Figure US20100009961A1-20100114-C02396
    1122 1306 89
    Figure US20100009961A1-20100114-C02397
    1123 1307 89
    Figure US20100009961A1-20100114-C02398
    1124 1308 89
    Figure US20100009961A1-20100114-C02399
    1125 1309 89
    Figure US20100009961A1-20100114-C02400
    1126 1351 89
    Figure US20100009961A1-20100114-C02401
    1127 1352 89
    Figure US20100009961A1-20100114-C02402
    1128 1353 89
    Figure US20100009961A1-20100114-C02403
    1129 1354 89
    Figure US20100009961A1-20100114-C02404
    1130 1355 89
    Figure US20100009961A1-20100114-C02405
    1131 1356 89
    Figure US20100009961A1-20100114-C02406
    1132 1357 89
    Figure US20100009961A1-20100114-C02407
    1133 1358 89
    Figure US20100009961A1-20100114-C02408
    1134 1359 89
    Figure US20100009961A1-20100114-C02409
    1135 1401 89
    Figure US20100009961A1-20100114-C02410
    1136 1402 89
    Figure US20100009961A1-20100114-C02411
    1137 1403 89
    Figure US20100009961A1-20100114-C02412
    1138 1404 89
    Figure US20100009961A1-20100114-C02413
    1139 1405 89
    Figure US20100009961A1-20100114-C02414
    1140 1406 89
    Figure US20100009961A1-20100114-C02415
    1141 1407 89
    Figure US20100009961A1-20100114-C02416
    1142 1408 89
    Figure US20100009961A1-20100114-C02417
    1143 1409 89
    Figure US20100009961A1-20100114-C02418
    1144 1450 Step K  2
    Figure US20100009961A1-20100114-C02419
    1145 1450 Step O  2
    Figure US20100009961A1-20100114-C02420
    1146 1451 Step F  2
    Figure US20100009961A1-20100114-C02421
    1147 1451 Step J  2
    Figure US20100009961A1-20100114-C02422
    1148 1452 Step F  2
    Figure US20100009961A1-20100114-C02423
    1149 1452 Step J  2
    Figure US20100009961A1-20100114-C02424
    1150 1453 Step J  2
    Figure US20100009961A1-20100114-C02425
    1151 1453 Step M  2
    Figure US20100009961A1-20100114-C02426
    1152 1454 Step I  2
    Figure US20100009961A1-20100114-C02427
    1153 1454 Step L  2
    Figure US20100009961A1-20100114-C02428
    1154 1500  2
    Figure US20100009961A1-20100114-C02429
    1155 1501  2
    Figure US20100009961A1-20100114-C02430
    1156 1502  2
    Figure US20100009961A1-20100114-C02431
    1157 1450 Step K 89
    Figure US20100009961A1-20100114-C02432
    1158 1450 Step O 89
    Figure US20100009961A1-20100114-C02433
    1159 1451 Step F 89
    Figure US20100009961A1-20100114-C02434
    1160 1451 Step J 89
    Figure US20100009961A1-20100114-C02435
    1161 1452 Step F 89
    Figure US20100009961A1-20100114-C02436
    1162 1452 Step J 89
    Figure US20100009961A1-20100114-C02437
    1163 1453 Step J 89
    Figure US20100009961A1-20100114-C02438
    1164 1453 Step M 89
    Figure US20100009961A1-20100114-C02439
    1165 1454 Step I 89
    Figure US20100009961A1-20100114-C02440
    1166 1454 Step L 89
    Figure US20100009961A1-20100114-C02441
    1167 1500 89
    Figure US20100009961A1-20100114-C02442
    1168 1501 89
    Figure US20100009961A1-20100114-C02443
  • Examples 1169-1499 have been intentionally excluded.
    • Example 1500-1709
  • If one were to follow a similar procedure as that described in Preparative Example 48, except using the compounds from the Preparative Examples as indicated in the Table below, one would obtain the desired amine product.
