# Patent

## Title
Dipeptidyl peptidase-IV inhibitors

## 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.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. application Ser. No. 12/492,254, filed 26 Jun. 2009, now pending, which is a continuation of U.S. application Ser. No. 11/409,481, filed Apr. 21, 2006, now U.S. Pat. No. 7,553,861, which claims the benefit of U.S. Provisional Application No. 60/674,151, filed 22 Apr. 2005, 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:




B is:




and D is:




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:




comprising (a) coupling prolinamide with fumarylchloride to provide a compound of the following formula:





(b) dehydrating the carboxamides of the compound from step (a) to cyano to provide a compound of formula:




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:




comprising: (a) coupling a compound of formula:





with fumaryl chloride to provide a compound of formula





(b) dehydrating the carboxamide in the compound from step (a) to provide a compound of formula:




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:





B is:





and
D is:




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:





B is:





and
D is:




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, (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.
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 (l) 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 ulcerative 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 atherosclerosis, preferably atherosclerosis 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; migraine; 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, Streptococcus, 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:




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:




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:




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:




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:




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 aluminum 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




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 aluminum hydride or to the desired amine products with Y═C(R4R5)C(R4R5) by reduction with lithium aluminum 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




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.




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.




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)




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




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)




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)




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




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:




A is desirably




The “B” structures are chosen from:




Desirably, B is one of structure (a), (b), (c), and (d). More desirably, B is structure (b)

The “D” structures are chosen from:




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




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




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




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




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 formate (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




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




NH4OH




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












1. 97% 2. 281


 


8












1. 60% 2. 288


 


9












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




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












1. 64% 2. 279


 


12












1. 56% 2. 265









Preparative Example 13




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




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




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




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




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




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




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.













Preparative


1. Yield


Example
Aminoalcohol
Product
2. 1H-NMR


















20








1. 69% 2. 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 21




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.













Preparative


1. Yield


Example
Aminoalcohol
Product
2. 1H-NMR







22








1. 58% 2. 1H-NMR δ (CDCl3): 0.02 (s, 9H), 1.00-1.15 (m, 2H), 4.00-4.10 (m, 2H),  4.25-4.40 (m, 2H), 4.55-4.65 (m, 2H).


 


23








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.












Preparative




Example
Aminoalcohol
Product







24










 


25










 


26










 


27










 


28










 


29










 


30










 


31










 


32










 


33










 


34










 


35










 


36










 


37










 


38










 


39










 


40










 


41










 


42










 


43










 


44










 


45










 


46

















Preparative Example 47




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












1. 80% 2. 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 49




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




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




Step A

Commercially available 2-bromo-4-fluorotoluene (5 g) was diluted with diethyl ether (10 ml). About 1⁄3 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




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




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




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, 2 H), 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




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




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




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




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




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 cannula 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 aqueous 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, 6 H), 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, 4 H), 7.23 (d, 2 H), 7.32 (dd, 2 H), 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




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




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








538


 


63
59








566


 


64
60








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

















Preparative Example 66




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




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




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




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 1⁄3 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




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








462


 


72
61








434


 


73
61








462


 


74
61








490


 


75
61








486


 


76
61








546


 


77
62








420


 


78
62








447


 


79
63
NH3




420


 


80
66








478


 


81
67








437


 


82
68








530


 


83
69 1-Me-tetrazole








406


 


84
69 2-Me-tetrazole








406


 


85
61 Step B
none




436


 


86
61
none




408


 


87
64
none




374









Preparative Example 88




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




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




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




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




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




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












1. 55% 2. 498


 


95












1. 90% 2. 537


 


96












1. 71% 2. 493


 


97












1. 70% 2. 504


 


98












1. 73% 2. 516


 


99












1. 65% 2. 493


 


100












1. 54% 2. 505


 


101












1. 78% 2. 493


 


102












1. 56% 2. 500


 


103












1. 65% 2. 512


 


104












1. 71% 2. 514


 


105












1. 68% 2. 511


 


106












1. 56% 2. 511


 


107












1. 62% 2. 526


 


108












1. 2.









Preparative Example 109




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




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




Step A

Commercially available N-cyclohexylcarbodiimide-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 (9 H, 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




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




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 acid

1. Yield


Example
chloride
Product
2. MH+







114








1. 69 2. 541 (MNH4+)


 


115








1. 92 2. 546 (MNa+)


 


116








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


1. Yield


Example
Acid chloride
Product
2. MH+







117








1. 100 2. 488 (MH+)


 


118








1. 49 2. 519 (MNH4+)


 


119








1. 70 2. 506 (MNa+)









Preparative Example 120




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








1. 69 2. 592 (MNH4+)









Preparative Example 122




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




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 Acid

1. Yield


Example
derivative
chloride
Product
2. MH+







124












1. 73% 2. 556


 


125




none




1. 27% 2. 492









Preparative Examples 126-129 have been intentionally excluded.
Preparative Example 130




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






 


201
25






 


202
26






 


203
27






 


204
28






 


205
29






 


206
30






 


207
31






 


208
32






 


209
33






 


210
34






 


211
35






 


212
36






 


213
37






 


214
38






 


215
39






 


216
40






 


217
41






 


218
42






 


219
43






 


220
44






 


221
45






 


222
46






 


223
24






 


224
23






 


225
25






 


226
26






 


227
27






 


228
28






 


229
29






 


230
30






 


231
31






 


232
32






 


233
33






 


234
34






 


235
35






 


236
36






 


237
37






 


238
38






 


239
39






 


240
40






 


241
41






 


242
42






 


243
43






 


244
44






 


245
45






 


246
46






 


247
24






 


248
23






 


249
25






 


250
26






 


251
27






 


252
28






 


253
29






 


254
30






 


255
31






 


256
32






 


257
33






 


258
34






 


259
35






 


260
36






 


261
37






 


262
38






 


263
39






 


264
40






 


265
41






 


266
42






 


267
43






 


268
44






 


269
45






 


270
46






 


271
24






 


272
23






 


273
25






 


274
26






 


275
27






 


276
28






 


277
29






 


278
30






 


279
31






 


280
32






 


281
33






 


282
34






 


283
35






 


284
36






 


285
37






 


286
38






 


287
39






 


288
40






 


289
41






 


290
42






 


291
43






 


292
44






 


293
45






 


