Title of Invention

INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1

Abstract discloses novel compounds of Formula 1: 5 having 11β-HSD type I antagonist activity, as well as methods for preparing such compounds, in another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula 1. as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension. hypcrlipidemia. metabolic syndrome, and other conditions associated with 11β-HSD type 10 1 activity.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1"


ELI LILLY AND COMPANY, a corporation of the State of Indiana, having a principal place of business at Lilly Corporate Center, City of Indianapolis, State of Indiana 46285, United States of America.
The following specification particularly describes the invention and the manner in which it is to be performed.


INHIBITORS OF 11-BETA-HYDROXYSTKROID DEHYDROGENASE 1
This application claims the benefit of U.S. Provisional Application No. 60/745,574 filed April 25. 2006.
This invention relates to compounds that arc inhibitors of 11 -p-hydroxystcroid dehydrogenase type I {"11-β-HSDI"). and to pharmaceutical compositions thereof and the uses of these compounds and compositions in the treatment of the human or animal body, and to novel intermediates useful in preparation of the inhibitors. The present compounds show potent and selective inhibition of 11-β-HSDI, and as such arc useful in the treatment of disorders responsive to the modulation of 11-β-HSDl, such as diabetes, metabolic syndrome, cognitive disorders, and the like.
Glucocorticoids acting in the liver, adipose tissue, and muscle, arc important regulators of glucose, lipid, and protein metabolism. Chronic glucocorticoid excess is associated with insulin resistance, visceral obesity, hypertension, and dyslipidcmia. which also represent the classical hallmarks of metabolic syndrome. 11-β-HSDI catalyses the conversion of inactive cortisone to active cortisol, and has been implicated in the development of metabolic syndrome. Evidence in rodents and humans links 11-β-HSDI to metabolic syndrome. Evidence suggests that a drug which specifically inhibits 11-β-HSDI in type 2 diabetic patients will lower blood glucose by reducing hepatic gluconeogencsis, reduce central obesity, improve atherogenic lipoprotessin phenotypes. lower blood pressure, and reduce insulin resistance. Insulin effects in muscle will be enhanced, and insulin secretion from the beta cells of the islet may also be increased. Evidence from animal and human studies also indicates thai an excess of glucocorticoids impair cognitive function. Recent results indicate that inactivalion of 11-β-HSDI enhances memory function in both men and mice. The 1 1-β-HSD inhibitor carbenoxoione was shown to improve cognitive function in healthy elderly men and type 2 diabetics, and inactivalion of the 11-β-HSDI gene prevented aging-induced impairment in mice. Selective inhibition of 11-β-HSDI with a pharmaceutical agent has recently been shown to improve memory retention in mice.
A number of publications have appeared in recent years reporting agents that inhibit 11-β-IISDI. See International Application WO2004/056744 which discloses adamantyl acclamides as inhibitors of 11 -β-HSO, International Application

WO2005/I08360 which discloses pyrrolidin-2-onc and pipcridin-2-onc derivatives as inhibitors of 11-β-HSD and International Application WO2005/10836I which discloses adamantyl pyrrolidin-2-one derivatives as inhibitors of 11 -β-HSD. In spite of the number of treatments for diseases thai involve 11-β-HSDI, the current therapies suffer from one or more inadequacies, including poor or incomplete efficacy, unacceptable side effects, and contraindications for certain patient populations. Thus, there remains a need for an improved treatment using alternative or improved pharmaceutical agents that inhibit 11-β-HSDI and treat the diseases that could benefit from 11-β-HSDI inhibition. The present invention provides such a contribution to the art based on the finding that a novel class of compounds has a potent and selective inhibitory activity on 11-β-HSDI. The present invention is distinct in the particular structures and their activities. There is a continuing need for new methods of treating diabetes, metabolic syndrome, and cognitive disorders, and it is an object of this invention to meet these and other needs.
The present invention provides a compound structurally represented by formula l: The present invention provides a compound structurally represented by formula t:

or a pharmaceutical!}' acceptable salt thereof, wherein
Ra is -11 or -O11;
Rb is-H;or
Ra and Rb combine with the cyclohexyl ring to which they arc attached to form
; wherein the asterisk represents the carbon atom shared with the lactam ring of formula 1;
R1 is -H. -halogen. -O-CH3(optionally substituted with one to three halogens), or -CH3 (optionally substituted with one to three halogens):
R2 is -H. -halogen. -O-CH3 (optionally substituted with one to three halogens), or -CH3, (optionally substituted with one to three halogens);

R3 is 11 or -halogen; R4is
-OI I, -halogen, -CN, -(C1-C4)alkyl(optionaliy substituted with one to three halogens). -(C1-C6)alkoxy(oplionally substituted with one lo three halogens).
-SCF3-C(O)O(C1-C4)alkyl, -O-CH2-C(O)NH2, -(C3-C8)cycloalkyl. -O-phcnyl-C(O)O-(C1-C4)alkyl,-CH2-phenyl, -NHSO2-(C1-C4)alkyl. -NHSO2-phenyl(R2l)(R21),-(C1-C4)alkyl-C(O)N(R10)(R11),

dashed line represents the point of attachment to the R4 position in formula 1; R5 is
-H, -halogen, -OH, -CN, -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens), -C(O)OH, -C(O)O-(C1-C4)alkyl, -C(O)-.(C1-C4)alkyl, -O-(C1-C4)alkyl(optionally substituted with l to 3 halogens), -SO2-(C1-C4)alkyl, -N(R8)(R8), -phenyl(R21)(R21), -C(O)-NH-(C3-C6)cycloalkyl,


represents the point of attachment to the position indicated by R5
wherein m is 1, 2, or 3:
wherein n is 0, 1, or 2. and wherein when n is 0, then "(CH2) n" is a bond:
R6 is
11. -halogen. -CN, or -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens): R7 is
-11. -halogen, or -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens): R8 is independently at each occurrence -H or -(C1-C6)alkyl(optionally substituted with 1 to 3 halogens); R9 is-H or-halogen; R10and R11 arc each independently
-11 or-(C1-C4)alkyl or R10 and R11 taken together with the nitrogen to which they arc attached form pipcridinyk pipcrazinyl, or pyrrolidinyl; R20 is independently at each occurrence -H. or -(C1-C3)alkyl(optionalty substituted with 1 to 3 halogens);

R21 is independently al each occurrence -H. -halogen, or -(C1-C3)alkyl(optionally
substituted wilh 1 to 3 halogens);
R22 is independently at each occurrence-H or -(C1-C6)alkyl(oplionally substituted with I
to 3 halogens); and
R23 is independently at each occurrence -H. -(C1-C4)alkyl(optionally substituted wilh I to
3 halogens), or -C(O)O-(C1-C4)alkyl.
The present invention provides compounds of formula 1 that arc useful as potent and selective inhibition of 11-β-HSDI. The present invention further provides a pharmaceutical composition which comprises a compound of formula 1. or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipicnl. In addition, the present invention provides a method for the treatment of metabolic svndromc. and related disorders, which comprise administering lo a patient in need thereof an effective amount of a compound ol" formula I or a pharmaccutically acceptable salt thereof.
In one embodiment, the present invention provides compounds of Formula 1 or a pharmaceutically acceptable salt thereof as described in detail above. While all of the compounds of the present invention arc useful, certain of the compounds are particularly interesting and are preferred. The following listings set out several groups of preferred compounds.

In another embodiment the invention provides a compound structurally represented by formula I, or a pharmaceutical!)' acceptable salt thereof, wherein Ra is -H or -OH: Rbis-H;or Ra and Rb combine with the cyclohexyl ring to which they are attached to form
; wherein the asterisk represents the carbon atom shared with the lactam ring
of formula I:
R1 is -halogen; R2 is -halogen; R3 is -H or -halogen;
R4 is
-OH. -halogen. -CN. -(C1-C4)alkyl(optionally substituted with one to three halogens). -(C1-C6,)alkoxy(optionallv substituted with one to three halogens).



-SCF3. -C(O)O(C1-C4)alkyl, -O-CH2-C(O)NH2 -(C3-C8)cycloalkyl. -O-phcnyl-C(O)O-(C1-C4)alkyl, -CH2-phenyl. -NHSO2-(C1-C4)alkyI, -NHSO2-phenyl(R2l)(R21).-(C1-C4)alkyl-C(O)N(R10)(R11),
dashed line represents the point of attachment to the R position in formula I: R5 is
-11. -halogen. -OH, -CN, -(C1-C4)alkyi(optiona!ly substituted with I to 3 halogens), -C(O)OH, -C(O)O-(C1-C4)alkyl -C(O)-(C1-C4)alkyl. -O-(C1-C4)alkyl(opiionally substituted with 1 to 3 halogens), -SO2-(C1-C4)alkyl -N(R8)(R8), -phenyI(R2l)(R21), -C(O)-NH-(C3-C6)cycloalkyl,



represents the point of attachment to the position indicated by R5
wherein m is 1, 2, or 3;
wherein n is 0, I. or 2, and wherein when n is 0. then "(CH2) n" is a bond: R6 is
11 -halogen. -CN. or -(C1-C1)alkyl(oplionally substituted with 1 to 3 halogens}: R7 is
11, -halogen, or -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens): R8 is independently at each occurrence -H or -(C1-C6)alkyl(oplionally substituted with I tO 3 halogens); R9 is-H or halogen; R10 and R11 are each independently
-H or-(C1-C4)alkyl, or R10 and R11 taken together with the nitrogen to which they
are attached form piperidinyl, pipcrazinyl. or pyrrolidinyl; R20 is independently at each occurrence -H, or -(C1-C3)alkyl(optionally substituted with I to 3 halogens);
R21 is independently at each occurrence -H, -halogen, or -(C1-C3)alkyl(optionally substituted with 1 to 3 halogens);
R22 is independently at each occurrence -H -(C1 -C6)alkyl(optionally substituted with 1 to 3 halogens); and
R23 is independently at each occurrence -H, -(C1-C4)alkyl(op(ionally substituted with I to 3 halogens), or -C(O)O-(C1-C4)alkyl.
In another embodiment the invention provides a compound structurally represented by formula I, or a pharmaceutically acceptable salt thereof, wherein Ra is -H or -OH;

Rh is H: or
Ra and Rb combine with the cyclohexyl ring to which they arc attached to form

: wherein the asterisk represents the carbon atom shared with the lactam ring of formula I; 5 R1 is -chlorine, -fluorine, or-bromine; R2 is -chlorine, -fluorine, or-bromine; R3 is H or -halogen;
R4 iS




R5 is

represents the point of attachment to the R4 position in formula 1;
-H. -halogen, -OH, -CN, -{C1-C4)alkyl(optionalIy substitulcd with I to 3 halogens), -C(O)OH, -C(O)O-(C1-C4)alkyl, -C(O)-(C1-C4,)alkyl. -O-(C1-C4)alkyl(optionally substituted with I to 3 halogens). -SO2-(C1-C4)alkyl -N(R8)(R8), -phenyl(R2l)(R21), -C(O)-NH-(C3-C6)cycloalkyl,




R6 is

represents the point of attachment to the position indicated by R5 wherein m is I.
2, or 3;
-H. -halogen, -CN. or -(C1-C4)alkyl(optionaIly substituted with 1 to 3 halogens);

R7is
-H. -halogen, or -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens); R8 is independently at each occurrence -H or -(C1-C6)alkyI(optionally substituted with I to 3 halogens); R9 is— H or -halogen;
R20is independently at each occurrence -H, or -(C1-C3)alkyl(optionally substituted with I to 3 halogens);
R21 is independently at each occurrence -H, -halogen, or -(C1-C3)alkyl(optionally substituted with 1 to 3 halogens);
R22 is independently at each occurrence —H or -(C1-C6)alkyl(optionally substituted with I to 3 halogens); and

R23 is independently at each oceurrcncc -H. -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens), or -C(O)O-(C1-C4)alkyl
In another embodiment the invention provides a compound structurally represented by formula I, or a pharmaceutically acceptable salt thereof, wherein Ra is -H or-OH; Rb is-H;or Ra and Rb combine with the cyclohcxyl ring to which they arc attached to form
; wherein the asterisk represents the carbon atom shared with the lactam ring of formula 1;
R1 is chlorine, -fluorine, or -bromine: R2 is chlorine, -fluorine, or -bromine: R2 is H or
-halogen:
R4 is




R5is

point of attachment to the R" position in formula I;
-H, -halogen. -(C1-C4)a!kyl{optionally substituted with I to 3 halogens). -C(O)OH, -C(O)O-(C1-C4)alkyl -C(O)-(C1-C4)alkyl, -O-(C1-C4)alkyi(optionally substituted with 1 lo 3 halogens), -SO2-(C1-C4)alkyl, -N(R8)(R8).