  • Compound
    Preparative
    Example Example Product
    1500 1000
    Figure US20100009961A1-20100114-C02444
    1501 1001
    Figure US20100009961A1-20100114-C02445
    1502 1002
    Figure US20100009961A1-20100114-C02446
    1503 1003
    Figure US20100009961A1-20100114-C02447
    1504 1004
    Figure US20100009961A1-20100114-C02448
    1505 1005
    Figure US20100009961A1-20100114-C02449
    1506 1006
    Figure US20100009961A1-20100114-C02450
    1507 1007
    Figure US20100009961A1-20100114-C02451
    1508 1008
    Figure US20100009961A1-20100114-C02452
    1509 1009
    Figure US20100009961A1-20100114-C02453
    1510 1010
    Figure US20100009961A1-20100114-C02454
    1511 1011
    Figure US20100009961A1-20100114-C02455
    1512 1012
    Figure US20100009961A1-20100114-C02456
    1513 1013
    Figure US20100009961A1-20100114-C02457
    1514 1014
    Figure US20100009961A1-20100114-C02458
    1515 1015
    Figure US20100009961A1-20100114-C02459
    1516 1016
    Figure US20100009961A1-20100114-C02460
    1517 1017
    Figure US20100009961A1-20100114-C02461
    1518 1018
    Figure US20100009961A1-20100114-C02462
    1519 1019
    Figure US20100009961A1-20100114-C02463
    1520 1020
    Figure US20100009961A1-20100114-C02464
    1521 1021
    Figure US20100009961A1-20100114-C02465
    1522 1022
    Figure US20100009961A1-20100114-C02466
    1523 1023
    Figure US20100009961A1-20100114-C02467
    1524 1024
    Figure US20100009961A1-20100114-C02468
    1525 1025
    Figure US20100009961A1-20100114-C02469
    1526 1026
    Figure US20100009961A1-20100114-C02470
    1527 1027
    Figure US20100009961A1-20100114-C02471
    1528 1028
    Figure US20100009961A1-20100114-C02472
    1529 1029
    Figure US20100009961A1-20100114-C02473
    1530 1030
    Figure US20100009961A1-20100114-C02474
    1531 1031
    Figure US20100009961A1-20100114-C02475
    1532 1032
    Figure US20100009961A1-20100114-C02476
    1533 1033
    Figure US20100009961A1-20100114-C02477
    1534 1034
    Figure US20100009961A1-20100114-C02478
    1535 1035
    Figure US20100009961A1-20100114-C02479
    1536 1036
    Figure US20100009961A1-20100114-C02480
    1537 1037
    Figure US20100009961A1-20100114-C02481
    1538 1038
    Figure US20100009961A1-20100114-C02482
    1539 1039
    Figure US20100009961A1-20100114-C02483
    1540 1040
    Figure US20100009961A1-20100114-C02484
    1541 1041
    Figure US20100009961A1-20100114-C02485
    1542 1042
    Figure US20100009961A1-20100114-C02486
    1543 1043
    Figure US20100009961A1-20100114-C02487
    1544 1044
    Figure US20100009961A1-20100114-C02488
    1545 1045
    Figure US20100009961A1-20100114-C02489
    1546 1046
    Figure US20100009961A1-20100114-C02490
    1547 1047
    Figure US20100009961A1-20100114-C02491
    1548 1048
    Figure US20100009961A1-20100114-C02492
    1549 1049
    Figure US20100009961A1-20100114-C02493
    1550 1050
    Figure US20100009961A1-20100114-C02494
    1551 1051
    Figure US20100009961A1-20100114-C02495
    1552 1052
    Figure US20100009961A1-20100114-C02496
    1553 1053
    Figure US20100009961A1-20100114-C02497
    1554 1054
    Figure US20100009961A1-20100114-C02498
    1555 1055
    Figure US20100009961A1-20100114-C02499
    1556 1056
    Figure US20100009961A1-20100114-C02500
    1557 1057