294
46













Examples 295-299 have been intentionally excluded.
Preparative Example 300




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




NH3






 


302
300




NH3






 


303
300




NH3






 


304
61




NH3






 


305
61




NH3






 


306
61




NH3






 


307
61




NH3






 


308
65




NH3






 


309
65




NH3






 


310
65




NH3






 


311
65




NH3






 


312
300




CH3NH2






 


313
300




CH3NH2






 


314
300




CH3NH2






 


315
300




CH3NH2






 


316
61




CH3NH2






 


317
61




CH3NH2






 


318
61




CH3NH2






 


319
61




CH3NH2






 


320
65




CH3NH2






 


321
65




CH3NH2






 


322
65




CH3NH2






 


323
65




CH3NH2






 


324
300




(CH3)2NH






 


325
300




(CH3)2NH






 


326
300




(CH3)2NH






 


327
300




(CH3)2NH






 


328
61




(CH3)2NH






 


329
61




(CH3)2NH






 


330
61




(CH3)2NH






 


331
61




(CH3)2NH






 


332
65




(CH3)2NH






 


333
65




(CH3)2NH






 


334
65




(CH3)2NH






 


335
65




(CH3)2NH













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




NH3






 


401
300




NH3






 


402
300




NH3






 


403
300




NH3






 


404
 61




NH3






 


405
 61




NH3






 


406
 61




NH3






 


407
 61




NH3






 


408
 65




NH3






 


409
 65




NH3






 


410
 65




NH3






 


411
 65




NH3






 


412
300




CH3NH2






 


413
300




CH3NH2






 


414
300




CH3NH2






 


415
300




CH3NH2






 


416
 61




CH3NH2






 


417
 61




CH3NH2






 


418
 61




CH3NH2






 


419
 61




CH3NH2






 


420
 65




CH3NH2






 


421
 65




CH3NH2






 


422
 65




CH3NH2






 


423
 65




CH3NH2






 


424
300




(CH3)2NH






 


425
300




(CH3)2NH






 


426
300




(CH3)2NH






 


427
300




(CH3)2NH






 


428
 61




(CH3)2NH






 


429
 61




(CH3)2NH






 


430
 61




(CH3)2NH






 


431
 65




(CH3)2NH






 


432
 65




(CH3)2NH






 


433
 65




(CH3)2NH






 


434
 65




(CH3)2NH













Example numbers 435-499 were intentionally excluded.
Preparative Example 500




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




NH3






 


502
300




NH3






 


503
300




NH3






 


504
 61
N2H4
NH3






 


505
 61




NH3






 


506
 61




NH3






 


507
 61




NH3






 


508
 65
N2H4
NH3






 


509
 65




NH3






 


510
 65




NH3






 


511
 65




NH3






 


512
300
N2H4
CH3NH2






 


513
300




CH3NH2






 


514
300




CH3NH2






 


515
300




CH3NH2






 


516
 61
N2H4
CH3NH2






 


517
 61




CH3NH2






 


518
 61




CH3NH2






 


519
 61




CH3NH2






 


520
 65
N2H4
CH3NH2






 


521
 65




CH3NH2






 


522
 65




CH3NH2






 


523
 65




CH3NH2






 


524
300
N2H4
(CH3)2NH






 


525
300




(CH3)2NH






 


526
300




(CH3)2NH






 


527
300




(CH3)2NH






 


528
 61
N2H4
(CH3)2NH






 


529
 61




(CH3)2NH






 


530
 61




(CH3)2NH






 


531
 61




(CH3)2NH






 


532
 65
N2H4
(CH3)2NH






 


533
 65




(CH3)2NH






 


534
 65




(CH3)2NH






 


535
 65




(CH3)2NH













Example numbers 536-599 were intentionally excluded.
Preparative Example 600




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






 


602
300




NH3






 


603
300




NH3






 


604
 61
NH3
NH3






 


605
 61
CH3NH2
NH3






 


606
 61




NH3






 


607
 61




NH3






 


608
 65
NH3
NH3






 


609
 65
CH3NH2
NH3






 


610
 65




NH3






 


611
 65




NH3






 


612
300
NH3
CH3NH2






 


613
300
CH3NH2
CH3NH2






 


614
300




CH3NH2






 


615
300




CH3NH2






 


616
 61
NH3
CH3NH2






 


617
 61
CH3NH2
CH3NH2






 


618
 61




CH3NH2






 


619
 61




CH3NH2






 


620
 65
NH3
CH3NH2






 


621
 65
CH3NH2
CH3NH2






 


622
 65




CH3NH2






 


623
 65




CH3NH2






 


624
300
NH3
(CH3)2NH






 


625
300
CH3NH2
(CH3)2NH






 


626
300




(CH3)2NH






 


627
300




(CH3)2NH






 


628
 61
NH3
(CH3)2NH






 


629
 61
CH3NH2
(CH3)2NH






 


630
 61




(CH3)2NH






 


631
 61




(CH3)2NH






 


632
 65
NH3
(CH3)2NH






 


633
 65
CH3NH2
(CH3)2NH






 


634
 65




(CH3)2NH






 


635
 65




(CH3)2NH













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.













Preparative
Preparative




Example
Example
Amine
Product







680
300
NH3






 


681
61
NH3






 


682
65
NH3






 


683
300
CH3NH2






 


684
61
CH3NH2






 


685
65
CH3NH2






 


686
300
(CH3)2NH






 


687
65
(CH3)2NH













Example numbers 688-699 were intentionally excluded.
Preparative Example 700




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




NH3






 


702
300




NH3






 


703
300




NH3






 


704
61




NH3






 


705
61




NH3






 


706
61




NH3






 


707
61




NH3






 


708
65




NH3






 


709
65




NH3






 


710
65




NH3






 


711
65




NH3






 


712
300




CH3NH2






 


713
300




CH3NH2






 


714
300




CH3NH2






 


715
300




CH3NH2






 


716
61




CH3NH






 


717
61




CH3NH2






 


718
61




CH3NH2






 


719
61




CH3NH2






 


720
65




CH3NH2






 


721
65




CH3NH2






 


722
65




CH3NH2






 


723
65




CH3NH2






 


724
300




(CH3)2NH






 


725
300




(CH3)2NH






 


726
300




(CH3)2NH






 


727
300




(CH3)2NH






 