R6 is

represents the point of attachment to the position indicated by R5: wherein m is 1. 2, or 3;
H, -halogen. -CN. or -(C1-C4)alkyl(oplional!y substituted with 1 to 3 halogens):

R7 is
-H. -halogen, or -(C1-C4)alkyl(oplionally substituted with 1 to 3 halogens): R8 is independently at each occurrence -H or -(C1-C6)alkyl(oplionally substituted with 1 to 3 halogens); R9 is H or -halogen;
R20 is independently at each occurrence -H, or -(C1-C3)alkyl(oplionally substituted with 1 to 3 halogens);
R21 is independently at each occurrence -H, -halogen, or -(C1-C3)alkyl(optionally substituted with 1 to 3 halogens);
R22 is indepcndently at each occurrence-H or -(C1-C6)alkyl(oplionally substituted with 1 to 3 halogens); and
R23 is independently at each occurrence -H, -(C1-C4)alkyl(oplionally substituted with 1 to 3 halogens), or -C(O)O-(C1-C4)alkyi.
In another embodiment the invention provides a compound structurally represented by formula 1, or a pharmaceutically acceptable salt thereof, wherein Rais H or-OH; Rb is H: or


Ra and Rb combine with the cyclohcxyl ring to which they arc attached to form
wherein the asterisk represents the carbon atom shared with the lactam ring of formula I;
R1 is chlorine, -fluorine, or -bromine; R2 is - chlorine, -fluorine, or -bromine: R3' is H or
-halogen; R4 is

. wherein the dashed line represents the point of attachment lo the R4 position in formula I:

R5 is
R6 is
R7 is

wherein the dashed line represents the point of attachment to the position indicated by R5;
H, -halogen. -CN: or -(C1-C4)alkyl(oplionally substituted with I lo 3 halogens):
H, -halogen, or -(C1-C4)alkyl(oplionally substituted with 1 lo 3 halogens):

R8 is independently al each occurrence -H or-(C1-C6)alkyl(optionally substituted with I
to 3 halogens);
R9 is -H or -halogen;
R20 is independently at each occurrence -H, or -(C1-C3)alkyl(optionally substituted with I
to 3 halogens);
R21 is independently at each occurrence -H -halogen, or -(C1-C3)alkyl(optionally
substituted with 1 to 3 halogens):
R22 is independently at each occurrence -H or -(C1-C6)alkyl(oplionally substituted with I
to 3 halogens); and
R23 is independently at each occurrence -H, -(C1-C4)alkyl(optionally substituted with 1 to
3 halogens), or -C(O)O-(C1-C4)alkyl
In another embodiment the invention provides a compound structurally represented by formula I. or a pharmaceutically acceptable salt thereof, wherein Ra,is-H or-OH: Rb is -H: or Ra and Rb combine with the cyclohexyl ring to which they are attached to form
; wherein the asterisk represents the carbon atom shared with the lactam ring of formula I:
R is -chlorine, -fluorine, or -bromine; R2 is -chlorine, -fluorine, or -bromine: R3 is H or ■halogen;

wherein the dashed line represents the point of attachment to the R4 position in formula 1;

R5 is

R6 is

, wherein the dashed line represents the point of attachment to the position indicated by R5; wherein m is 1.2, or 3;
-H, -halogcn: -CN, or -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens):

R7 is
--H, -halogen, or -(C1-C4)afkyl(optionally substituted with i to 3 halogens): and R8 is independently at each occurrence -H or-(C1-C6)alkyl(optionally substituted with 1 to 3 halogens).
In another embodiment the invention provides a compound structurally epresented by formula 1, or a pharmaceutical!}' acceptable salt thereof wherein Ra is-H or-OH: Rb is -H; or Ra and Rb combine with the cyclohcxyl ring to which they arc attached to form


; wherein the asterisk represents the carbon atom shared with the lactam rim of formula 1;
R1 is -chlorine, -fluorine, or-bromine; R2 is-chlorine, -fluorine, or-bromine: R3 is H or
-halogen:
R4 is

wherein the dashed line represents the point of attachment to the R4 position in formula I:.

R3 is


-N(R8)(R8).
wherein the dashed line represents the point of attachment to the position
indicated by R5;

R6 is
H, -halogen, -CN. or -(C1-C4)alkyl(oplionally substituted with 1 to 3 halogens):
R7 is
-H. -halogen, or -(C1-C4)alkyl(oplionally substituted with 1 lo 3 halogens); and R is independently at each occurrence -H or -(C1-C6)alkyl(oplional[y subsliluled with I to 3 halogens)
Other embodiments of the invention are provided wherein each of (he embodiments described herein above is further narrowed as described in the following preferences. Specifically, each of the preferences below is independently combined with each of the embodiments above, and the particular combination provides another embodiment in which the variable indicated in the preference is narrowed according to the preference.
Preferably embodiments of the invention are structurally represented by the

wherein Ra is -OH. Preferably Ra and Rb combine with the cyclohcxyi ring to which they
arc attached to form wherein the asterisk represents the carbon atom shared
with the lactam ring of formula 1.
Preferably R1 is halogen. Preferably R1 is -CH3. Preferably R1 is chlorine, -fluorine, or bromine. Preferably R1 is -chlorine. Preferably R1 is -fluorine. Preferably Rl is bromine. Preferably R2 is -hafogen. Preferably R2 is -CH3. Preferably R2 is chlorine.

-fluorine, or--bromine. Preferably R2 is--chlorine. Preferably R2 is -fluorine. Preferably R2 is-bromine. Preferably R1 is-chlorine and R2 is-chlorine. Preferably R3 is-H Preferably R3 is-halogen. Preferably R1 is-chlorine and R2 is -chlorine, and R3 is -H.




-C1-C3)alkyl (optionally substituted wilh 1 lo 3 halogens). Preferably R3 is chlorine or fluorine. Preferably R6 is- H. Preferably R6 is-halogen. Preferably R6 is -(C1-C4)alkyl(optionally substituted wilh I lo 3 halogens). Preferably R7 is -H. Preferably R7 is -halogen, or -(C1-C4)alkyl(optionally substitulcd with 1 lo 3 halogens). Preferably R7 is -halogen. Preferably R7 is -(C1-C4)alkyl(oplionally substiluled with 1 to 3 halogens).
Prclcrably R is independently al each occurrence H. Preferably R8 is independently al each occurrence -(C1-C3)alkyl. Preferably R8 is independently al each occurrence -CH3 Preferably R9 is-H. Preferably R9 is-halogen. Preferably R9 is -CF3. Preferably R7 is -fluorine and R is -fluorine.
In another embodiment the invention provides a compound structurally represcnled by formula 1. or a pharmaceuticallv acceptable salt thereof, wherein Ra is H or-OH: Rb is H; or Ra and Rb combine with the cyclohcxyl ring to which they arc attached to form

; wherein the asterisk represents the carbon atom shared with (he lactam ring of formula 1;
R1 is -chlorine; R2 is-chlorine; R3 is -H: R4 is

R5 is

-halogen,
point of attachment to the R4 position in formula 1;
-H. -chlorine, -fluorine. -CH3. -CF3, -C(CH3)3, -CH(CH3)2.-O-C(CH3)2 -C(O)O-CH3. -N(-CH3)(-CH3).


. wherein the dashed line represents the point of attachment to
the position indicated by R5 wherein m is 1 .2. or 3; R6 is- H. -chlorine, -fluorine.-brominc. -CH3- CF3j: R7 is H.-chlorine,-fluorine,-brominc;
R8 is independently at each occurrence -H or -CH3. -CH2-CH3 -C(CH3)3 -CH(CH3)2 R9 is -H or -chlorine, -fluorine,-bromine; R20 is independently at each occurrence -H, -CH3; and R22 is independently at each occurrence -H.
A preferred embodiment of the invention are compounds of the formula 2-|3.5-Dichloro-4'-(4-trinuoromethyl-piperidine-l-carbonyl)-biphenyl-4-ylmelhyl|-2-aza-spiro|4.5|dccan-l-one and 2-{3,5-Dichloro-4'-f4-(2-fluoro-ethyl)-pipcrazinc-l-carbonyl|-biphenyl-4-ylmcthyl}-2-aza-spiro[4.5]decan-l-one. A further embodiment of the invention are the novel intermediate preparations described herein which are useful for preparing the 11-β-HSDI inhibitors according to formula 1 and the embodiments described herein. A further embodiment of the invention arc the novel intermediate preparations described herein which are useful for preparing 2-|3.5-Dichloro-4'-(4-trifluoromethyl-piperidine-l-carbonyl)-biphenyl-4-ylmcthyl|-2-aza-spiro|4.5|dccan-l-onc and 2-{3.5-Dichloro-4'-|4-(2-11uoro-elhyl)-piperazine-l-carbonyl|-biphcnyl-4-ylmelhyl;-2-aza-spiro|4.5|dccan-l-one or a pharmaceutically acceptable salt thereof.
Patients with type 2 diabetes often develop "insulin resistance" which results in abnormal glucose homeostasis and hyperglycemia leading to increased morbidity and

premature mortality. Abnormal glucose homeostasis is associated with obesity, hypertension, and alterations in lipid, lipoprotein, and apolipoprotcin metabolism. Type 2 diabetics arc at increased risk of developing cardiovascular complications, e.g.. atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension. 5 nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are important in the management and treatment of diabetes mcllitus. Many patients who have insulin resistance but have not developed type 2 diabetes are also at risk of developing 'Syndrome X" or "Metabolic syndrome". Metabolic syndrome is characterized by
10 insulin resistance along with abdominal obesity, hypcrinsulinemia, high blood pressure, low HDL. high VLDL, hypertension, atherosclerosis, coronary heart disease, and chronic renal failure. These patients arc at increased risk of developing the cardiovascular complications listed above whether or not they develop overt diabetes mcllitus.
Due to their inhibition of H-β-HSDl. the present compounds arc useful in the
15 trcalmcnl of a wide range of conditions and disorders in which inhibition of H-β-HSDl is beneficial. These disorders and conditions are defined herein as "diabetic disorders" and "metabolic syndrome disorders". One of skill in the art is able to identify "diabetic disorders" and "metabolic syndrome disorders" by the involvement of H-β-HSDl activity either in the pathophysiology of the disorder, or in the homcostalic response to
20 the disorder. Thus, the compounds may find use for example to prevent, treat, or alleviate, diseases or conditions or associated symptoms or sequelae, of "Diabetic disorders" and "metabolic syndrome disorders".
"Diabetic disorders'" and "metabolic syndrome disorders" include, but are not limited to, diabetes, type 1 diabetes, type 2 diabetes, hyperglycemia, hyper insulincmia.
25 beta-cell rest, improved beta-cell function by restoring first phase response, prandial hyperglycemia, preventing apoptosis. impaired fasting glucose (IFG), metabolic syndrome, hypoglycemia, hypcr-/hypokalcmia. normalizing glucagon levels, improved LDL/HDL ratio, reducing snacking. eating disorders, weight loss, polycystic ovarian syndrome (PCOS). obesity as a consequence of diabetes, latent autoimmune diabetes in
30 adults (LADA). insulitis, islet transplantation, pediatric diabetes, gestational diabetes, diabetic late complications. micro-Anacroalbuminuria. nephropathy, retinopathy, neuropathy, diabetic foot ulcers, reduced intestinal motility due to glucagon