    Figure US20100009961A1-20100114-C02501
    1558 1058
    Figure US20100009961A1-20100114-C02502
    1559 1059
    Figure US20100009961A1-20100114-C02503
    1560 1060
    Figure US20100009961A1-20100114-C02504
    1561 1061
    Figure US20100009961A1-20100114-C02505
    1562 1062
    Figure US20100009961A1-20100114-C02506
    1563 1063
    Figure US20100009961A1-20100114-C02507
    1564 1064
    Figure US20100009961A1-20100114-C02508
    1565 1065
    Figure US20100009961A1-20100114-C02509
    1566 1066
    Figure US20100009961A1-20100114-C02510
    1567 1067
    Figure US20100009961A1-20100114-C02511
    1568 1068
    Figure US20100009961A1-20100114-C02512
    1569 1069
    Figure US20100009961A1-20100114-C02513
    1570 1070
    Figure US20100009961A1-20100114-C02514
    1571 1071
    Figure US20100009961A1-20100114-C02515
    1572 1072
    Figure US20100009961A1-20100114-C02516
    1573 1073
    Figure US20100009961A1-20100114-C02517
    1574 1074
    Figure US20100009961A1-20100114-C02518
    1575 1075
    Figure US20100009961A1-20100114-C02519
    1576 1076
    Figure US20100009961A1-20100114-C02520
    1577 1077
    Figure US20100009961A1-20100114-C02521
    1578 1078
    Figure US20100009961A1-20100114-C02522
    1579 1079
    Figure US20100009961A1-20100114-C02523
    1580 1080
    Figure US20100009961A1-20100114-C02524
    1581 1081
    Figure US20100009961A1-20100114-C02525
    1582 1082
    Figure US20100009961A1-20100114-C02526
    1583 1083
    Figure US20100009961A1-20100114-C02527
    1584 1084
    Figure US20100009961A1-20100114-C02528
    1585 1085
    Figure US20100009961A1-20100114-C02529
    1586 1086
    Figure US20100009961A1-20100114-C02530
    1587 1087
    Figure US20100009961A1-20100114-C02531
    1588 1088
    Figure US20100009961A1-20100114-C02532
    1589 1089
    Figure US20100009961A1-20100114-C02533
    1590 1090
    Figure US20100009961A1-20100114-C02534
    1591 1091
    Figure US20100009961A1-20100114-C02535
    1592 1092
    Figure US20100009961A1-20100114-C02536
    1593 1093
    Figure US20100009961A1-20100114-C02537
    1594 1094
    Figure US20100009961A1-20100114-C02538
    1595 1095
    Figure US20100009961A1-20100114-C02539
    1596 1096
    Figure US20100009961A1-20100114-C02540
    1597 1097
    Figure US20100009961A1-20100114-C02541
    1598 1098
    Figure US20100009961A1-20100114-C02542
    1599 1099
    Figure US20100009961A1-20100114-C02543
    1600 1100
    Figure US20100009961A1-20100114-C02544
    1601 1101
    Figure US20100009961A1-20100114-C02545
    1602 1102
    Figure US20100009961A1-20100114-C02546
    1603 1103
    Figure US20100009961A1-20100114-C02547
    1604 1104
    Figure US20100009961A1-20100114-C02548
    1605 1105
    Figure US20100009961A1-20100114-C02549
    1606 1106
    Figure US20100009961A1-20100114-C02550
    1607 1107
    Figure US20100009961A1-20100114-C02551
    1608 1108
    Figure US20100009961A1-20100114-C02552
    1609 1109
    Figure US20100009961A1-20100114-C02553
    1610 1110
    Figure US20100009961A1-20100114-C02554
    1611 1111
    Figure US20100009961A1-20100114-C02555
    1612 1112
    Figure US20100009961A1-20100114-C02556
    1613 1113
    Figure US20100009961A1-20100114-C02557
    1614 1114
    Figure US20100009961A1-20100114-C02558
    1615 1115