728
61




(CH3)2NH






 


729
61




(CH3)2NH






 


730
61




(CH3)2NH






 


731
61




(CH3)2NH






 


732
65




(CH3)2NH






 


733
65




(CH3)2NH






 


734
65




(CH3)2NH






 


735
65




(CH3)2NH













Example numbers 736-779 were intentionally excluded.
Preparative Example 780




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






 


782
 65
NH3






 


783
300
CH3NH2






 


784
 61
CH3NH2






 


785
 65
CH3NH2






 


786
300
(CH3)2NH






 


787
 61
(CH3)2NH






 


788
 65
(CH3)2NH













Example numbers 789-799 were intentionally excluded.
Preparative Example 800




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




22






 


802




21






 


803




24






 


804




21






 


805




24













Examples 806-809 have been intentionally excluded.
Preparative Example 810




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




24






 


812




21













Examples 813-829 have been intentionally excluded.
Preparative Example 830




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




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






 


832
24
NH3






 


833
22
NH3






 


834
21
CH3NH2






 


835
24
CH3NH2






 


836
22
CH3NH2






 


837
24
(CH3)2NH






 


838
22
(CH3)2NH













Examples 839 to 849 have been intentionally excluded.
Preparative Example 850




Step AA

If one were to treat commercially available thiophene-3-carbaldehyde with bromine and aluminum 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




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






 


853
24
NH3






 


854
22
NH3






 


855
21
CH3NH2






 


856
24
CH3NH2






 


857
22
CH3NH2






 


858
24
(CH3)2NH






 


859
22
(CH3)2NH













Examples 860-899 have been intentionally excluded.
Preparative Example 900




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




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






 


903
24
NH3






 


904
22
NH3






 


905
21
CH3NH2






 


906
24
CH3NH2






 


907
22
CH3NH2






 


908
24
(CH3)2NH






 


909
22
(CH3)2NH













Examples 910-919 have been intentionally excluded.
Preparative Example 920




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




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






 


923
24
NH3






 


924
22
NH3






 


925
21
CH3NH2






 


926
24
CH3NH2






 


927
22
CH3NH2






 


928
24
(CH3)2NH






 


929
22
(CH3)2NH













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














 


1001














 


1002














 


1003














 


1004














 


1005














 


1006














 


1007














 


1008














 


1009














 


1010














 


1011














 


1012














 


1013














 


1014














 


1015














 


1016














 


1017














 


1018














 


1019














 


1020














 


1021














 


1022














 


1023














 


1024














 


1025














 


1026














 


1027














 


1028














 


1029














 


1030














 


1031














 


1032














 


1033














 


1034














 


1035














 


1036














 


1037














 


1038














 


1039














 


1040














 


1041














 


1042














 


1043














 


1044














 


1045














 


1046














 


1047














 


1048














 


1049














 


1050














 


1051














 


1052














 


1053














 


1054














 


1055














 


1056














 


1057














 


1058














 


1059














 


1060














 


1061














 


1062














 


1063














 


1064














 


1065














 


1066














 


1067














 


1068














 


1069














 


1070














 


1071














 


1072














 


1073














 


1074














 


1075














 


1076














 


1077














 


1078














 


1079














 


1080














 


1081














 


1082














 


1083














 


1084














 


1085














 


1086














 


1087














 


1088














 


1089














 


1090














 


1091














 


1092














 


1093














 


1094














 


1095














 


1096














 


1097














 


1098














 


1099














 


1100














 


1101














 


1102














 


1103














 


1104














 


1105














 


1106














 


1107














 


1108














 


1109














 


1110














 


1111














 


1112














 


1113














 


1114














 


1115














 


1116














 


1117














 


1118














 


1119














 


1120














 


1121














 


1122














 


1123














 


1124














 


1125














 


1126














 


1127














 


1128














 


1129














 


1130














 


1131














 


1132














 


1133














 


1134














 


1135














 


1136














 


1137














 


1138














 


1139














 


1140














 


1141














 


1142














 


1143














 


1144














 


1145














 


1146














 


1147














 


1148














 


1149














 


1150














 


1151














 


1152














 


1153














 


1154














 


1155














 


1156














 


1157














 


1158














 


1159














 


1160














 


1161














 


1162














 


1163














 


1164














 


1165














 


1166














 


1167














 


1168














 


1169














 


1170














 


1171














 


1172














 


1173














 


1174














 


1175














 


1176














 


1177














 


1178














 


1179














 


1180














 


1181














 


1182














 


1183














 


1184














 


1185














 


1186














 


1187














 


1188














 


1189














 


1190














 


1191














 


1192














 


1193














 


1194














 


1195














 


1196














 


1197














 


1198














 


1199














 


1200














 


1201














 


1202














 


1203














 


1204














 


1205














 


1206














 


1207














 


1208














 


1209





















Examples 1210-1299 have been intentionally excluded.
Preparative Example 1300




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




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






 


1303
24
NH3






 


1304
22
NH3






 


1305
21
CH3NH2






 


1306
24
CH3NH2






 


1307
22
CH3NH2






 


1308
24
(CH3)2NH






 


1309
22
(CH3)2NH













Examples 1310-1349 have been intentionally excluded.
Preparative Example 1350




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




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






 


1353
24
NH3






 


1354
22
NH3






 


1355
21
CH3NH2






 


1356
24
CH3NH2






 


1357
22
CH3NH2






 


1358
24
(CH3)2NH






 


1359
22
(CH3)2NH













Examples 1360-1399 have been intentionally excluded.
Preparative Example 1400




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




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






 


1403
24
NH3






 


1404
22
NH3






 


1405
21
CH3NH2






 


1406
24
CH3NH2






 


1407
22
CH3NH2






 


1408
24
(CH3)2NH






 


1409
22
(CH3)2NH













Examples 1410-1449 have been intentionally excluded.
Preparative Example 1450




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 dimethylester 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 aluminum 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 aluminum 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 recrystallization 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




Step A

If one were to treat the title compound from Preparative Example 1450 Step E with 10 eq. of aluminum 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 recrystallization 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 I 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 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 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 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




Step A

If one were to treat commercially available 1,2,3,4,5,6,7,8-octahydro-anthracene with 10 eq. of aluminum 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 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 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




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 aluminum 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 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 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




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 aluminum 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 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 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