administration, short bowel syndrome, antidiarrhcic, increasing gastric secretion, decreased blood (low, erectile dysfunction, glaucoma, post surgical stress, ameliorating organ tissue injury caused by repcrfusion of blood flow after ischemia, ischemic heart damage, heart insufficiency, congestive heart failure, stroke, myocardial infarction, 5 arrhythmia, premature death, anli-apoplosis, wound healing, impaired glucose tolerance (IGT), insulin resistance syndromes, metabolic syndrome, syndrome X, hyperlipidcmia. dyslipidcmia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders.
!0 obesity, diabetes as a consequence of obesity, diabetic dyslipidemia. etc. Thus the present invention also provides a method of treatment of "Diabetic disorders" and "'metabolic syndrome disorders"" while reducing and or eliminating one or more of the unwanted side effects associated with the current treatments.
in addition, the present invention provides a compound of formula I. or a
15 pharmaceutical salt thereof, or a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier, diluent, or excipienl: for use in inhibiting 1 l-β-HSDI activity: for use in inhibiting a H-β-HSDl activity mediated cellular response in a mammal; for use in reducing the glycemic level in a mammal; for use in treating a disease arising from
20 excessive 11-β-HSDI activity; for use in treating diabetic and other metabolic syndrome disorders in a mammal; and for use in treating diabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy, and wound healing. Thus, the methods of this invention encompass a prophylactic and therapeutic administration of a compound of Formula I.
25 The present invention further provides the use ofa compound of Formula I. or a
pharmaceutical salt thereof for the manufacture ofa medicament for inhibiting 11-β-HSDI activity; for the manufacture of a medicament for inhibiting 11-β-HSDl activity mediated cellular response in a mammal; for the manufacture of a medicament for reducing the glycemic level in a mammal; for the manulacturc of a medicament for
30 treating a disease arising from excessive 11-β-HSDI aclivily: for the manulacturc ofa medicament for treating diabetic and other metabolic syndrome disorders in a mammal;

and for the manufacture of a medicament for preventing or treating diabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy, and improper wound healing.
The present invention further provides a method of treating conditions resulting from excessive 11-β-HSDl activity in a mammal; a method of inhibiting 11-β-HSD1 activity in a mammal; a method of inhibiting a 11-β-HSDl activity mediated cellular response in a mammal; a method of reducing the glycemic level in a mammal; a method of treating diabetic and other metabolic syndrome disorders in a mammal; a method of preventing or treating diabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy, and improper wound healing; said methods comprising administering to a mamma! in need of such treatment a 1l-β-HSDI activity inhibiting amount of a compound of Formula 1. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which comprises a compound of Formula 1, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
In addition, the present invention provides a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient: adapted for use in inhibiting 11-β-HSDl activity; adapted for use in inhibiting 11-β-HSDl activity mediated cellular responses; adapted for use in reducing the glycemic level in a mammal; adapted for use in treating diabetic and other metabolic syndrome disorders in a mammal; and adapted for use in preventing or treating diabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy, and wound healing.
A pharmaceutical composition of the present invention comprising a compound such as herein described, or a pharmaceutical^ acceptable salt thereof, and a pharmaceutically acceptable carrier showed surprising and enhanced effects. Therefore, the said composition is synergistic in nature.
In a further aspect of the invention the present compounds are administered in combination with one or more further active substances in any suitable ratios. Such further active substances may for example be selected from antidiabetics, antiobesity agents, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity. The following listing sets out several groups of combinations. It will be understood that each of the agents named may be combined with other agents named to create additional combinations.

Thus, in a further embodiment of the invention the present compounds may be administered in combination with one or more antidiabetics.
Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S). for example NAB29-tetradccanoyl 5 dcs(B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S). for example AspB28 human insulin, US 5.504,188 (Eli Lilly), for example LysB28 ProB29 human insulin. EP 368 187 (Avcntis), for example Lanlus®, GLP-I andGLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), as well as orally active hypoglycemic agents.
10 The orally active hypoglycemic agents preferably comprise imidazolines,
sulphonylurcas, biguanides. meglilinides, oxadiazolidincdioncs. thiazolidincdioncs. insulin sensitizers, insulin sccrclagogucs. such as glimepiridc. a-glucosidasc inhibitors, agents acting on the ATP-dcpcndcnt potassium channel ofihc β-cells for example potassium channel openers such as those disclosed in WO 97/26265. WO 99/03861 and
15 WO 00/37474 (Novo Nordisk A/S), or mitiglinidc. or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals. Inc.). GLP-1 antagonists, DPP-IV (dipeptidyl peplidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of
20 gluconcogcncsis and/or glycogenosis, glucose uptake modulators, activators of glucokinasc (GK) such as those disclosed in WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and WO 02/08209 (Hoffman-La Roche) or those disclosed in WO 03/00262. WO 03/00267 and WO 03/15774 (AslraZcneca), GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the
25 lipid metabolism such as antilipidemic agents such as HMG CoA inhibitors (statins), compounds lowering food intake, PPAR (Peroxisome proliferator-activatcd receptor) jgands including the PPAR-alpha, PPAR-gamma and PPAR-dclla subtypes, and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or LG-1069.
in another embodiment, the present compounds are administered in combination
30 with insulin or an insulin analogue or derivative, such as NEB29-tclradccanoyl des (B30) human insulin. AspB28 human insulin. LysB28 ProB29 human insulin. Lanlus®. or a mix-preparation comprising one or more of these.

in a further embodiment of the invention the present compounds arc administered in combination with a sulphonylurca such as glibcnclainide, glipizide, tolbautamide. chloropamidcm. tolazamide, glimcpride, glicazidc and glyburidc.
In another embodiment of the invention the present compounds arc administered 5 in combination with a biguanide, for example, metformin.
In yet another embodiment of the invention the present compounds arc administered in combination with a meglitinidc. for example, repaglinidc or nateglinide.
In still another embodiment of the invention the present compounds arc administered in combination with a thiazolidinedionc insulin sensitizer, for example. 10 troglitazone, ciglitazonc, pioglitazone, rosiglitazonc. isaglitazonc, darglilazonc.
cnglilazonc. CS-OI l/CI-1037 or T 174 or the compounds disclosed in WO 97/41097. WO 97/41119. WO 97/4 1 120. WO 00/41121 and WO 98/45292 (Dr. Roddy's Research foundation).
In still another embodiment of the invention the present compounds may be 15 administered in combination with an insulin sensitizer, for example, such as GI 262570. YM-440. MCC-555. JTT-50I. AR-H039242. KRP-297. GW-409544. CRI-16336. AR-11049020. LY510929, MBX-102, CLX-0940. GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191. WO 00/63192. WO 00/63193 such as ragaglitazar (NN 622 or (-)DRF 2725) (Dr. Rcddy's Research Foundation) and WO 20 00/23425. WO 00/23415. WO 00/23451, WO 00/23445. WO 00/23417. WO 00/23416. WO 00/63153, WO 63196, WO 00/63209. WO 00/63190 and WO 00/63189 (Novo Nordisk A/S).
In a further embodiment of the invention the present compounds are administered in combination with an α-glucosidase inhibitor, for example, voglibosc. cmiglitatc, 25 miglitol or acarbosc.
In another embodiment of the invention the present compounds arc administered
in combination with an agent acting on the ATP-dcpcndcnt potassium channel of the β-
cells, for example, tolbutamide, glibenclamidc. glipizide, glicazidc. BTS-67582 or
repaglinidc.
30 In yet another embodiment of the invention the present compounds may be
administered in combination with nateglinide.

In still another embodiment of the invention the present compounds are administered in combinalion with an antilipidcmic agent or antihypcrlipidcmic agent for example cholestyramine, colestipol, clofibrate. gemfibrozil, lovastatin, pravastatin, simvastatin, pravastatin, rosuvastatin. probucoi, dcxtrothyroxine. fcnollbrate or 5 atorvaslin.
In still another embodiment of the invention the present compounds are administered in combination with compounds lowering food intake.
In another embodiment of the invention, the present compounds arc administered in combination with more than one of the above-mentioned compounds for example in
10 combinalion with metformin and a sulphonylurea such as glyburidc; a sulphonylurea and acarbosc; nalcglinide and metformin; rcpaglinide and metformin, acarbosc and metformin: a sulfonylurea, met form in and trogliiazone: insulin and a sulfonylurea: insulin and metformin; insulin, metformin and a sulfonylurea: insulin and troglilazone: insulin and lovastalin; etc.
15 General terms used in the description of compounds herein described bear their
usual meanings.
As used herein, the terms *'(C1-C3)aikyl". '(C1-C4)alkyl" or "(C1-C6)alkyl" refer to straight-chain or branched-chain saturated aliphatic groups of the indicated number of carbon atoms, such as methyl, ethyl, n-propyl. isopropyl, n-butyl. isobutyl. sec-butyl, t-
20 bulyl, and the like. The term "(C1-C3)alkoxy" represents a C1-C6 alkyl group attached through an oxygen and include moieties such as. for example, mcthoxy. ethoxy, n-propoxy, isopropoxy, and the like. The term "halogen" refers lo fluoro, chloro. bromo. and iodo. The term "(C3-C8) cycloalkyl" refers to a saturated or partially saturated carbocyclc ring of from 3 to 8 carbon atoms, typically 3 to 7 carbon atoms. Examples of
25 (C3-C8) cycloalkyl include but are not limited to cyclopropyf cyclobutyl, cyclopentyl. cyciohcxyl. cyclohcptyl, and the like.
The term "optionally substituted," or "optional substitucnts." as used herein, means that the groups in question arc either unsubslituted or substituted with one or more of the substituents specified. When the groups in question arc substituted with more than
30 one substilucnt. the substituents may be the same or different. Furlhermorc. when using the terms "independently." 'Independently are." and "independently selected from" mean that the groups in question may be the same or different. Certain of the herein defined

terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
It is understood that guinea pigs, dogs. cats, rats, mice, hamsters, and primates, including humans, are examples of patients within the scope of the meaning of the term 5 "patient". Preferred patients include humans. The term "patient'" includes livestock
animals. Livestock animals arc animals raised for food production. Ruminants or "cud-chewing" animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goals and antelopes arc examples of livestock. Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese. The patient to be treated is
10 preferably a mammal, in particular a human being.
The terms 'treatment'", "treating" and "treat", as used herein, include their generally accepted meanings, i.e.. the management and care of a patient for the purpose of preventing, reducing the risk in incurring or developing a given condition or disease, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, delaying, or
15 reversing the progression or severity, and holding in check and/or treating existing characteristics, of a disease, disorder, or pathological condition, described herein, including the alleviation or relief of symptoms or complications, or the cure or elimination of the disease, disorder, or condition. The present method includes both medical therapeutic and/or prophylactic treatment, as appropriate.
20 As used herein, the term "therapeutically effective amount" means an amount of
compound of the present invention that is capable of alleviating the symptoms of the various pathological conditions herein described. The specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered.
25 the route of administration, the state of being of the patient, and the pathological condition being treated.
"Composition" means a pharmaceutical composition and is intended to encompass a pharmaceutical product comprising the active ingredicnt(s) including compound(s) of Formula I. and the inert ingredicnt(s) that make up the carrier. Accordingly, the
30 pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical!)' acceptable carrier.