    Figure US20100009961A1-20100114-C02559
    1616 1116
    Figure US20100009961A1-20100114-C02560
    1617 1117
    Figure US20100009961A1-20100114-C02561
    1618 1118
    Figure US20100009961A1-20100114-C02562
    1619 1119
    Figure US20100009961A1-20100114-C02563
    1620 1120
    Figure US20100009961A1-20100114-C02564
    1621 1121
    Figure US20100009961A1-20100114-C02565
    1622 1122
    Figure US20100009961A1-20100114-C02566
    1623 1123
    Figure US20100009961A1-20100114-C02567
    1624 1124
    Figure US20100009961A1-20100114-C02568
    1625 1125
    Figure US20100009961A1-20100114-C02569
    1626 1126
    Figure US20100009961A1-20100114-C02570
    1627 1127
    Figure US20100009961A1-20100114-C02571
    1628 1128
    Figure US20100009961A1-20100114-C02572
    1629 1129
    Figure US20100009961A1-20100114-C02573
    1630 1130
    Figure US20100009961A1-20100114-C02574
    1631 1131
    Figure US20100009961A1-20100114-C02575
    1632 1132
    Figure US20100009961A1-20100114-C02576
    1633 1133
    Figure US20100009961A1-20100114-C02577
    1634 1134
    Figure US20100009961A1-20100114-C02578
    1635 1135
    Figure US20100009961A1-20100114-C02579
    1636 1136
    Figure US20100009961A1-20100114-C02580
    1637 1137
    Figure US20100009961A1-20100114-C02581
    1638 1138
    Figure US20100009961A1-20100114-C02582
    1639 1139
    Figure US20100009961A1-20100114-C02583
    1640 1140
    Figure US20100009961A1-20100114-C02584
    1641 1141
    Figure US20100009961A1-20100114-C02585
    1642 1142
    Figure US20100009961A1-20100114-C02586
    1643 1143
    Figure US20100009961A1-20100114-C02587
    1644 1144
    Figure US20100009961A1-20100114-C02588
    1645 1145
    Figure US20100009961A1-20100114-C02589
    1646 1146
    Figure US20100009961A1-20100114-C02590
    1647 1147
    Figure US20100009961A1-20100114-C02591
    1648 1148
    Figure US20100009961A1-20100114-C02592
    1649 1149
    Figure US20100009961A1-20100114-C02593
    1650 1150
    Figure US20100009961A1-20100114-C02594
    1651 1151
    Figure US20100009961A1-20100114-C02595
    1652 1152
    Figure US20100009961A1-20100114-C02596
    1653 1153
    Figure US20100009961A1-20100114-C02597
    1654 1154
    Figure US20100009961A1-20100114-C02598
    1655 1155
    Figure US20100009961A1-20100114-C02599
    1656 1156
    Figure US20100009961A1-20100114-C02600
    1657 1157
    Figure US20100009961A1-20100114-C02601
    1658 1158
    Figure US20100009961A1-20100114-C02602
    1659 1159
    Figure US20100009961A1-20100114-C02603
    1660 1160
    Figure US20100009961A1-20100114-C02604
    1661 1161
    Figure US20100009961A1-20100114-C02605
    1662 1162
    Figure US20100009961A1-20100114-C02606
    1663 1163
    Figure US20100009961A1-20100114-C02607
    1664 1164
    Figure US20100009961A1-20100114-C02608
    1665 1165
    Figure US20100009961A1-20100114-C02609
    1666 1166
    Figure US20100009961A1-20100114-C02610
    1667 1167
    Figure US20100009961A1-20100114-C02611
    1668 1168
    Figure US20100009961A1-20100114-C02612
    1669 1169
    Figure US20100009961A1-20100114-C02613
    1670 1170
    Figure US20100009961A1-20100114-C02614
    1671 1171
    Figure US20100009961A1-20100114-C02615
    1672 1172
    Figure US20100009961A1-20100114-C02616
    1673 1173