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 methanesulfonate intermediate. If one were to treat the methanesulfonate 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






 


1502
24













Example 1




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




1. 17% 2. 346


 


3
1
 7




1. 8% 2. 417


 


4
1
13




1. 19% 2. 360


 


5
1
14 Step B




1. 18% 2. 389


 


6
1
14




1. 15% 2. 375


 


7
1
15 Step C




1. 8% 2. 372


 


8
1
15




1. 8% 2. 374


 


9
1
16




1. 16% 2. 389


 


10
1
17 Step D




1. 7% 2. 390


 


11
1
17




1. 8% 2. 372


 


12
1
10




1. 16% 2. 429


 


13
1
11




1. 19% 2. 415


 


14
1
12




1. 19% 2. 401









Example 15




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




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




1. 17% 2. 417


 


18
2
47
A




1. 41% 2. 431


 


19
2
48
A




1. 18% 2. 431


 


20
2
8
A




1. 25% 2. 424


 


21
2
9
A




1. 18% 2. 390


 


22
2
49
A




1. 21% 2. 478


 


23
2
50
B




1. 30% 2. 442


 


24
2
51
B




1 .5% 2. 478


 


25
2
87
B




1. 46% 2. 510


 


26
2
110
A




1. 15% 2. 414


 


27
2
70
C




1. 36% 2. 542


 


28
2
72
C




1. 14% 2. 570


 


29
2
71
C




1. 38% 2. 598


 


30
2
73
C




1. 21% 2. 598


 


31
2
74
C




1. 8% 2. 626


 


32
2
75
C




1. 58% 2. 622


 


33
2
76
C




1. 9% 2. 682


 


34
2
56
C




1. 11% 2. 528


 


35
2
77
C




1. 7% 2. 556


 


36
2
78
C




1. 10% 2. 584


 


37
2
79
C




1. 12% 2. 556


 


38
2
80
C




1. 43% 2. 614


 


39
2
81
C




1. 2% 2. 573


 


40
2
82
C




1. 26% 2. 666


 


41
2
83
C




1. 12% 2. 542


 


42
2
84
C




1. 10% 2. 542


 


43
2
85
C




1. 60% 2. 572


 


44
2
86
C




1. 28% 2. 544


 


45
2
52
C




1. 14% 2. 503


 


46
2
88
C




1. 2% 2. 471


 


47
89 
56
C




1. 9% 2. 540









Example 48




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




1. 77%  2. 436


 


50
 96




1. 92%  2. 393


 


51
 97




1. 89%  2. 404


 


52
 98




1. 96%  2. 416


 


53
 99




1. 57%  2. 393


 


54
100




1. 95%  2. 404


 


55
101




1. 93%  2. 393


 


56
102




1. 98%  2. 393


 


57
108




1. 96%  2. 400


 


58
103




1. 95%  2. 412


 


59
104




1. 95%  2. 414


 


60
105




1. 92%  2. 411


 


61
106




1. 95%  2. 411


 


62
107




1. 81%  2. 426


 


63
109




1. 85%  2. 412


 


64
 94




1. 95%  2. 398









Example 65




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




1. 100 2. 424


 


67
115




1. 33 2. 424


 


68
116




1. 40 2. 482


 


69
117




1. 85 2. 388


 


70
118




1. 96 2. 402


 


71
119




1. 84 2. 384


 


72
122




1. 30 2. 510


 


73
112 Step D




1. 50 2. 500


 


74
121




1. 97 2. 475


 


75
120




1. 100 2. 377









Example 76




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.
















1. Yield


Example
Preparative Example
Product
2. MH+







77
124




1. 10% 2. 422


 


78
125




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




Prep Ex 62
Prep Ex 2 






 


101




Prep Ex 62
Prep Ex 2 






 


102




Prep Ex 62
Prep Ex 2 






 


103




Prep Ex 62
Prep Ex 2 






 


104




Prep Ex 62
Prep Ex 2 






 


105




Prep Ex 62
Prep Ex 2 






 


106




Prep Ex 62
Prep Ex 2 






 


107




Prep Ex 62
Prep Ex 2 






 


108




Prep Ex 62
Prep Ex 2 






 


109




Prep Ex 62
Prep Ex 2 






 


110
NH3
Prep Ex 55
Prep Ex 2 






 


111
MeNH2
Prep Ex 55
Prep Ex 2 






 


112
(Me)2NH
Prep Ex 55
Prep Ex 2 






 


113




Prep Ex 55
Prep Ex 2 






 


114




Prep Ex 55
Prep Ex 2 






 


115




Prep Ex 55
Prep Ex 2 






 


116




Prep Ex 55
Prep Ex 2 






 


117




Prep Ex 55
Prep Ex 2 






 


118




Prep Ex 55
Prep Ex 2 






 


119




Prep Ex 55
Prep Ex 2 






 


120




Prep Ex 55
Prep Ex 2 






 


121




Prep Ex 55
Prep Ex 2 






 


122




Prep Ex 55
Prep Ex 2 






 


123




Prep Ex 65
Prep Ex 2 






 


124




Prep Ex 65
Prep Ex 2 






 


125




Prep Ex 65
Prep Ex 2 






 


126




Prep Ex 65
Prep Ex 2 






 


127




Prep Ex 65
Prep Ex 2 






 


128




Prep Ex 65
Prep Ex 2 






 


129




Prep Ex 65
Prep Ex 2 






 


130




Prep Ex 65
Prep Ex 2 






 


131




Prep Ex 65
Prep Ex 2 






 


132




Prep Ex 61
Prep Ex 2 






 


133




Prep Ex 61
Prep Ex 2 






 


134




Prep Ex 61
Prep Ex 2 






 


135




Prep Ex 61
Prep Ex 2 






 


136




Prep Ex 61
Prep Ex 2 






 


137




Prep Ex 61
Prep Ex 2 






 


138
MeNH2
Prep Ex 62
Prep Ex 89






 


139
(Me)2NH
Prep Ex 62
Prep Ex 89






 


140




Prep Ex 62
Prep Ex 89






 


141




Prep Ex 62
Prep Ex 89






 


142




Prep Ex 62
Prep Ex 89






 


143




Prep Ex 62
Prep Ex 89






 


144




Prep Ex 62
Prep Ex 89






 


145




Prep Ex 62
Prep Ex 89






 