The term "substantially pure" refers to pure crystalline form of a compound comprising greater than about 90% of the desired crystalline form, and preferably, greater than about 95% of the desired crystal form.
The term "suitable solvent' refers to any solvent, or mixture of solvents, inert lo 5 the ongoing reaction that sufficiently soiubiiizes the rcactanls lo afford a medium within which lo effect the desired reaction.
The term "unit dosage form" means physically discrete units suitable as unitary dosages for human subjects and other non-human animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic
10 effect, in association with a suitable pharmaceutical carrier.
The compounds of the present invention may have one or more chiral centers and may exist in a variety of stereoisomer^ configurations. As a consequence of these chiral centers the compounds of the present invention can occur as racemates. as individual cnanliomcrs or mixtures of enantiomcrs, as well as diaslercomcrs and mixtures of
15 diastcrcomers. All such racemates. enantiomers. diastereomers and mixtures are within the scope of the present invention, whether pure, partially purified, or unpurificd mixtures, for the examples provided herein, when a molecule which contains a chiral center or centers of known configuration is presented, its stereochemistry is designated in the name and in the structural representation of the molecule. If the stereochemistry is
20 unknown or undefined its stereochemistry is not designated in the name or in the
structural representation of the molecule. Embodiments of the invention include the Examples provided herein, and although the Example provided may be of one chiral or conformational form, or a sail thereof, further embodiments of the invention include all other steroisomeric and or conformational forms of the examples described, as well as
25 pharmaceutically acceptable salts thereof. These embodiments include any isolated cnanliomcrs. diastcrcomers, and orconformcrs of these structures, as well as any mixtures containing more than one form.
Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotalability is present in the
30 molecule diastcrcomers may be formed. It is intended that any diaslercomcrs. as
separated, pure or partially purified diastcrcomers or mixtures thereof arc included within the scope of the invention, Furthcrmore, some of the compounds of the present invention

may exist in different tautomeric forms and it is intended that any tautomeric forms which Vhc compounds are able lo form are included within the scope of the present invention. The term "enantiomeric enrichment" as used herein refers lo the increase in the amount of one cnantiomer as compared to the other. A convenient method of expressing 5 the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee". which is found using the following equation:

wherein E is the amount of the first enantiomer and E is the amount of the second
enantiomer. Thus, if the initial ratio of the two enantiomcrs is 50:50. such as is present in a raecmic mixture, and an enantiomeric enrichment sufficient lo produce a final ratio of 70:30 is achieved, the ee with respect lo the first cnanliomer is 40%. However. if the final ratio is 90:10. the ee with respect lo the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an cc of greater
than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chira! column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the
20 specific stereoisomers and enantiomers of compounds of formula 1 can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers, Raccmatcs. and Resolutions". John Wiley and Sons, Inc., 1981 and E.L. Eliel and S.H. Wilen." Stereochemistry of Organic Compounds", (Wiley-Interscience 1994), and European Patent Application No. EP-A-
25 838448, published April 29, 1998. Examples of resolutions include recryslallization techniques or chiral chromatography.
When a compound of formula ( i ) is designated by "cis" or "trans", the designation describes the relative position of the carbonyl lo Ra in the 2-aza-spiro|4.5|dccan-l-one core.
30 A compound designated as "trans" has the following relative position of R31 to the
carbonyl in compound II and III. wherein Ral is -OH. and O-Pg. where Pg is a protecting group, for example -Si(phcnyl)2-C(CH3)3:


A compound designated as "cis" has the following relative position of R21 to the earbonyl in compound IV and V. wherein Ral is -OH, and O-Pg. where Pg is a protecting group, for example -Si(phenyl)2-C(CH3)3:

The compounds of formula I. can be prepared by one of ordinary skill in the art following a variety of procedures, some of which arc illustrated in the procedures and schemes set forth below. The particular order of steps required to produce the compounds of formula I is dependent upon the particular compound to being synthesized, the starting compound, and the relative lability of the substituted moieties. The reagents or starting materials are readily available lo one of skill in the art. and to the extent not commercially available, are readily synthesized by one of ordinary skill in the art following standard procedures commonly employed in the art. along with the various procedures and schemes set forth below.
The following Schemes, Preparations. Examples and Procedures arc provided to better elucidate the practice of the present invention and should not be interpreted in any way as to limit the scope of the same. Those skilled in the art will recognize that various modifications may be made while not departing from the spirit and scope of the invention. All publications mentioned in the specification arc indicative of the level of those skilled in the art lo which this invention pertains.
The optimal lime for performing the reactions of the Schemes. Preparations. Examples and Procedures can be determined by monitoring the progress of the reaction via conventional chromatographic techniques. Furthermore, it is preferred lo conduct the reactions of the invention under an inert atmosphere, such as. for example, argon.

nitrogen. Choice of solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reaclants to effect the desired reaction. The compounds arc preferably isolated and purified before their use in subsequent reactions. Some compounds may crystallize Out of the reaction solution 5 during their formation and then collected by filtration, or the reaction solvent may be
removed by extraction, evaporation, or decantation. The intermediates and final products of formula I may be further purified, if desired by common techniques such as recrystallizalion or chromatography over solid supports such as silica gel or alumina.
The skilled artisan will appreciate that not all substituents arc compatible with all
10 reaction conditions. These compounds maybe protected or modified at a convenient point m the synthesis by methods well known in the art.
The terms and abbreviations used in the instant Schemes. Preparations. Examples and Procedures have their normal meanings unless otherwise designated, For example, as used herein,the following terms have the meaning indicated"psi"refers to pounds per
15 square inch; "'H,C" refers to thin layer chromatography: "HPLC" refers to high performance liquid chromatography; "R|" refers to retention factor; "R1" refers to retention time; "5"rcfers to part per million down-field from tetramelhylsilanc: *'MS" refers to mass spectrometry. Observed Mass indicates [M-|-H| unless indicated otherwise. "MS(APCi) refers to atmospheric pressure chemical ionization mass spectrometry. "UV"
20 refers to ultraviolet spectrometry, "HNMR" refers to proton nuclear magnetic resonance spectrometry. "LCMS;' refers to liquid chromatography-mass spectrometry. "GC/MS" refers to gas chromatography/mass spectrometry. "IR" refers to infra red spectrometry, and the absorption maxima listed for the IR spectra are on|y those of interest and not all of the maxima observed. "RT" refers to room temperature.
25 "THF" refers to tetrahydrofuran. "LAH" refers to lithium aluminum hydride.
"LDA" refers to lithium diisopropylamide. "DMSO" refers to dimelhylsulfoxidc. "DMF" refers to dimelhylforamidc, "'FtOAc" refers to ethyl acclate. "Pd-C" refers to palladium on carbon. "*DCM" refers to dichloromethanc, "DMAP" refers to dimcthylaminopyridinc. "LiHMDS" refers to Lithium Hexamcthyldisilisanc, "TFA" refers to trifluoroacctic acid.
30 "EDAC" refers to N-Ethyl-N-(3-dimcthylaminopropyl)carbodimide hydrochloride. "HOBI' refers to 1-1 lydroxy bcnzotriazolc. "Bn-9-BBN" refers to Bcnzyl -9-borabicyclol 3.3.1 |nonanc. "Pd(dppf)Cl2" refers to |1.F'-Bis(diphcnylphosphino)-

ferroccnc)dichloropalladium(H). "EDCI" refers to N-Ethyl-N-(3-dimethylaminopropyl)carbodiimidc hydrochloride. "DBU" refers to 1,8-Diazabicyclo|5.4.0jundccenc-7, "TBSCI" refers to tcrt-butyl-dimelhyl-silanyloxymethyl chloride, "NHS" refers to N-Bromosuccinimidc. "TsOH" refers to p-toluencsulfonic acid. 5 "DCE" refers to dichlorocihanc. "DAST" refers to (Diethylamino)sulfur trifluoride. "EA/H" refers to ethyl acetate/hexancs mixture. "Pd2(dba)3" refers to Bis(dibcnzylidcncacctonc)palladium, "BINAP" refers to 2.2'-Bis(diphcnylphospino-l. I '-binaphthalene, "NMP" refers to N-Methylpyrrollidinc, "TMSCN" refers to Trimcthylsilyl cyanide. "TBAF" refers to Tetrabutylammonium fluoride, 'Tf2O" refers to
10 trifluoromcthancsulfonic anhydride, "TBSO" refers to tert-butyl-dimethyl-silanyloxy, "OTP refers to trifluoromethanesulfonate, McTi(Oi-Pr)3 refers to mcthyltitanium triisopropoxide. "BBr3 refers to boron tribromidc. "PBr3," refers to phosphorous iribromide. "Pd(PPh;,).|" refers to telrakis(triphcnylphoshinc)palladium ({)). "OAc" relers
15 refers to tctrakis(triphenylphoshinc)paliadium (0). "DMFDMA" refers to N.N-
dimclhylformamidc dimethyl acetal, "Et3N" refers to triethylaminc, "tBu" refers to 1-butyl. "DIPEA" refers to diisopropylethyi amine. "EDC" refers to -(3-Dimclhylaminopropyl)-3-ethylcarbodiimide hydrochloride, "HOAc" refers to acetic acid, "boc" refers to t-butoxycarbonyl. In a structure. "Ph" refers to phenyl. "Me" refers to
20 methyl, "Et" refers to ethyl, "'Bn" refers to benzyl. "McOH" refers to methanol. "Off" refers to irifiuoromelhanesulfonale, "HPSO" refers to triisopropylsilanyloxy. "TBSO" refers to tert-butyl-dimethyl-silanyloxy.
The Examples provided herein are illustrative of the invention claimed herein and are not intended to limit the scope of the claimed invention in any way. The preparations
25 and examples arc named using AutoNom 2.2 in Chem Draw Ultra, or AutoNom 2000 in MDI- ISIS/Draw version 2.5 SPI from MDL Information Systems. Inc.. or arc provided by Chemical Abstracts Services.
A Varian INOVA 400 MHz spectrometer is used to obtain 'H NMR Specta the in the solvent indicated. An Agilent HPI 100 instrument equipped with a Mass
30 Spectrometer (Agilent MSDSL) is used to obtain I.CMS. A Waters Xtcrra C 18 (2.1 X 50 mm. 3.5 micron) is used as stationary phase and a standard method is a gradient of 5-100 % aectonitritc/mcthanol (50:50) with 0.2 % ammonium formate over 3.5 minutes

then held at 100 % B for 0.5 minutes at a column temperature of 50 °C and a flow rate oi" 1.0 ml/min. Another standard method is a gradient of 5-100 % acctonitrile/methanol (50:50) with 0.2 % ammonium formate over 7.0 minulcs then held at 100 % B for 1.0 minutes at a column temperature of50°C and a flow rate of 1.0 mL/min. Additional MS analysis via Agilent MSD (loop machine) is standard Flow injection Analysis (F1A). no column is present and flow is 0.5 ml/min of 80% McOH with 6.5mM Ammonium Acetate for 30sccs run time.
Scheme A
R1

In Scheme A. an optionally substituted aniline is converted to compound 2 and then to compound 3 which has a leaving group (l.g). Preferably, compound 2 is treated with N-bromosuccinimidc to form the bromomcthyl compound.
Scheme B

15 In Scheme B. an optionally substituted phenol (4) is protected (e.g. with TBSCI)
to form compound 5. and then compound 5 is converted to the aldehyde (6). Compound 6 is reacted with a compound containing a protecting group (Pg) and leaving group (l.g) to give the clher compound 7. Pg can be CH3 or CH2-phenyl and Lg can be mesylate
or halo. Preferably, the Lg-Pg compound is ICH3, or Br-CH2-phenyl. The aldehyde is
20 reduced to form the alcohol (8) and then converted to compound 9. Preferably, compound 8 is halogenated with PBr3 to give the 2-bromo-methyl compound.

Protection and dcprolcction of the compounds to form compounds of formula ID and others arc well known to the skilled artisan and arc described in the literature, (for example, see: Greene and Wuts. Protective Groups in Organic Synthesis. Third Edition. John Wiley and Sons Inc.. 1999).

In Scheme C. a cyclohcxane carboxylatc ester (]()) is reacted with a base such as LDA and is alkylated in a non-protic solvent (preferably THF) with bromoacetonitrilc to form compound (11). Nitrile (11) is reduced and cyclized to afford (i2) as described in the literature (see Reddy, P.A.: Hsiang, B.C.H.; Latifi, T.N.; Hill. M.W.; Woodward K.l-;. Rolhman, S.M.; Ferrendelli. J.A.; Covey. D.F..J. Med. Chem. 1996. 39. 1898-1906). Compound (12) is treated with a base (preferably NaH) and is alkylated with (3) to form (13). A coupling reaction is performed on (13) using a phcnylboronie acid reagent and a catalyst, such as palladium tclrakistriphcnylphosphinc to prepare ester (14). I lydrolysis

of( 14) affords acid (15) which is coupled with an amine using standard amide coupling conditions such as l.1-carbonyldiimidazole to afford (16).
Scheme D

In Scheme D (12) is treated with a base {preferably NaH) and is alkylated with (9) to form (17). Compound (17) is dcproiccled by a suitable method, such as using hydrogen with a catalyst, and the resulting phenol is reacted with triflic anhydride (trifluoromethancsulfonic anhydride) and a basc: for example pyridine to prepare (18). Triflalc 18 is reacted with an amine such as morpholinc in NMP (l-mcthyl-2-pyrrolidinonc) to afford (19) as described in the literature (see Xu G.; Wang. Y.G. Org. Left. 2004. 6, 985-987).


In Scheme E a cis/lrans mixture of 4-hydroxycyclohcxanc carboxylatc cslcr (20) is protected with a suitable protecting group, such as TBDPS (tertbutyldiphenylsilyi). to prepare (21) (see: Greene and Wuts, Protective Groups in Organic Synthesis. Third Edition. John Wiley and Sons Inc., 1999). lister (2!) is reacted with a base such as LDA. and then alkylated in a non-protic solvent (preferably THF) with bromoacctonilrile to form compound (22). Nitrile (22) is reduced and cyclized to afford (23) as described in the literature (see Rcddy, P.A.; Hsiang, B.C.H.; Latifi, T.N.; Hill, M.W.; Woodward K.E:.: Rothman, S.M.;Ferrendelli, J.A.; Covey, D.P.J. Med Chem. 1996,39, 1898-1906). Compound (23) is treated with a base (preferably NaH) and is alkylated with (9) to form (24) as a mixture of cis/trans isomers that arc separated by normal purification techniques.