    Figure US20100009961A1-20100114-C02617
    1674 1174
    Figure US20100009961A1-20100114-C02618
    1675 1175
    Figure US20100009961A1-20100114-C02619
    1676 1176
    Figure US20100009961A1-20100114-C02620
    1677 1177
    Figure US20100009961A1-20100114-C02621
    1678 1178
    Figure US20100009961A1-20100114-C02622
    1679 1179
    Figure US20100009961A1-20100114-C02623
    1680 1180
    Figure US20100009961A1-20100114-C02624
    1681 1181
    Figure US20100009961A1-20100114-C02625
    1682 1182
    Figure US20100009961A1-20100114-C02626
    1683 1183
    Figure US20100009961A1-20100114-C02627
    1684 1184
    Figure US20100009961A1-20100114-C02628
    1685 1185
    Figure US20100009961A1-20100114-C02629
    1686 1186
    Figure US20100009961A1-20100114-C02630
    1687 1187
    Figure US20100009961A1-20100114-C02631
    1688 1188
    Figure US20100009961A1-20100114-C02632
    1689 1189
    Figure US20100009961A1-20100114-C02633
    1690 1190
    Figure US20100009961A1-20100114-C02634
    1691 1191
    Figure US20100009961A1-20100114-C02635
    1692 1192
    Figure US20100009961A1-20100114-C02636
    1693 1193
    Figure US20100009961A1-20100114-C02637
    1694 1194
    Figure US20100009961A1-20100114-C02638
    1695 1195
    Figure US20100009961A1-20100114-C02639
    1696 1196
    Figure US20100009961A1-20100114-C02640
    1697 1197
    Figure US20100009961A1-20100114-C02641
    1698 1198
    Figure US20100009961A1-20100114-C02642
    1699 1199
    Figure US20100009961A1-20100114-C02643
    1700 1200
    Figure US20100009961A1-20100114-C02644
    1701 1201
    Figure US20100009961A1-20100114-C02645
    1702 1202
    Figure US20100009961A1-20100114-C02646
    1703 1203
    Figure US20100009961A1-20100114-C02647
    1704 1204
    Figure US20100009961A1-20100114-C02648
    1705 1205
    Figure US20100009961A1-20100114-C02649
    1706 1206
    Figure US20100009961A1-20100114-C02650
    1707 1207
    Figure US20100009961A1-20100114-C02651
    1708 1208
    Figure US20100009961A1-20100114-C02652
    1709 1209
    Figure US20100009961A1-20100114-C02653
  • Examples 1710-1799 have been intentionally excluded.
    • Example 1800
  • Figure US20100009961A1-20100114-C02654
    • Step A
  • If one were to treat allyl bromide with 1.0 eq. catechol borane, heat the mixture at 100° C., distillate at reduced pressure, treat the intermediate with 2.0 eq. pinacol in THF at 0° C. and room temperature, evaporate, dissolve in hexane and remove pinacol by filtration, distillate at reduced pressure, one would obtain the title compound.
    • Step B
  • If one were to dissolve methylene chloride (1.0 eq.) in THF and then slowly add 1.54 N nBuLi in hexane (1.1 eq.) at −100° C., and would then add the title compound from Step A above (1.0 equ.), dissolved in THF, cooled to the freezing point of the solution, to the reaction mixture, followed by adding a suspension of zinc chloride (0.55 eq.) in THF, cooled to 0° C., in several portions to the reaction mixture, subsequently allowing the mixture to slowly warm to room temperature and to stir overnight, then, after evaporation of the solvent and redissolving the residue in hexane and washing with water, discarding insoluble material, drying (MgSO4) and evaporation of the solvent, followed by distillation, one would obtain the title compound.