146




Prep Ex 62
Prep Ex 89






 


147




Prep Ex 62
Prep Ex 89






 


148




Prep Ex 62
Prep Ex 89






 


149




Prep Ex 62
Prep Ex 89






 


150
NH3
Prep Ex 55
Prep Ex 89






 


151
MeNH2
Prep Ex 55
Prep Ex 89






 


152
(Me)2NH
Prep Ex 55
Prep Ex 89






 


153




Prep Ex 55
Prep Ex 89






 


154




Prep Ex 55
Prep Ex 89






 


155




Prep Ex 55
Prep Ex 89






 


156




Prep Ex 55
Prep Ex 89






 


157




Prep Ex 55
Prep Ex 89






 


158




Prep Ex 55
Prep Ex 89






 


159




Prep Ex 55
Prep Ex 89






 


160




Prep Ex 55
Prep Ex 89






 


161




Prep Ex 55
Prep Ex 89






 


162




Prep Ex 55
Prep Ex 89






 


163




Prep Ex 65
Prep Ex 89






 


164




Prep Ex 65
Prep Ex 89






 


165




Prep Ex 65
Prep Ex 89






 


166




Prep Ex 65
Prep Ex 89






 


167




Prep Ex 65
Prep Ex 89






 


168




Prep Ex 65
Prep Ex 89






 


169




Prep Ex 65
Prep Ex 89






 


170




Prep Ex 65
Prep Ex 89






 


171




Prep Ex 65
Prep Ex 89






 


172
NH3
Prep Ex 61
Prep Ex 89






 


173
MeNH2
Prep Ex 61
Prep Ex 89






 


174
(Me)2NH
Prep Ex 61
Prep Ex 89






 


175




Prep Ex 61
Prep Ex 89






 


176




Prep Ex 61
Prep Ex 89






 


177




Prep Ex 61
Prep Ex 89






 


178




Prep Ex 61
Prep Ex 89






 


179




Prep Ex 61
Prep Ex 89






 


180




Prep Ex 61
Prep Ex 89






 


181




Prep Ex 61
Prep Ex 89






 


182




Prep Ex 61
Prep Ex 89






 


183




Prep Ex 61
Prep Ex 89






 


184




Prep Ex 61
Prep Ex 89













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






 


201
201
2






 


202
202
2






 


203
203
2






 


204
204
2






 


205
205
2






 


206
206
2






 


207
207
2






 


208
208
2






 


209
209
2






 


210
210
2






 


211
211
2






 


212
212
2






 


213
213
2






 


214
214
2






 


215
215
2






 


216
216
2






 


217
217
2






 


218
218
2






 


219
219
2






 


220
220
2






 


221
221
2






 


222
222
2






 


223
223
2






 


224
224
2






 


225
225
2






 


226
226
2






 


227
227
2






 


228
228
2






 


229
229
2






 


230
230
2






 


231
231
2






 


232
232
2






 


233
233
2






 


234
234
2






 


235
235
2






 


236
236
2






 


237
237
2






 


238
238
2






 


239
239
2






 


240
240
2






 


241
241
2






 


242
242
2






 


243
243
2






 


244
244
2






 


245
245
2






 


246
246
2






 


247
247
2






 


248
248
2






 


249
249
2






 


250
250
2






 


251
251
2






 


252
252
2






 


253
253
2






 


254
254
2






 


255
255
2






 


256
256
2






 


257
257
2






 


258
258
2






 


259
259
2






 


260
260
2






 


261
261
2






 


262
262
2






 


263
263
2






 


264
264
2






 


265
265
2






 


266
266
2






 


267
267
2






 


268
268
2






 


269
269
2






 


270
270
2






 


271
271
2






 


272
272
2






 


273
273
2






 


274
274
2






 


275
275
2






 


276
276
2






 


277
277
2






 


278
278
2






 


279
279
2






 


280
280
2






 


281
281
2






 


282
282
2






 


283
283
2






 


284
284
2






 


285
285
2






 


286
286
2






 


287
287
2






 


288
288
2






 


289
289
2






 


290
290
2






 


291
291
2






 


292
292
2






 


293
293
2






 


294
294
2






 


295
200
89






 


296
201
89






 


297
202
89






 


298
203
89






 


299
204
89






 


300
205
89






 


301
206
89






 


302
207
89






 


303
208
89






 


304
209
89






 


305
210
89






 


306
211
89






 


307
212
89






 


308
213
89






 


309
214
89






 


310
215
89






 


311
216
89






 


312
217
89






 


313
218
89






 


314
219
89






 


315
220
89






 


316
221
89






 


317
222
89






 


318
223
89






 


319
224
89






 


320
225
89






 


321
226
89






 


322
227
89






 


323
228
89






 


324
229
89






 


325
230
89






 


326
231
89






 


327
232
89






 


328
233
89






 


329
234
89






 


330
235
89






 


331
236
89






 


332
237
89






 


333
238
89






 


334
239
89






 


335
240
89






 


336
241
89






 


337
242
89






 


338
243
89






 


339
244
89






 


340
245
89






 


341
246
89






 


342
247
89






 


343
248
89






 


344
249
89






 


345
250
89






 


346
251
89






 


347
252
89






 


348
253
89






 


349
254
89






 


350
255
89






 


351
256
89






 


352
257
89






 


353
258
89






 


354
259
89






 


355
260
89






 


356
261
89






 


357
262
89






 


358
263
89






 


359
264
89






 


360
265
89






 


361
266
89






 


362
267
89






 


363
268
89






 


364
269
89






 


365
270
89






 


366
271
89






 


367
272
89






 


368
273
89






 


369
274
89






 


370
275
89






 


371
276
89






 


372
277
89






 


373
278
89






 


374
279
89






 


375
280
89






 


376
281
89






 


377
282
89






 


378
283
89






 


379
284
89






 


380
285
89






 


381
286
89






 


382
287
89






 


383
288
89






 


384
289
89






 


385
290
89






 


386
291
89






 


387
292
89






 


388
293
89






 


389
294
89













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






 


401
301
2






 


402
302
2






 


403
303
2






 


404
304
2






 


405
305
2






 


406
306
2






 


407
307
2






 


408
308
2






 


409
309
2






 


410
310
2






 


411
311
2






 


412
312
2






 


413
313
2






 