In Scheme F, compound (24) is deprotected by a suitable method, such as using hydrogen with a catalyst, lo afford the phenol (25) which is reacted with triflic anhydride (trifluoromcthancsulfonic anhydride) and a base, for example pyridine to prepare (26). A coupling reaction is performed on (26) using a phenylboronic acid reagent and a catalyst, such as palladium tclrakistriphcnylphosphine lo prepare esler (27). Hydrolysis of (27) affords the protected acid (28) which is coupled with an amine using standard amide coupling conditions such as 1.1'-carbonyldiimidazole to afford alcohol (29) alter

dcprotection. The pure trans (or cis) alcohol (29) can be oxidized and reduced under standard conditions to produce a mixture of cis/trans alcohols (30) that arc separated using standard purification techniques.

In Scheme G, compound (31) is oxidized using standard conditions such as TEMPO (2,2,6,6-letramcthyl-l-piperidinyloxy) and NaOCI to prepare ketone (32). Racemic pyrazolc (33) is prepared by reacting ketone (32) stepwise wilh tcrt-butoxybis(dimcthylamino)niethanc and then hydrazine hydrate. The pure cnantiomcrs arc separated by chiral HPLC purification.
Preparation 1 3,5-dichloro-4-methylaniline
Dissolve I,3-dichIoro-2-mcthyl-5-nitrobenzenc (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydratc (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for I hour and dilute wilh ethyl acetate and filter through celilc. Wash the filtrate four times wilh water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography cluting with a gradient of 5% to 10% ethyl acetate in hexanes to give 342 mg (80%) of the titled product as white flakes.
Preparation 2 5-bromo-l,3-dichloro-2-mcthylbcnzenc Suspend the 3.5-dichloro-4-mcthylaniline in 48% HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 0°C with an ice/brine bath. Add a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL) dropwisc. After the addition is complete, stir

the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g. 7.53 mmol) in 48% MBr (2 mL) and heat the rapidly stirring reaction to 50°C for 1 hour. Cool the reaction to room temperature, dilute the reaction with ethyl acetate and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45%) of the product as a yellow solid.
Preparation 3 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene Heat a solution of 5-bromo-1,3-dichloro-2-methylbcnzcnc (97 mg. 0.40 mmol). N-bromosuccinimidc (76 mg. 0.425 mmol) and benzoyl peroxide (16 mg. 0.06 mmol) in CCL (5 mL) to reflux for 3 hours under N2. Cool the reaction to room temperature and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 1 12 mg (87%) of the product as white crystals.
Preparation 4 Tert-butyl-(3.5-dichloro-phenoxy)-dimethyl-silanc Dissolve 3,5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide and cool to 0°C. Add imidazole (918.74 g, 6.75 mol), followed by tertbutyldimethylsilyl chloride (1017.13g, 6.75 mol). Warm the mixture to room temperature and stir for 15 min. Pour into water (6 L) and extract with ether (4 L). Wash the organic layer with water 2 limes. 10% aqueous lithium chloride solution then brine before drying over sodium sulfate. Filter and concentrate under vacuum to 135 g of an oil.
Preparation 5 2,6-dichloro-4-hydroxy-bcnzaldchydc Dissolve tcrt-butyl-(3,5-dichloro-phenoxy)-dimcthyl-silane (425 g. 1.5 mol) in 4 L dry tetrahydrofuran and cool to -68°C. Slowly add 1.1 equivalents of sec-butyl lithium (103.1 g, 1.61 mol) at -68°C (-1.75 hr). After addition is complete, stir the reaction al -70°C for 30 min. Add dimethylformamide (168.5 g: 2.3 mol) and stir the reaction at -70°C for 1 hr. Add 1 M hydrochloric acid in water (3.5 L) and allow the reaction to warm to room temperature. Pour the reaction mixture into ether (5 L). wash with water

then brine. Dry over sodium sulfate and concentrate under vacuum to an orange solid. Triturate with cold dichloromethane and filler to recover 250 g (80 %) pale yellow solid.
Preparation 6
2,6-dichloro-4-benzyloxy-benzaldchyde
5 Treat a mixture of 2,6-dichloro-4-hydroxy-bcnzaldchydc (250 g. 1.3 mol) and
potassium carbonate (361.8 g, 2.62 mol) in 2 L dimethyiformamidc with benzyl bromide (268.64 g, 1.57 mol). Stir the reaction at room temperature for 1 hour. Filter off solids and pour into 12 L of water. Filter off solid, wash several times with water, air dry and dissolve in ethyl acetate. Dry over magnesium sulfate, filter and concentrate under 10 vacuum to ~1.5 L. Allow to sit overnight then filler. Wash solid with minimal amount of hexanc and vacuum dry. Concentrate the filtrate under vacuum and triturate with hcxanc to yield a second crop of product which when combined with the first crop equals 245 g white crystals. Repeal to obtain a third crop of 80 g as a light-tan powder (88% overall yield): 'H NMR (400 MHz, DMSO-d6) 5 10.26 (s, 1H), 7.43 (m, 5H), 7.28 (s, 2H). 5.25 15 (s, 2H).
Preparation 7 (2,6-dichloro-4-benzyloxy-phenyl)-methanol Treat a 0°C mixture of 2,6-dichloro-4-benzyloxy-benzaldchyde (245 g. 0.871 mol) in ethanol (3 L) with sodium borohydride (32.97 g, 0.897 mol). Warm the reaction to 20 room temperature and stir for 2 hours. Add the reaction mixture to saturated ammonium chloride (8L). Extract the mixture with CH2CI2 and dry the organic layer with Na2SO4-Remove the solvent in vacuo to afford 247 g (100%) of the titled product. 1H NMR (400 MHz, DMSO-d6) 5 7.38 (m, 4H), 7.33 (m, 1H), 7.12 (s, 2H), 5.14 (s, 2H), 5.05 (t, 1H), 4.59 (d, 2H).
25 Preparation 8
2-bromomethyI-],3-dichloro-5-bcnzyloxy-bcnzcnc Treat a 0°C solution of (2,6-dichloro-4-benzyloxy-phcnyl)-methanol (247 g. 0.872 mol) in THF (2.5 L) with phosphorous tribromidc (94.45 g. 0.35 mol) and stir for 30 minutes at 0°C under N2. Pour the reaction into saturated NaHCO3 and extract twice wilh 30 ethyl acetate. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 269 g (89%) of the titled product. ES MS (m/z): 346 (M+l).

Preparation 9 l-Cyanomethyl-cyclohexanccarboxylic acid methyl ester Treat a -78°C solution of methyl cyclohexane carboxylatc (15.0 g; 0.105 mol) in THF (150 mL) with a 2M solution of lithium diisopropylamidc in 5 heptane/THF/ethylbenzene (63.3 mL, 0.126 mol) and stiral-78°C for 20 minutes under N2. Treat the reaction with bromoacetonilrile (25.31 g, 0.211 mol) and stir at -78°C for 15 minutes. Warm the reaction to room temperature and stir 4 hours. Acidify the reaction with 1 N HO and then dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product. 10 Purify with a 0 to 30% ethyl acetate in hexanes gradient on silica gel to afford 7.78 g (41%) of the titled product. Rr= 0.32 (3/1 hexanes/ethyl acetate).
Preparation 10 2-Aza-spiro[4.5]decan-1-one A 0°C mixture an-cyanamcthyl-cyclohexanecarboxylic acid methyl ester (4.28 15 g, 23.6 mmol) and cobalt (II) chloride hexahydrate (2.8] g, M.8mmol) in THF (80 mL) and water (40 mL) is treated portion-wise with sodium borohydride (4.47 g, 0.1 18 mol) and is warmed to room temperature and stirred for 48 hours under N2. The reaction is treated with 28% ammonium hydroxide (3.1 mL) and filtered through hyflo. The solvent is removed from the filtrate in vacuo and the residue is diluted with minimal water and 20 brine and is extracted three times with 3:1 chloroform:isopropanol. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is purified with a 0 to 10% methanol in CH2CI2 gradient on silica gel to afford 1.95 g (54%) of the titled product. Rf= 0.46 (9/1 CH2CI2/methanol). MS (m/z): I54(M+).
Preparation 11
25 l-(2-Fluoro-ethyl)-piperazine bis trifluoroacetic acid salt
Heat a mixture of I-boc-piperazine (4.08 g, 21.9 mmol), l-bromo-2-fluoroethanc (16.68 g, 0.131 mol) and N,N-diisopropyl ethyl amine (17.0 g, 0.131 mol) in acctonitrile (40 mL) to 50°C for 16 hours and then heat to reflux for 7 additional hours. Cool the reaction to room temperature and remove the solvent in vacuo. Treat the residue with 1 N 30 NaOH (25 mL) and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and purify the crude product on silica with a 0 to 10% Methanol in CH2CI2 gradient to

afford 5.01 g (99%) of 4-(2-fluoro-ethyl)-piperazine-l-carboxylic acid tcrt-butyl cstcr (Rf = 0.36 (9/1 CH2CI2/Methanol, I2 stain).
Treat a solution of4-(2-fluoro-ethyl)-pipcrazine-l-carboxylic acid tert-butyl ester (2.0 g, 8.62 mmol) in CH2CI2 (20 mL) with TFA (10 mL) and stir at room temperature for 5 2 hours. Remove the solvent in vacuo to afford an oil and then add diethylcther. A solid precipitates to give a slurry which is filtered under a cone of N2. Dry on the filter to afford 2.73 g (88%) salt of the titled product. MS (m/z): 133 (M+).
Preparation 12
2-(4-Benzyloxy-2,6-dichloro-benzyl)-2-aza-spiro|4,5]decan-l-one
10 Treat a solution of 2-aza-spiro[4.5]decan-l-one (0.50 g, 3.26 mmol) in DMF (8
mL) with 60% sodium hydride (0.20 g, 5.0 mmol) and stir al room temperature for 20 minutes under N2. Cool the reaction to 0°C. treat with 2-bromoniclhyl-1.3-dichloro-5-benzyloxy-bcn/.cnc (1.24 g. 3.58 mmol). stir for 15 minutes al 0°C warm to room temperature, and stir for 2 hours under N2. Acidify the reaction with 1 NHCI. dilute the 15 reaction with diethyl ether, and then wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 1.23 g (90%) of the titled product. Rt -0.23 (3/1 ethyl acetate/hexanes). MS (m/z): 418 (M+).
Preparation 13
20 2-(2.6-Dichloro-4-hydroxy-benzyl)-2-aza-spiro[4.5]dccan-l-onc
Purge with N2 and H2 a mixture of 2-(4-benzyloxy-2,6-dichloro-bcnzyl)-2-aza-spiro[4.5]decan-l-one (1.18 g. 2.82 mmol) and 20% palladium (II) hydroxide on carbon (0.50 g) in ethyl acetate (100 mL) and stir under a balloon of H2 for 4 hours al room temperature. Add sodium sulfate to the mixture and filter through hyflo. Remove the 25 solvent in vacuo and purify the crude product on silica isocratically with 9:1
chloroformrmethyl l-butyl ether on silica gel to affort 0.72 g (78%) of the titled product. Rf= 0.18 (9:1 chloroform:methyl t-butyl ether).
Preparation 14
Trifluoro-methanesulfonic acid 3,5-dichloro-4-(l-oxo-2-aza-spiro[4.51dec-2-ylmelhy!)-
30 phenyl ester
Treat a 0°C solution of 2-(2,6-dichloro-4-hydroxy-bcnzyl)-2-aza-spiro|4.5|decan-1 -one (0.229 g, 0.38 mmol), pyridine (0.35 g, 4.42 mmol) and 4-dimcthylaminopyridinc