    • Step C
  • If one were to treat a fresh prepared LiHMDS solution in THF with 1 eq. of the title compound from Step B at −78° C., one would obtain after stirring overnight at rt, filtering of the precipitant and distillation of the filtrate the title compound as an oil.
    • Step D
  • If one were to treat the title compound from Step C above with 3 eq. of a 4 M HCl solution in dioxane at −78° C., one would obtain after stirring for 1 hour at rt and evaporation of the solvent the title compound as a HCl salt.
    • Step E
  • If one were to treat the title compound from Step D above with bromo acetyl bromide as described in Example 1, one would obtain the title compound.
    • Step F
  • If one were to treat the title compound from Step E above with the title compound from Preparative Example 15 as described in Example 1, one would obtain the title compound.
    • Step G
  • If one were to treat the title compound from Step F above with 6.0 eq. diethanolamine in THF at room temperature, add Et2O to the mixture, separate the precipitate by filtration, dissolve the solid in an appropriate solvent and add Dowex AG 50-X8, filtrate and evaporate the filtrate, one would obtain the title compound.
  • Examples 1801-1849 have been intentionally excluded.
    • Example 1850
  • Figure US20100009961A1-20100114-C02655
    • Step A
  • If one were to treat the title compound from Preparative Example 92 with the title compound from Example 1800, Step D, as described in Preparative Example 93, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Example 48, one would obtain the title compound. If one were to use a reverse phase HPLC separation (5-pm Nucleosil C18 HPLC column, acetonitrile:H2O: 0.1% TFA), one could obtain the individual diastereomers.
    • Step C
  • If one were to treat the title compound from Step B above with 6.0 eq. diethanolamine in THF at room temperature, add Et2O to the mixture, separate the precipitate by filtration, dissolve the solid in an appropriate solvent and add Dowex AG 50-X8, filtrate and evaporate the filtrate, one would obtain the title compound.
  • Examples 1851-1899 have been intentionally excluded.
    • Example 1900
  • Figure US20100009961A1-20100114-C02656
    • Step A
  • If one were to treat the title compound from Preparative Example 130 with bromoacetyl bromide as described in Preparative Example 1, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above with the title compound from Preparative Example 15 as described in Example 1, one would obtain the title compound. Examples 1901-1949 have been intentionally excluded.
    • Example 1950
  • Figure US20100009961A1-20100114-C02657
    • Step A
  • If one were to treat title compound from Preparative Example 130 with the title compound from Preparative Example 92 as described in Preparative Example 93, one would obtain the title compound.
    • Step B
  • If one were to treat the title compound from Step A above as described in Example 48, one would obtain the title compound.
    • Assay for Determining DP-IV Inhibition
  • The inhibitory activity of compounds against DPP-IV can be determined by in vitro assay systems, which are themselves well established in the art. The assay results given in Table 5 were obtained according to the following method, employing a modified version of the assay described by Leiting et al., in an article entitled “Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII” in Biochem. J. Vol. 371, pages 525-532 (2003):
  • DPP-IV activity was determined fluorometrically with Gly-Pro-AMC (where AMC stands for 7-amido-4-methylcoumarin, Bachem AG, Switzerland) as substrate. The reaction mixture contained 10 μl of 1 ng/μl DPP-IV (R&D Systems GmbH, Germany) and 80 μl of 25 mM Tris/HCl buffer, pH 8.0. Compounds were supplied as DMSO stock solutions and diluted in assay buffer to a maximal DMSO concentration of 1% in the assay. Prior to start of the reaction, the mixture was incubated for 30 min at room temperature. The reaction was started by addition of 10 μl of 100 μM substrate solution.
  • The fluorescence intensity was measured at excitation and emission wavelengths of 355 and 460 nm, respectively, in a FluoStar Galaxy Multiwell Plate (BMG Labtech, Germany). Fluorescence was determined 3 and 4 minutes after start of reaction and increase in fluorescence was used for determination of enzymatic activity. IC(50) values of tested compounds were determined via plotting enzymatic activity versus concentration of test compound and determining the concentration of test compound which yields a 50% inhibition of enzymatic activity.