414
314
2






 


415
315
2






 


416
316
2






 


417
317
2






 


418
318
2






 


419
319
2






 


420
320
2






 


421
321
2






 


422
322
2






 


423
323
2






 


424
324
2






 


425
325
2






 


426
326
2






 


427
327
2






 


428
328
2






 


429
329
2






 


430
330
2






 


431
331
2






 


432
332
2






 


433
333
2






 


434
334
2






 


435
335
2






 


436
400
2






 


437
401
2






 


438
402
2






 


439
403
2






 


440
404
2






 


441
405
2






 


442
406
2






 


443
407
2






 


444
408
2






 


445
409
2






 


446
410
2






 


447
411
2






 


448
412
2






 


449
413
2






 


450
414
2






 


451
415
2






 


452
416
2






 


453
417
2






 


454
418
2






 


455
419
2






 


456
420
2






 


457
421
2






 


458
422
2






 


459
423
2






 


460
424
2






 


461
425
2






 


462
426
2






 


463
427
2






 


464
428
2






 


465
429
2






 


466
430
2






 


467
431
2






 


468
432
2






 


469
433
2






 


470
434
2






 


471
500
2






 


472
501
2






 


473
502
2






 


474
503
2






 


475
504
2






 


476
505
2






 


477
506
2






 


478
507
2






 


479
508
2






 


480
509
2






 


481
510
2






 


482
511
2






 


483
512
2






 


484
513
2






 


485
514
2






 


486
515
2






 


487
516
2






 


488
517
2






 


489
518
2






 


490
519
2






 


491
520
2






 


492
521
2






 


493
522
2






 


494
523
2






 


495
524
2






 


496
525
2






 


497
526
2






 


498
527
2






 


499
528
2






 


500
529
2






 


501
530
2






 


502
531
2






 


503
532
2






 


504
533
2






 


505
534
2






 


506
535
2






 


507
600
2






 


508
601
2






 


509
602
2






 


510
603
2






 


511
604
2






 


512
605
2






 


513
606
2






 


514
607
2






 


515
608
2






 


516
609
2






 


517
610
2






 


518
611
2






 


519
612
2






 


520
613
2






 


521
614
2






 


522
615
2






 


523
616
2






 


524
617
2






 


525
618
2






 


526
619
2






 


527
620
2






 


528
621
2






 


529
622
2






 


530
623
2






 


531
624
2






 


532
625
2






 


533
626
2






 


534
627
2






 


535
628
2






 


536
629
2






 


537
630
2






 


538
631
2






 


539
632
2






 


540
633
2






 


541
634
2






 


542
635
2






 


543
680
2






 


544
681
2






 


545
682
2






 


546
683
2






 


547
684
2






 


548
685
2






 


549
686
2






 


550
687
2






 


551
700
2






 


552
701
2






 


553
702
2






 


554
703
2






 


555
704
2






 


556
705
2






 


557
706
2






 


558
707
2






 


559
708
2






 


560
709
2






 


561
710
2






 


562
711
2






 


563
712
2






 


564
713
2






 


565
714
2






 


566
715
2






 


567
716
2






 


568
717
2






 


569
718
2






 


570
719
2






 


571
720
2






 


572
721
2






 


573
722
2






 


574
723
2






 


575
724
2






 


576
725
2






 


577
726
2






 


578
727
2






 


579
728
2






 


580
729
2






 


581
730
2






 


582
731
2






 


583
732
2






 


584
733
2






 


585
734
2






 


586
735
2






 


587
780
2






 


588
781
2






 


589
782
2






 


590
783
2






 


591
784
2






 


592
785
2






 


593
786
2






 


594
787
2






 


595
788
2













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






 


601
337
89






 


602
338
89






 


603
339
89






 


604
340
89






 


605
341
89






 


606
342
89






 


607
343
89






 


608
344
89






 


609
345
89






 


610
346
89






 


611
347
89






 


612
348
89






 


613
349
89






 


614
350
89






 


615
351
89






 


616
352
89






 


617
353
89






 


618
354
89






 


619
355
89






 


620
356
89






 


621
357
89






 


622
358
89






 


623
359
89






 


624
360
89






 


625
361
89






 


626
362
89






 


627
363
89






 


628
364
89






 


629
365
89






 


630
366
89






 


631
367
89






 


632
368
89






 


633
369
89






 


634
370
89






 


635
371
89






 


636
435
89






 


637
436
89






 


638
437
89






 


639
438
89






 


640
439
89






 


641
440
89






 


642
441
89






 


643
442
89






 


644
443
89






 


645
444
89






 


646
445
89






 


647
446
89






 


648
447
89






 


649
448
89






 


650
449
89






 


651
450
89






 


652
451
89






 


653
452
89






 


654
453
89






 


655
454
89






 


656
455
89






 


657
456
89






 


658
457
89






 


659
458
89






 


660
459
89






 


661
460
89






 


662
461
89






 


663
462
89






 


664
463
89






 


665
464
89






 


666
465
89






 


667
466
89






 


668
467
89






 


669
468
89






 


670
469
89






 


671
536
89






 


672
537
89






 


673
538
89






 


674
539
89






 


675
540
89






 


676
541
89






 


677
542
89






 


678
543
89






 


679
544
89






 


680
545
89






 


681
546
89






 


682
547
89






 


683
548
89






 


684
549
89






 


685
550
89






 


686
551
89






 


687
552
89






 


688
553
89






 


689
554
89






 


690
555
89






 


691
556
89






 


692
557
89






 


693
558
89






 


694
559
89






 


695
560
89






 


696
561
89






 


697
562
89






 


698
563
89






 


699
564
89






 


700
565
89






 


701
566
89






 


702
567
89






 


703
568
89






 


704
569
89






 


705
570
89






 


706
571
89






 


707
636
89






 


708
637
89






 


709
638
89






 


710
639
89






 


711
640
89






 


712
641
89






 


713
642
89






 


714
643
89






 


715
644
89






 


716
645
89






 


717
646
89






 


718
647
89






 


719
648
89






 


720
649
89






 


721
650
89






 


722
651
89






 


723
652
89






 


724
653
89






 


725
654
89






 


726
655
89






 


727
656
89






 


728
657
89






 


729
658
89






 


730
659
89






 


731
660
89






 


732
661
89






 


733
662
89






 