(0.027 g. 0.22 mmol) in CH2CI2 (20 mL) with trifluoromclhancsulfonic anhydride (0.87 g, 3.08 mmol) and stir for 1 hour at 0°C under N2. Dilute the reaction with CH2CI2and wash with 1N HCI and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo lo afford 0.83 g (82%) of the titled product. Rf = 0.54 (1/1 hexanes/cthyl 5 acetate). MS (m/z): 460 (M+).
Preparation 15 4-(lcrt-Bulyl-diphcnyl-silanyloxy)-cyclohexanecarboxylic acid elhyl ester Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylatc(21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl 10 chloride (37.39 g. 0.136 mol) and stir for 72 hours at room temperature. Dilute the
reaction with diethyl ether and wash wilh IN HCI and water. Dry the organic layer wilh
Na2SO4 and remove thc solvent in vacuo to afford crude product. Purify wilh a 0 lo 20%
elhyl acetatc in hexanes gradient on silica gel lo afford 40.4 g (80%) of the tilled product.
Rf= 0.49 and 0.29 (5/1 hcxanes/ethyl acetate).
15 Preparation 16
4-(tert-Butyl-diphenyl-silanyloxy)-l-cyanomcthyl-cyclohexanccarboxylic acid ethyl esler
Treal a -78°C solution of 4-(tert-butyl-diphenyl-silanyloxy)-cyclohexanecarboxylicacid elhyl esler (21.22 g, 51.7 mmol) in THF (200 mL) wilh a 2M solution of lithium diisopropylamide in heptane/THF/ethylbcnzcnc (31 mL, 62.0 mmol) 20 and stir at -78°C for 15 minutes under N2. Warm the reaction to -20°C and then re-cool to -78°C. Treat the reaclion with bromoacetonitrile (9.30 g, 77.5 mmol) and stir al -78°C for 1 hour. Warm the reaclion to room temperature and stir 1 hour. Acidify the reaction with 1 N HCI, dilute with ethyl acetate, and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product that is purified wilh a 0 25 to 20% ethyl acetate in hexanes gradient on silica gel to afford 10.96 g (47%) of the tilled product. Rf= 0.25 and 0.21 (5/1 hexanes/elhyl acetate). MS (m/z): 450 (M+).
Preparation 17 8-(tcrt-Bulyl-diphenyl-silanyloxy)-2-aza-spiro[4.5]decan-l-onc Treat a 0°C mixture of 4-(tert-butyl-diphcnyI-silanyloxy)-l-cyanomclhyl-30 cyclohexanecarboxylic acid elhyl ester (7.19 g. 15.9 mmol), cobalt (II) chloride
hexahydrate (1.90 g, 7.98 mmol) in THF (130 mL), and water (65 mL) porlion-wisc wilh sodium borohydridc (3.02 g. 7.98 mmol). Warm lo room temperature and stir for 16

hours under N2. Heat the reaction lo 50°C for 8 hours, cool lo room temperaturc and stir 16 hours under N2. Treat the reaction with 28% ammonium hydroxide (2 mL) and filler through hyflo. Remove the solvent from the filtrate in vacuo and dilute the residue with minimal water and brine and extract three times with 3:1 chloroform:rsopropanol. Dry 5 the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 10% methanol in CH2CI2 gradient on silica gel to afford 1.20 g (18%) of the tilled product. Rf= 0.48 and 0.61 (9/1 CH2CI2/melhanol). MS (m/z): 408 (Ml).
Preparation 18
cis/trans 2-(4-Bcnzyloxy-2,6-dichloro-benzyl)-8-(tert-butyl-diphenyl-silanyloxy)-2-aza-
10 spiro[4.5]decan-1 -one
Treat a solution of 8-(tert-butyl-diphenyl-silanyloxy)-2-aza-spiro[4.5]dccan-l-onc (2.37 g. 5.81 mmol) in DMF (25 mL) with 60% sodium hydride (0.35 g. 8.72 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction lo 0°C. treat with 5-bcnzyloxy-2-bromomclhyl-1.3-dichioro-benzcne (2.21 g. 6.39 mmol). stir for 15 minutes 15 at 0°C. warm lo room temperature, and stir for 4 hours under N2. Acidify the reaction with 1 N HCI. Dilute the reaction with diethyl elhcr and wash with water. Dry the .organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 2.96 g of isomer 1 (cis) Rf =0.46 (3/1 ethyl acetate/hexancs) and 0.236 g of isomer 2 (trans) Rr~ 20 0.37 (3/1 ethyl acetate/hexanes). MS (m/z): 672 (M+).
Preparation 19 trans 8-(tcrl-Butyl-diphenyl-silanyloxy)-2-(2,6-dichloro-4-hydroxy-bcnzyl)-2-aza-
spiro[4.5]dccan-1 -one Purge with N2 and H2 a mixture of isomer 2 (trans) 2-(4-bcnzyloxy-2,6-dichloro-25 benzyl)-8-(tert-bulyl-diphenyl-silanyloxy)-2-aza-spiro[4.5]decan-l-onc (0.236 g, 0.35 mmol) and 20% palladium (II) hydroxide on carbon (50 mg) in THF (25 mL) and ethyl acelatc(5 mL) and stir under a balloon of H2 for 16 hours al room temperature. Add sodium sulfate to the mixture and filter through hyflo. Remove the solvent in vacuo from the filtrate to afford 0.229 g (100%) of the titled product. Rf = 0.22 (1/1 ethyl 30 acetate/hexancs).

Preparation 20 Trifluoro-methancsulfonic acid trans-4-[8-(tert-butyl-diphenyl-silanyloxy)-l-oxo-2-aza-spiro[4.5]dec-2-ylmethyl]-3,5-dichloro-phenyl ester Treat a 0°C solution of 8-(tert-bulyl-diphenyl-si!anyloxy)-2-(2,6-dichloro-4-5 hydroxy-bcnzyI)-2-aza-spiro[4.5Jdecan-l-one (0.229 g, 0.38 mmol). pyridine (0.061 g, 0.77 mmol) and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) in CH2CI2(25 mL) with trifluoromcthanesulfonic anhydride (0.167 g, 0.59 mmol) and stir for 1 hour at 0°C under N2. Dilute the reaction with CH2CI2and wash with IN HCI and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 0.230 g (82%) of the titled 10 product. Rf= 0,29 (3/1 hexanes/ethyl acetate).
Preparation 21 trans 4'-| 8-(tcrt-Butyl-diphcnyl-silanyloxy)-!-oxo-2-aza-spiro|4.5|dcc-2-ylmcthyl|-3'.5'-dichloro-biphcnyl-4-carboxylic acid methyl estcr Purge with N2 a mixture of trifluoro-mcthanesulfonic acid 4-(8-(tcrt-butyl-15 diphcnyl-silanyloxy)-l-oxo-2-aza-spirof4.5]dec-2-ylmethyl]-3.5-dichloro-phcnyl ester (0.23 g, 0.31 mmol) and 4-methoxycarbonyl phenylboronic acid (0.068 g, 0.38 mmol) in THF (5 mL) and 2M sodium carbonate (0.5 mL). Treat the reaction with Pd(PPh3)4 (0.018 g, 0.015 mmol) and heal to 80°C for 90 minutes under N2. Cool the reaction, dilute with ethyl acetate, and wash with IN HCI and water. Dry the organic layer with 20 Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to
100% ethyl acetate in hexanes gradient on silica gel to afford 0.22 g (100%) of the titled product. Rf = 0.20 (3/1 hexancs/ethyl acetate). MS (m/z): 700 (M+).
Preparation 22
trans 4'-[8-(tert-Butyl-diphenyl-silanyloxy)-l-oxo-2-aza-spiro[4.5]dec-2-ylmcthyl]-3',5'-
25 dichloro-biphenyl-4-carboxylic acid
Treat a mixture Preparation 21 (0.22 g, 0.31 mmol) in THF (5 mL) and methanol
(0.5 ml.) with 2M lithium hydroxide (0.8 mL) and stir for 16 hours at room temperaturc.
Dilute the reaction with ethyl acetate and wash with IN HCI and water. Dry the organic
layer with Na2S04 and remove the solvent in vacuo to afford 0.185 g (86%) of the titled
30 product. Rf- = 0.H (1/1 hexanes/ethyl acetate). MS (m/z): 700 (M+).

Preparation 23 trans 8-(tcrt-Butyl-diphenyl-silanyloxy)-2-[3,5-dichloro-4-(4-trifluoromcthyl-piperidinc-1 -carbonyl)-biphenyl-4-ylmethyl]-2-aza-spiro[4.5Jdccan-1 -one Treat a solution of Preparation 22 (0.183 g, 0.27 mmol) in CH2CI2 (8 mL) with 5 1.1-carbonyldiimidazole (0.069 g, 0.43 mmol) and stir for 1 hour at room temperature under N2. Then, treat the reaction with 4-(trifluoromethyl)piperidine HCI (0.101 g. 0.53 mmol) and diisopropylethyl amine (0.14 g, 1.09 mmol) and stir for 16 hours at room temperature under N2. Dilute the reaction with ethyl acetate and wash with IN HCI and water. Dry the organic layer with Na2S04 and remove the solvent in vacuo to afford 10 crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.19 g (87%) of the titled product. Rr= 0.26 (1/1 hexanes/ethyl acetate). MS (m/z): 821 (M+).
Preparation 24
2-|3.5-Dichloro-4'-(4,4-difluoro-piperidinc-l-carbonyl)-biphcnyl-4-ylmclhyl|-2-aza-
15 spiro[4.5]decane-l,8-dionc
Combine a solution of cis-[3,5-dichloro-4'-(4,4-difluoro-piperidinc-1-carbonyl)-
biphcnyl-4-ylmcthyl]-8-hydroxy-2-aza-spiro|4.5]dccan-l-onc (0.582 g, 1.06 mmol) and
2,2,6,6-letramcthyl-l-piperidinyloxy (TEMPO) (0.013 g, 0.083 mmol) in CH2CI2 (30 mL)
with a solution of potassium bromide (0.010 g, 0.083 mmol) in water (5 ml.) and cool lo
20 0°C. Add a solution of 5.25% NaOCl (3 mL) and NaHCO3 (0.133 g. 1.58 mmol) to the
0°C reaction mixture and stir for 30 minutes. Dilute the reaction with ethyl acetate and
wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo lo
afford 0.5479 g (94%) of the titled product. Rf = 0.43 (100% ethyl acetate). MS (m/z):
549 (M+).
25 Preparation 25
cis 8-(tert-Butyl-diphenyl-silanyloxy)-2-(3,5-dichIoro-4'-nuoro-biphenyl-4-ylmelhyI)-2-
aza-spiro[4.5]dccan-l-onc Purge with N2 a mixture of trifluoro-methanesulfonic acid 4-|8-(tert-butyl-diphenyl-silanyloxy)-l-oxo-2-aza-spiro[4.5]dcc-2-ylmethyl]-3,5-dichloro-phenyl ester 30 (1.19 g, 1.63 mmol) and 4-fluorophenylboronic acid (0.27 g. 1.93 mmol) in THF (24 ml,) and 2M sodium carbonate (2.4 mL). Treat the reaclion with Pd(PPh3)4 (0.094 g. 0.081 mmol) and heat to 80°C for 90 minutes under N2. Cool the reaction and dilute with ethyl

acetate and wash with IN HCI and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 lo 100% ethyl acetate in hcxancs gradient on silica gel to afford 0.81 g (76%) of the titled product. Rf 0.47(3/1 hcxancs/clhyl acetate). MS (m/z): 700 (Ml).
Preparation 26 2-|3.5-Dichloro-4'-(4-lrifluoromethyl-pipcridinc-l-carbonyl)-biphcnyl-4-yImethyl|-2-aza-
spiro[4.5 ]dccanc-1,8-dionc A solution of cis 2-|3,5-dichloro-4'-(4-trifluoromethyl-pipcridinc-l-carbonyl)-biphcnyl-4-ylmclhyl]-8-hydroxy-2-aza-spiro[4.5]decan-l-one (0.232 g. 0.39 mmol) and 2.2.6,6-ictramcthyl-l-pipcridinyloxy (TEMPO) (0.005 g, 0.032 mmol) in CH2CI2 (12 mL) is combined with a solution of potassium bromide (0.004 g, 0.033 mmol) in water (2 ml,) and cooled lo 0°C. A solution of 5.25% NaOCI (1.13 ml.) and NaHCO.; (0.050 g. 0.59 mmol) is prepared and added to the 0 "C reaction mixture and the resultant mixture is stirred for 30 minutes. The reaction is diluted with ethyl acetate and washed with water. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is purified with silica using a 50 lo 100% gradient of ethyl acetate in hcxancs on silica gel lo afford 0.191 g (83%) of the titled product. Rf = 0.32 (100% ethyl acetate). MS (m/z): 549 (M+).
Example 1
2-(4-liromo-2.6-dichloro-bcn/.yl)-2-aza-spiro|"4.5"|dccan-l-onc

CI
Treat a solution of 2-aza-spiro[4.5|decan-l-one (0.138 g. 0.901 mmol) in DMF (5 mL) with 60% sodium hydride (0.054 g, 1.35 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0°C. treat with 5-bromo-2-(bromomcthyl)-1.3-dichlorobcnzcnc (0.316 g, 0.991 mmol). and slir for 15 minutes at 0°C. Warm lo room temperature and stir for 2 hours under N2. Acidify the reaction with I N HCI. Dilute with diethyl ether and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo lo afford crude product. Purify with a 0 lo 100% ethyl acetate in hcxancs gradient on silica gel to afford 0.258 g (73%) of the tilled product. Rf - 0.24 (3/1 ethyl acctatc/hcxancs). MS (m/z): 392 (M+).