  • K(i) values were calculated using the Michaelis-Menten equation for competitive inhibition:

  • IC(50)=K(i)(1+[S]/Km)
  • As set forth in Table A, K(i) for each compound corresponds to A is K(i)<6 nM, B is K(i) 6-50 nM, C is K(i) from 51-500 nM and D is K(i) from 0.5-30 μM.
  • TABLE A
    Activity Data for Inhibition of DPP-IV
    Activity
    Example (K(i))
    1 C
    2 D
    3 D
    4 D
    5 D
    6 C
    7 C
    8 C
    9 C
    10 C
    11 C
    12 C
    13 C
    14 D
    15 D
    16 C
    17 B
    18 A
    19 B
    20 C
    21 C
    22 A
    23 B
    24 A
    25 B
    26 C
    27 A
    28 A
    29 A
    30 A
    31 B
    32 A
    33 A
    34 A
    35 A
    36 B
    37 B
    38 B
    39 B
    40 D
    41 B
    42 C
    43 A
    44 A
    45 B
    46 D
    47 A
    48 A
    49 A
    50 B
    51 A
    52 A
    53 A
    54 A
    55 A
    56 A
    57 A
    58 A
    59 A
    60 A
    61 A
    62 A
    63 A
    64 A
    65 B
    66 B
    67 A
    68 B
    69 B
    70 B
    71 B
    72 A
    73 B
    74 C
    75 C
    76 B
    77 A
    78 B
  • All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (24)

1. A compound of formula (I):

A-B-D  (I)
or a pharmaceutically acceptable salt thereof,
wherein A is:
Figure US20100009961A1-20100114-C02658
B is:
Figure US20100009961A1-20100114-C02659
D is:
Figure US20100009961A1-20100114-C02660
Y is divalent and is: a bond, CR4R5, O, NR4, S, S═O, S(═O)2, C(═O), (C═O)N(R4), S(═O)2N(R4), C═N—OR4, —C(R4R5)C(R4R5)—, —C(R4R5) C(R4R5)C(R4R5)—, —C(R4R5)C(R4R5)C(R4R5)C(R4R5)—, —C(R4)═C(R5)—, —C(R4R5)NR4—, —C(R4R5)O—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, or NS(═O)2R4;
R1 and R2 are independently: hydrogen, —F, —Cl, —CONR4R5, or —CO2R4;
R3 is CONR4R5, tetrazolyl or oxadiazolonyl;
Ra is hydrogen, CN, NO2, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, or C(O)NR4R5;
each occurrence of R4 and R5 are each independently: hydrogen or alkyl, or R4 and R5 when taken together with a nitrogen to which they are attached form a 3- to 8-membered ring containing carbon atoms and may optionally contain a heteroatom selected from O, S, or NR50;
R50 is, in each occurrence, R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(═NRa)NR20R21, C(═NR20)NR21Ra, C(═NOR20)R21 or C(O)NR20R21;
each occurrence of R20 and R21 are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl;
each occurrence of R7 and R8 are each independently: halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C1-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl;
R9 is H or C1-6 alkyl;
R10 is halogen, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-alkyl-C(═NRa)NHR4, (C0-C6)-alkyl-C(═NR4)NHRa, (C0-C6)-alkyl-NR4C(═NR4)NR4R5, (C0-C6)-alkyl-C(O)OR4, (C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)—NH—CN, O—(C0-C6)-alkyl-C(O)NR4R5, S(O)t—(C0-C6)-alkyl-C(O)OR4, S(O)t—(C0-C6)-alkyl-C(O)NR4R5, (C0-C6)-alkyl-C(O)NR4—(C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4R5, (C0-C6)-alkyl-NR4—C(O)R5, (C0-C6)-alkyl-NR4—C(O)OR4, (C0-C6)-alkyl-NR4—C(O)—NR4R5, (C0-C6)-alkyl-NR4—SO2NR4R5, (C0-C6)-alkyl-NR4—SO2R4, hydrogen, B(OH)2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl;
Qb is CH or N;
U is —C(O)—, —C(═NR4)—, —(CR4R5—)p, NR50, S(═O)2, C(═O), (C═O)N(R4), N(R4)(C═O), S(═O)2N(R4), N(R4)S(═O)2, C═N—OR4, —C(R4)═C(R5)—, —C(R4R5)pNR50—, N(R50)C(R4R5)p—, —O—C(R4R5)—, —C(R4R5)S(═O)t—, —(C═O)O—, —(C═NRa)N(R4)—, —(C═NRa)—, N(C═O)NR4NR5, N(C═O)R4, N(C═O)OR4, NS(═O)2NR4NR5, or NS(═O)2R4;
W is —CH2—, —S—, —CHF— or —CF2—;
Z is C;
p is 0 to 6; and
t is 0, 1, or 2.