734
663
89






 


735
664
89






 


736
665
89






 


737
666
89






 


738
667
89






 


739
668
89






 


740
669
89






 


741
670
89






 


742
671
89






 


743
688
89






 


744
689
89






 


745
690
89






 


746
691
89






 


747
692
89






 


748
693
89






 


749
694
89






 


750
695
89






 


751
736
89






 


752
737
89






 


753
738
89






 


754
739
89






 


755
740
89






 


756
741
89






 


757
742
89






 


758
743
89






 


759
744
89






 


760
745
89






 


761
746
89






 


762
747
89






 


763
748
89






 


764
749
89






 


765
750
89






 


766
751
89






 


767
752
89






 


768
753
89






 


769
754
89






 


770
755
89






 


771
756
89






 


772
757
89






 


773
758
89






 


774
759
89






 


775
760
89






 


776
761
89






 


777
762
89






 


778
763
89






 


779
764
89






 


780
765
89






 


781
766
89






 


782
767
89






 


783
768
89






 


784
769
89






 


785
770
89






 


786
771
89






 


787
789
89






 


788
790
89






 


789
791
89






 


790
792
89






 


791
793
89






 


792
794
89






 


793
795
89






 


794
796
89






 


795
797
89













Examples 796-799 have been intentionally excluded.
Examples 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






 


801
62
2
NH3






 


802
65
2
NH3






 


803
61 Step B
2
NH3






 


804
62
2
NH3






 


805
65
2
NH3






 


806
61 Step B
2
CH3NH2






 


807
62
2
CH3NH2






 


808
65
2
CH3NH2






 


809
61 Step B
2
CH3NH2






 


810
62
2
CH3NH2






 


811
65
2
CH3NH2






 


812
61 Step B
2
(CH3)2NH






 


813
65
2
CH3NH2






 


814
61 Step B
2
CH3NH2






 


815
65
2
CH3NH2






 


816
61 Step B
89
NH3






 


817
62
89
NH3






 


818
65
89
NH3






 


819
61 Step B
89
NH3






 


820
62
89
NH3






 


821
65
89
NH3






 


822
61 Step B
89
CH3NH2






 


823
62
89
CH3NH2






 


824
65
89
CH3NH2






 


825
61 Step B
89
CH3NH2






 


826
62
89
CH3NH2






 


827
65
89
CH3NH2






 


828
61 Step B
89
CH3NH2






 


829
62
89
CH3NH2






 


830
65
89
CH3NH2






 


831
61 Step B
89
CH3NH2






 


832
62
89
CH3NH2






 


833
65
89
CH3NH2













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






 


1001
804
2






 


1002
805
2






 


1003
800
2






 


1004
802
2






 


1005
803
2






 


1006
801
89






 


1007
804
89






 


1008
805
89






 


1009
800
89






 


1010
802
89






 


1011
803
89






 


1012
810
2






 


1013
812
2






 


1014
811
2






 


1015
810
89






 


1016
812
89






 


1017
811
89






 


1018
831
2






 


1019
832
2






 


1020
833
2






 


1021
834
2






 


1022
835
2






 


1023
836
2






 


1024
837
2






 


1025
838
2






 


1026
839
2






 


1027
851
2






 


1028
852
2






 


1029
853
2






 


1030
854
2






 


1031
855
2






 


1032
856
2






 


1033
857
2






 


1034
858
2






 


1035
859
2






 


1036
901
2






 


1037
902
2






 


1038
903
2






 


1039
904
2






 


1040
905
2






 


1041
906
2






 


1042
907
2






 


1043
908
2






 


1044
909
2






 


1045
921
2






 


1046
922
2






 


1047
923
2






 


1048
924
2






 


1049
925
2






 


1050
926
2






 


1051
927
2






 


1052
928
2






 


1053
929
2






 


1054
831
2






 


1055
832
89






 


1056
833
89






 


1057
834
89






 


1058
835
89






 


1059
836
89






 


1060
837
89






 


1061
838
89






 


1062
839
89






 


1063
851
89






 


1064
852
89






 


1065
853
89






 


1066
854
89






 


1067
855
89






 


1068
856
89






 


1069
857
89






 


1070
858
89






 


1071
859
89






 


1072
901
89






 


1073
902
89






 


1074
903
89






 


1075
904
89






 


1076
905
89






 


1077
906
89






 


1078
907
89






 


1079
908
89






 


1080
909
89






 


1081
921
89






 


1082
922
89






 


1083
923
89






 


1084
924
89






 


1085
925
89






 


1086
926
89






 


1087
927
89






 


1088
928
89






 


1089
929
89






 


1090
1301
2






 


1091
1302
2






 


1092
1303
2






 


1093
1304
2






 


1094
1305
2






 


1095
1306
2






 


1096
1307
2






 


1097
1308
2






 


1098
1309
2






 


1099
1351
2






 


1100
1352
2






 


1101
1353
2






 


1102
1354
2






 


1103
1355
2






 


1104
1356
2






 


1105
1357
2






 


1106
1358
2






 


1107
1359
2






 


1108
1401
2






 


1109
1402
2






 


1110
1403
2






 


1111
1404
2






 


1112
1405
2






 


1113
1406
2






 


1114
1407
2






 


1115
1408
2






 


1116
1409
2






 


1117
1301
89






 


1118
1302
89






 


1119
1303
89






 


1120
1304
89






 


1121
1305
89






 


1122
1306
89






 


1123
1307
89






 


1124
1308
89






 


1125
1309
89






 


1126
1351
89






 


1127
1352
89






 


1128
1353
89






 


1129
1354
89






 


1130
1355
89






 


1131
1356
89






 


1132
1357
89






 


1133
1358
89






 


1134
1359
89






 


1135
1401
89






 


1136
1402
89






 


1137
1403
89






 


1138
1404
89






 


1139
1405
89






 


1140
1406
89






 


1141
1407
89






 


1142
1408
89






 


1143
1409
89






 


1144
1450 Step K
2






 


1145
1450 Step O
2






 


1146
1451 Step F
2






 


1147
1451 Step J
2






 


1148
1452 Step F
2






 


1149
1452 Step J
2






 


1150
1453 Step J
2






 


1151
1453 Step M
2






 


1152
1454 Step I
2






 


1153
1454 Step L
2






 


1154
1500
2






 