Example 2 2-(3,5-Dichioro-4'-fluoro-biphcnyl-4-ylmclhyl)-2-aza-spiro|4.5|dccan-I-onc
Purged wilh N2 a mixture of 2-(4-brorno-2.6-diehloro-bcn/yl)-2-aza-5 spiro|4.5|dccan-|-one (0.091 g. 0.23 mmol) and 4-fluorophcnylboronic acid (0.097 g. 0.69 mmol) in toluene (6 mL) and 2M sodium carbonate (0.8 ml,). Treat the reaction with Pd(PPh3)4 (0.013 g: 0.011 mmol) and heat to 90°C for 2 hours under N2. Cool the -caction and dilute with ethyl acetate, and then wash with IN HC1 and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. 10 Purify with a 0 to 100% ethyl acetate in hexancs gradient on silica gel to afford 0.096 g (100%) of the titled product. Rf 0.25 (3/1 hcxanes/elhyl acetate). MS (m/z): 406 (M+).
3,.5'-Dichloro-4'-(l-oxo-2-aza-spirof4.5'|dcc-2-ylmethyl)-biphcnyl-4-carboxylic acid
methyl ester

Purge with N2 a mixture of 2-(4-bromo-2.6-dichloro-bcnzyl)-2-aza-spiro[4.5]decan-|-one (0.14 g; 0.36 mmol) and 4-melhoxycarbonyl phenylboronic acid (0.19 g. 1.05 mmol) in toluene (10 mL) and 2M sodium, carbonate (1.25 mL). Treat the reaction with Pd(PPh3)4 (0.04 i g, 0.035 mmol) and heat to 90°C for 4 hours under N2. 20 Cool the reaction and dilute with ethyl acetate, and then wash with IN HCI and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.102 g (64%) of the tilled product. Rf=0.51 (1/1 hcxanes/ethyl acetate). MS (m/z): 446 (M+).

Example4 3'.5'-Dichloro-4'-(l-oxo-2-a/.a-spiro|4.5|dcc-2-ylmethyl)-biphcnyl-4-carboxylic acid


OH
Treat a solution of Example 3 (0.087 g. 0.19 mmol) in methanol (10 ml.) with 5N 5 NaOM (0.60 mL) and stir at room temperature for 16 hours. Remove the solvent in vacuo to give a residue that is acidified with IN HCI. Dilute the mixture with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 0.086 g (100%) of the titled product. MS (m/z): 432 (M+).
Example 5 10 2-|3.5-Diehloro-4'-(4-trifluoromcthyl-pipcridine-l-carhonyl)-biphenyl-4-ylmethyl|-2-aza-

spiro[4.5[dccan-l-onc
Treat a solution of Example 4 (0.079 g, 0.18 mmol) in CH2CI2 (8 mL) with I. I '-carbonyldiimidazole (0.047 g. 0.29 mmol) and stir for I hour at room temperature under 15 N2. Then, treat the reaction with 4-(trifluoromclhyl)pipcridinc HCI (0.087 g. 0.46 mmol) and diisopropylethylamine (0.12 g, 0.92 mmol) and stir for 16 hours at room temperature under N2. Dilute the reaction with ethyl acetate and wash with IN HCI and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with a 0 to 10% methanol in CH2CI2 gradient on silica gel and then 20 isocratically with 50/50 ethyl acctale/hexanes gradient on silica gel to afford 0.067 g (64%) of the titled product. Rf - 0.68 (9/1 CH2Cl2/methanol). MS (m/z): 567 (M 1).
Example 6 2-{3.5-Dichloro-4'-|4-(2-fluoro-ethyl)-piperazinc-]-carbonyl|-biphcnyl-4-ylmcthyl|-2-
aza-spiro[ 4.5 ]decan-1 -one


Prepare Kxamplc 6 csscnlially by the method described in Kxamplc 3 using Kxamplc 4 and l-(2-fluoro-cthyl)-pipcrazine bis trifluoroacctic acid salt. Purification on silica gel affords 0.153 gofthe titled product. Rf=0.42 (9:1 CH2CI2:methanol). MS (m/z):546(M+).
Example 7 2-(2,6-Dichloro-4-morpholin-4-yl-bcnzyl)-2-aza-spiro|4.5|dccan-l-onc

Heat a solution of trifluoro-methanesulfonic acid 3.5-dichloro-4-( l-oxo-2-aza-10 spiro|4.5|dcc-2-ylmcthyl)-phenyl ester (0.15 g. 0.32 mmol) and morpholinc (0.099 g. 1.13 mmol) in l-mcthyl-2-pyrrolidine (2.5 ml) to 201 °C for 1.5 hours in a microwave reactor. Cool the reaction to room temperature and treat with 2M LiOH(1 ml.) and stir 16 hours at room temperature. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude I 5 product. Purify on silica isocralicaily using 5% methyl t-butyl ether in chloroform to afford 0.064 g (50%) of the titled product. Rf = 0.22 (9:1 chtoroform:mcthyl t-butyl ether). MS (m/z): 397 (M+).
Example 8
trans 2-|3,5-Dichloro-4'-(4-trifluoromethyl-piperidinc-l-carbonyl)-biphenyl-4-ylmcthyl]-
20 8-hydroxy-2-aza-spiro|4.5]decan-1 -one

Treat a mixture of 8-(terl-butyi-diphcnyl-silanyloxy)-2-|3.5-dichloro-4'-(4-tiinuoromclhyl-pipcridinc-l-carbonyl)-biphcnyl-4-ylmcthyl|-2-aza-spiro|4.5|dccan-l-onc

(0.19 g. 0.23 mmol) in THF (6 ml.) and water (3 ml.) wilh trifluoroacclic acid (2 ml,) and heal to reflux and stir for 2 hours under N2. Cool the reaction and dilute with ethyl acclalc and wash wilh water and saturated NaHCO3. Dry the organic layer wilh Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 50 to 100% ethyl acetate in hcxancs gradient on silica gel lo afford 0.89 g (57%) of the tilled product. Rt 0.09 (100% ethyl acetate). MS (m/z): 583 (M+).
Example 9 cis 2-|3;5-Dichloro-4'-(4-trif1uoromcthyl-piperidine-l-carbonyl)-biphcnyl-4-ylmelhyl|-8-

Prepare Kxamplc 9 essentially by the method described in Example 8 using isomer 1 (cis) 2-{4-bcn/.yloxy-2.6-dichloro-bcn/.yl)-8-(tert-bulyl-diphcnyl-silanyloxy)-2-aza-spiro|4.5|decan-l-one which affords 0.185 g of the titled product. Rf=0.15 (100% ethyl acetate). MS (m/z): 583 (M+).
Kxamplc 10
cis -|3.5-Diehloro-4'-(4.4-difluoro-pipcridinc-l-carbonyl)-biphcnyl-4-ylmclhvl|-8-
hydroxy-2-aza-spiro|4.5]dccan-1 -one
Prepare Example 10 essentially by the method described in Kxamplc 8 using isomer I (cis) 2-(4-benzyloxy-2.6-dichloro-bcnzyl)-8-(tcrt-butyl-diphenyl-silanyloxy)-2-aza-spiro|4.5|decan-l-one and 4.4-difluoropipcridinc HCI. Purification on silica gel affords 0.64 gofthc titled product. R,- = 0.14 (100% ethyl acetate). MS (m/z): 551 (Ml).
Examplc 11
trans-|3.5-Dichloro-4'-(4,4-difluoro-piperidinc-l-carbonyl)-biphcnyl-4-ylmethyl|-8-
hydroxy-2-aza-spiro|4.5|dccan-l-onc




15

Treat a 0°C solution of2-[3.5-dichloro-4'-(4.4-dinuoro-pipcridinc-l-carbonyl)-biphcnyl-4-ylmclhyl]-2-aza-spiro|4.5]dccanc-1,8-dionc (0.386 g. 0.70 mmol) in methanol (10 mL) with sodium borohydride (0.040 g, 1.06 mmol) and stir for 30 minutes at 0°C. Acidify the reaction with IN HCI, dilute with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford a mixture of cisitrans isomers. Purify on silica using a 50 to 100% gradient of ethyl acetate in hcxanes on si lica gel to afford 0.073 g (19%) of the titled product. Rf = 0.13 (100% ethyl acetate). VIS(m/z): 551 (M+).
Example 12 cis 2-|3;5-Dichloro-4'fluoro-biphcnyl-4-ylmethyl|-8-hydroxy-2-aza-spiro[4.5]decan-1-

Prepare Examplc 12 essentially by the method described in Example 8 using 8-(lcrt-bulyl-diphcnyl-silanyloxy)-2-(3,5-dichloro-4'-fluoro-biphcnyl-4-ylmcthyl)-2-aza-spiroj4.5jdccan-|-onc which affords 0.44 g of the titled product. Rf 0.22 (100% ethyl acetate). MS (m/z): 422 (M+).
Example 13






20

Treat a solution of 2-|3.5-dichloro-4'-(4-trifluoromcthyl-pipcridinc-l-carbonyl)-biphcnyl-4-ylmethyl|-2-aza-spiro|4.5|decanc-1.8-dione (0.160 g. 0.27 mmol) in toluene (4 mL) with tcrl-buloxybis(dimclhylamino)mcthanc (0.062 g, 0.36 mmol) and heat to 90°C and stir for 2.5 hours under N2. Cool the reaction, remove the solvent in vacuo lo

alford an oil. and dissolve the oil in methanol (3ml,). Add hydrazine hydrate (0.015 g. 0.31 mmol) and stir the reaction at room temperature for 16 hours under N2 Remove the solvent in vacuo to afford an oil and then dissolve in ethyl acetate. Extract the organic layer with water, dry with Na2SO4, and remove the solvent to afford crude product. Purify with silica gel using a 0 to 10% gradient of methanol in CH2CI2 to afford 0.109 g (66%) of the titled product. Rr = 0.40 (9/1 CH2CI2/mcthanol). MS (m/z): 605 (M I).
Example 14

Prepare Example 14 essentially by the method described in Example 13 using cis-2-{3.5--dichloro-4-floro-biphcnyl-4-ylmclhyl)-8-hydroxy-2-aza-spiro|4.5|decan-l-one which affords 0.319 g of the tilled product. Rf 0.39 (9/1 CH2CI2/mclhanoI). MS (m/z): 444 (M+).
Examples 15 and 16

Separate Example 14 into the enanliomcrs by chiral HPEC (Chiralcel OD 8 x 35 cm column, isocratic 50:50 3A cthanol:hcptane with 0.2% dimethylethylaminc. 400 mE/min. UV 260 nm) to afford 120 mg of enantiomcr I (97.0% ce) and 96 mg of enantiomcr 2 (95.6% ee). Analytical HPLC: Chiralcel OD-H 4.6 x 150 mm column, isocratic 50:50 3A ethanol:heptane with 0.2% dimclhylethylamine, 0.6 mL/min. UV 250 nm, isomer 1 elutes 5.5 minutes, isomer 2 elutes 6.6 minutes. ES MS (m/z): 444 (M+).
Example 15 = Isomer 1.
Example 16 = Isomer 2.
Examples 17 and 18