2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Qb is CH;
U is (—CH2—)p;
p is 1;
R7 and R8 are each independently H or alkyl; and
R9 is H.
3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
D is:
Figure US20100009961A1-20100114-C02661
4. A compound of claim 1, or a pharmaceutically acceptable salt, thereof, wherein:
Y is —CH2—CH2—.
5. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Y is —CH2—CH2—;
D is
Figure US20100009961A1-20100114-C02662
Qb is CH;
U is (—CH2—)p;
p is 1; and
R9 is H.
6. A compound of claim 1, or a pharmaceutically acceptable salt, thereof, wherein:
A is:
Figure US20100009961A1-20100114-C02663
7. A compound of claim 1, or a pharmaceutically acceptable salt, thereof, wherein:
A is:
Figure US20100009961A1-20100114-C02664
Y is —CH2—CH2—;
D is
Figure US20100009961A1-20100114-C02665
Qb is CH.
8. A compound according to the following formula:
Figure US20100009961A1-20100114-C02666
or a pharmaceutically acceptable salt thereof.
9. A compound according to the following formula:
Figure US20100009961A1-20100114-C02667
or a pharmaceutically acceptable salt thereof.
10. A compound according to the following formula:
Figure US20100009961A1-20100114-C02668
or a pharmaceutically acceptable salt thereof.
11. A compound according to the following formula:
Figure US20100009961A1-20100114-C02669
or a pharmaceutically acceptable salt thereof.
12. A compound according to the following formula:
Figure US20100009961A1-20100114-C02670
or a pharmaceutically acceptable salt thereof.
13. A compound according to the following formula:
Figure US20100009961A1-20100114-C02671
or a pharmaceutically acceptable salt thereof.
14. A compound according to the following formula:
Figure US20100009961A1-20100114-C02672
or a pharmaceutically acceptable salt thereof.
15. A compound according to the following formula:
Figure US20100009961A1-20100114-C02673
or a pharmaceutically acceptable salt thereof.
16. A compound according to the following formula:
Figure US20100009961A1-20100114-C02674
or a pharmaceutically acceptable salt thereof.
17. A compound according to the following formula:
Figure US20100009961A1-20100114-C02675
or a pharmaceutically acceptable salt thereof.
18. A compound according to the following formula:
Figure US20100009961A1-20100114-C02676
or a pharmaceutically acceptable salt thereof.
19. A compound according to the following formula:
Figure US20100009961A1-20100114-C02677
or a pharmaceutically acceptable salt thereof.
20. A compound according to the following formula:
Figure US20100009961A1-20100114-C02678
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof.
22. A method of treating type-2 diabetes comprising administering to a patient in need thereof an effective amount of a compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound in accordance with claim 7, or a pharmaceutically acceptable salt thereof.
24. A method of treating type-2 diabetes comprising administering to a patient in need thereof an effective amount of a compound in accordance with claim 7, or a pharmaceutically acceptable salt thereof.
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