1155
1501
2






 


1156
1502
2






 


1157
1450 Step K
89






 


1158
1450 Step O
89






 


1159
1451 Step F
89






 


1160
1451 Step J
89






 


1161
1452 Step F
89






 


1162
1452 Step J
89






 


1163
1453 Step J
89






 


1164
1453 Step M
89






 


1165
1454 Step I
89






 


1166
1454 Step L
89






 


1167
1500
89






 


1168
1501
89













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






 


1501
1001






 


1502
1002






 


1503
1003






 


1504
1004






 


1505
1005






 


1506
1006






 


1507
1007






 


1508
1008






 


1509
1009






 


1510
1010






 


1511
1011






 


1512
1012






 


1513
1013






 


1514
1014






 


1515
1015






 


1516
1016






 


1517
1017






 


1518
1018






 


1519
1019






 


1520
1020






 


1521
1021






 


1522
1022






 


1523
1023






 


1524
1024






 


1525
1025






 


1526
1026






 


1527
1027






 


1528
1028






 


1529
1029






 


1530
1030






 


1531
1031






 


1532
1032






 


1533
1033






 


1534
1034






 


1535
1035






 


1536
1036






 


1537
1037






 


1538
1038






 


1539
1039






 


1540
1040






 


1541
1041






 


1542
1042






 


1543
1043






 


1544
1044






 


1545
1045






 


1546
1046






 


1547
1047






 


1548
1048






 


1549
1049






 


1550
1050






 


1551
1051






 


1552
1052






 


1553
1053






 


1554
1054






 


1555
1055






 


1556
1056






 


1557
1057






 


1558
1058






 


1559
1059






 


1560
1060






 


1561
1061






 


1562
1062






 


1563
1063






 


1564
1064






 


1565
1065






 


1566
1066






 


1567
1067






 


1568
1068






 


1569
1069






 


1570
1070






 


1571
1071






 


1572
1072






 


1573
1073






 


1574
1074






 


1575
1075






 


1576
1076






 


1577
1077






 


1578
1078






 


1579
1079






 


1580
1080






 


1581
1081






 


1582
1082






 


1583
1083






 


1584
1084






 


1585
1085






 


1586
1086






 


1587
1087






 


1588
1088






 


1589
1089






 


1590
1090






 


1591
1091






 


1592
1092






 


1593
1093






 


1594
1094






 


1595
1095






 


1596
1096






 


1597
1097






 


1598
1098






 


1599
1099






 


1600
1100






 


1601
1101






 


1602
1102






 


1603
1103






 


1604
1104






 


1605
1105






 


1606
1106






 


1607
1107






 


1608
1108






 


1609
1109






 


1610
1110






 


1611
1111






 


1612
1112






 


1613
1113






 


1614
1114






 


1615
1115






 


1616
1116






 


1617
1117






 


1618
1118






 


1619
1119






 


1620
1120






 


1621
1121






 


1622
1122






 


1623
1123






 


1624
1124






 


1625
1125






 


1626
1126






 


1627
1127






 


1628
1128






 


1629
1129






 


1630
1130






 


1631
1131






 


1632
1132






 


1633
1133






 


1634
1134






 


1635
1135






 


1636
1136






 


1637
1137






 


1638
1138






 


1639
1139






 


1640
1140






 


1641
1141






 


1642
1142






 


1643
1143






 


1644
1144






 


1645
1145






 


1646
1146






 


1647
1147






 


1648
1148






 


1649
1149






 


1650
1150






 


1651
1151






 


1652
1152






 


1653
1153






 


1654
1154






 


1655
1155






 


1656
1156






 


1657
1157






 


1658
1158






 


1659
1159






 


1660
1160






 


1661
1161






 


1662
1162






 


1663
1163






 


1664
1164






 


1665
1165






 


1666
1166






 


1667
1167






 


1668
1168






 


1669
1169






 


1670
1170






 


1671
1171






 


1672
1172






 


1673
1173






 


1674
1174






 


1675
1175






 


1676
1176






 


1677
1177






 


1678
1178






 


1679
1179






 


1680
1180






 


1681
1181






 


1682
1182






 


1683
1183






 


1684
1184






 


1685
1185






 


1686
1186






 


1687
1187






 


1688
1188






 


1689
1189






 


1690
1190






 


1691
1191






 


1692
1192






 


1693
1193






 


1694
1194






 


1695
1195






 


1696
1196






 


1697
1197






 


1698
1198






 


1699
1199






 


1700
1200






 


1701
1201






 


1702
1202






 


1703
1203






 


1704
1204






 


1705
1205






 


1706
1206






 


1707
1207






 


1708
1208






 


1709
1209













Examples 1710-1799 have been intentionally excluded.
Example 1800




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




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




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




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















Activ-

Activ-

Activ-

Activ-


Exam-
ity
Exam-
ity
Exam-
ity
Exam-
ity


ple
(K(i))
ple
(K(i))
ple
(K(i))
ple
(K(i))

















1
C
21
C
41
B
61
A


2
D
22
A
42
C
62
A


3
D
23
B
43
A
63
A


4
D
24
A
44
A
64
A


5
D
25
B
45
B
65
B


6
C
26
C
46
D
66
B


7
C
27
A
47
A
67
A


8
C
28
A
48
A
68
B


9
C
29
A
49
A
69
B


10
C
30
A
50
B
70
B


11
C
31
B
51
A
71
B


12
C
32
A
52
A
72
A


13
C
33
A
53
A
73
B


14
D
34
A
54
A
74
C


15
D
35
A
55
A
75
C


16
C
36
B
56
A
76
B


17
B
37
B
57
A
77
A


18
A
38
B
58
A
78
B


19
B
39
B
59
A




20
C
40
D
60
A









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

1. A compound of formula (I):


A-B-D  (I)


or a pharmaceutically acceptable salt thereof,
wherein A is:



B is:




D is:




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—(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 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:

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




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:

7. A compound of claim 1, or a pharmaceutically acceptable salt, thereof, wherein:
A is:




Y is —CH2—CH2—;
D is





and
Qb is CH.

8. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

9. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

10. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

11. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

12. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

13. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

14. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

15. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

16. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

17. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

18. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

19. A compound according to the following formula:




or a pharmaceutically acceptable salt thereof.

20. A compound according to the following formula:




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.