Separate Example 13 into the enantiomers by chiral HPLC (Chiralpak AD 5 x 33 cm column, isocratic 60:40 3 A clhanohhcplanc with 0.2% dimclhylclhylaminc. ! 50 mL/min. UV 270 nm) to afford 32 mg of enanliomcr 1 (>99% ee) and 28 mg of 5 cnantiomer 2 (98.2% cc). Analytical HPLC: Chiralpak AD-H 4.6 x 150 mm column, isocratic 60:40 3A ethanol:hcptanc with 0.2% dimcthylcthylaminc. 0.6 mL/min. UV 270 nm. isomer 1 elutes 1 i .6 minutes, isomer 2 clules 14.7 minutes. IvS MS (m/z): 605 (M i).
Example 17 _ Isomer 1.
Example I8 Isomer 2. 10
In the following section enzyme and functional assays arc described which arc useful for evaluating the compounds of the invention. 11β-HSD type 1 enzyme assay
1 luman 11 β-HSD type 1 activity is measured by assaying NADPH production by 15 fluorescence assay. Solid compounds are dissolved in DMSO lo a concentration of 10 mM. Twenty microliters of each are then transferred to a column of a 96-well polypropylene Nunc plate where they are further diluted 50-fold followed by subsequent two-fold titration, ten times across the plate with additional DMSO using a Tccan Genesis 200 automated system. Plates are then transferred to a Tccan Freedom 200 system with 20 an attached Tecan Temo 96-wcll head and an Ultra 384 plate reader. Reagents are
supplied in 96-well polypropylene Nunc plates and are dispensed individually into black 96-wcll Molecular Devices High Efficiency assay plates (40 μL/ well capacity) in the following fashion: 9 μL/well of substrate (2.22 mM NADP, 55.5 ΜM Cortisol, 10 mM Tris. 0.25% Prionex, 0.1 % Triton XI00), 3 μL/well of water to compound wells or 3 μl. 25 lo conlrol and standard wells. 6 μL/well recombinant human 11β-HSD type I enzyme. 2 μL/well of compound dilutions, For ultimate calculation of percent inhibition, a series of wells are added that represent assay minimum and maximum: one set containing substrate with 667 μM carbenoxolonc (background), and another set containing substrate and

enzyme without compound (maximum signal). Pinal DMSO concentration is 0.5% for all compounds, controls and standards. Plates arc then placed on a shaker by the robotic arm of the Tccan for 15 seconds before being covered and stacked for a three hour incubation period at room temperature. Upon completion of this incubation, the Tccan robotic arm 5 removes each plate individually from the stacker and places them in position for addition of 5 μ/well of a 250 μM carbenoxolone solution to slop the enzymatic reaction. Plates are then shaken once more for 15 seconds then placed into an Ultra 384 microplatc reader (355BX/460EM) for detection of NADPH fluorescence.
Data for example compounds in the 11-βHSDl assay arc shown below:


Compounds of the invention can also tested for selectivity against 11-βHSD2 in an assay similar to that described for 11-βHSDl, but using the 11-βHSD2 enzyme. The assay using the 11-βHSD2 enzyme can be carried out by the methods described herein and supplemented by methods known in the art. 15
Human aortic smooth muscle cell assay
Primary human aortic smooth muscle cells (AoSMC) arc cultured in 5% FIBS growth medium lo a passage number of 6, then pelleted by centrifugation and resuspended at a density of 9x104 cclls/mL in 0.5% FBS assay medium containing 12 20 ng/mL hTNFa lo induce expression of 11β-HSDI. Cells arc seeded into 96-wcll lissue culture assay plates al 100 μL/wcll (9x 103 cells/well) and incubated for 48 hours al 37°C.

5% CO2. Following induction, cells are incubated for 4 hours at 37 C. 5% CO2 in assay medium containing test compounds then treated with 10 μL/well of 10 μM cortisone solubilized in assay medium, and incubated for 16 hours at 37 C. 5% CO2 Medium from each well is transferred to a plate for subsequent analysis of Cortisol using a competitive fluorescence resonance lime resolved immunoassay. In solution, an allophycocyanin (APC)-cortisoI conjugate and free Cortisol analyte compete for binding to a mouse anti-corlisol antibody/Europium (Eu)-anli mouse IgG complex. Higher levels of free Cortisol result in diminishing energy transfer from the Europium-lgG to the APC-cortisol complex resulting in less APC fluorescence. Fluorescent intensities for Europium and APC are measured using a LJL Analyst AD. Europium and APC excitation is measured using 360 nm excitation and 615 nm and 650 nm emission filters respectively. Time resolved parameters for Luropuium were 1000 us integration lime with a 200 μs delay. APC parameters arc set at 150 μs integration time with a 50 us delay. Fluorescent intensities measured for APC arc modified by dividing by the Eu fluorescence (APC/Fu). This ratio is then used to determine the unknown Cortisol concentration by interpolation using a Cortisol standard curve fitted with a 4-parameler logistic equation. These concentrations arc then used to determine compound activity by plotting concentration versus % inhibition, fitting with a 4-paramclcr curve and reporting the IC50.
All of the examples disclosed herein demonstrate activity in the human aortic smooth muscle cell assay with IC50 ofless than 500 nM. Preferred examples demonstrate activity in the human aortic smooth muscle cell assay with IC50 of less than 300 nM. Data for example compounds in the human aortic smooth muscle cell assay arc shown below;



Acute In Vivo Cortisone Conversion Assay
In general, compounds are dosed orally into mice, the mice arc challenged with a subcutaneous injection of cortisone at a set timepoint after compound injection, and the blood of each animal is collected some time later. Separated scrum is then isolated and analyzed for levels of cortisone and Cortisol by I.C-MS/MS. followed by calculation of mean Cortisol and percent inhibition of each dosing group. Specifically, male C57BI./6 mice arc obtained from Harlan Sprague Dawley at average weight of 25 grams, lixact weights arc taken upon arrival and the mice randomized into groups of similar weights. Compounds arc prepared in 1% w-w HFC, 0.25%) w-vv polysorbate 80, 0.05% w-w Dow Corning.antifoam // 510-US at various doses based on assumed average weight of 25 grams. Compounds are dosed orally, 200 μl per animal, followed by a subcutaneous dose, 200 ul per animal, of 30 mg/kg cortisone at 1 to 24 hours post compound dose. At 10 minutes post cortisone challenge, each animal is euthanized for 1 minute in a CO2 chamber, followed by blood collection via cardiac puncture into scrum separator tubes. Once fully clotted, tubes are spun at 2500 x g. 4°C for 15 minutes, the serum transferred to wells of 96-well plates (Corning Inc. Costar #4410, cluster tubes, 1.2 ml, polypropylene), and the plates arc frozen at-20°C until analysis by LC-MS/MS. For analysis, scrum samples arc thawed and the proteins arc precipitated by the addition of acctonilrilc containing d4-cortisol internal standard. Samples arc vortex mixed and centrifuged. The supernatant is removed and dried under a stream of warm nitrogen. Extracls arc reconstituted in mcthanol/watcr (1:1) and injected onto the l.C-MS/MS system. The levels of cortisone and Cortisol arc assayed by selective reaction monitoring mode following positive ACPI ionization on a triple quadrupolc mass spectrophotometer.


Data for example compounds in the acute in vivo cortisone conversion assay arc shown below:
Pharmaceutically acceptable salts and common methodology for preparing them 5 arc well known in the art. See. e.g., P. Stahl, el al..HANDBOOK OF
PHARMACEUTICAL SALTS: PROPERTIES. SELECTION AND USE. (VCHA/Wiley-VCH. 2002); S.M. Berge, et al., "Pharmaceutical Salts." Journal of Pharmaceutical Sciences. Vol. 66, No. 1, January 1977. The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a 10 variety of routes. Most preferably, such compositions are for oral administration. Sueh pharmaceutical compositions and processes for preparing same are well known in the ail. See. e.g.. REMINGTON: THE SCIENCE AND PRACTICE OP PHARMACY (A.
Gennaro. ef al., eds., 19 ed., Mack Publishing Co., 1995).
The particular dosage of a compound of formula (1) or a pharmaceutical!)'
15 acceptable salt thereof required to constitute an effective amount according to this
invention will depend upon the particular circumstances of the conditions to be treated. Considerations such as dosage, route of administration, and frequency of dosing arc best decided by the attending physician. Generally, accepted and effective dose ranges for oral or parenteral administration will be from about 0.1 mg/kg/day to about 10 mg/kg/day
20 which translates into about 6 mg to 600 mg. and more typically between 30 mg and 200 mg for human patients. Such dosages will be administered lo a patient in need of

treatment from one to three times each day or as often as needed to effectively treat a disease selected from those described herein.
One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the 5 compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. (Remington's Pharmaceutical Sciences. 18th Edition, Mack Publishing Co. (1990)). The compounds claimed herein can be administered by a variety of routes. In effecting trcatment of a patient afflicted with or at risk of developing the disorders described herein, a compound of formula (I) or a 10 pharmaceutically acceptable salt thereof can be administered in anv form or mode that makes the compound bioavailable in an effective amount, including oral and parenteral routes, For example, the active compounds can be administered rectally. orallv. bv inhalation, or by the subcutaneous, intramuscular, intravenous, transdermal, intranasal. rectal', occular. topical', subungual', buccal', or other routes. Oral administration may be 15 preferred for treatment of the disorders described herein in those instances where oral
administration is impossible or not preferred, the composition may be made available in a form suitable for parenteral administration, e.g.. intravenous, intraperitoneal or intramuscular.

X 17378 EPO National Stage Entry Amendments ,W 9.4.08
We Claim:
1. A compound structurally represented by the formula:

or a pharmaceutical ly acceptable salt thereof, wherein
Rais-H or-OH;
Rbis-H;or
Ra and R combine with the cyclohexyl ring to which they are attached to form
; wherein the asterisk represents the carbon atom shared with the
lactam ring;
R1 is -H, -halogen, -O-CH3 (optionally substituted with one to three halogens), or
-CH3 (optionally substituted with one to three halogens);
R2 is -H, -halogen, -O-CH3 (optionally substituted with one to three halogens), or
-CH3 (optionally substituted with one to three halogens);
R3 is-H or-halogen:
R4 is
-OH, -halogen, -CN, -(C1-C4)alkyl(optionally substituted with one to three halogens), -(C1-C6)alkoxy(optionally substituted with one to three halogens), -SCF3, -C(O)O(C1-C4)aIkyl, -O-CH2-C(O)NH2, -(C3-C8)cycloalkyl, -O-phenyl-C(O)O-(C1-C4)alkyl, -CH2-phenyl,
-NHSO2-(C1-C4)alkyl,-NHSO2-phenyl(R21XR2l)) -(C1-C4)alkyl-C(O)N(R10)(R11),

X 17378 EPO National Stage Entry Amendments LW 9.4.08

R5 is

, wherein the dashed line represents the point of attachment to the R4 position;

-H, -halogen, -OH, -CN, -(C1-C4)alkyl(optionally substituted with 1 to 3 halogens), -C(O)OH, -C(O)O-(C1-C4)alkyl, -C(O)-(C1-C4)alkyl, -O-(C1-C4)alkyl(optionally substituted with 1 to 3 halogens), -SO2-(C1-C4)alkyl, -N(R8)(R8), -phenyl(R2l)(R21), -C(O)-NH-(C3-C6)cycloalkyl,





X 17378 EPO National Stage Entry Amendments N.W 9.4.08

wherein the dashed
line represents the point of attachment to the position indicated by R5;
wherein m is 1, 2, or 3;
wherein n is 0. 1, or 2, and wherein when n is 0, then "(CH2) n" is a bond; R6is
-H, -halogen, -CN, or -(C1-C4)aIkyl(optionally substituted with 1 to 3
halogens); R7 is
-H, -halogen, or -(C1-C4)alkyl(optionally substituted with 1 to 3
halogens); R8 is independently at each occurrence -H or -(C1-C6)alkyl(optionally substituted with 1 to 3 halogens); R9 is -H or -halogen; R10 and R11 are each independently
-H or -(C1-C4)alkyl, or R10 and R11 taken together with the nitrogen to
which they are attached form piperidinyl, piperazinyl, or pyrrolidinyl; R20 is independently at each occurrence -H, or -(C1-C3)alkyl(optionalIy substituted
with 1 to 3 halogens); R21 is independently at each occurrence -H, -halogen, or -(C1-C3)alkyl(optionally
substituted with 1 to 3 halogens);

X 17378 EPO National Stage Entry Amendments LW 9.4.08
R22 is independently at each occurrence -H or -(C1-C6)alkyl(optionally substituted
with 1 to 3 halogens); and R" is independently at each occurrence -H, -(C1-C4)alkyl(optionally substituted
with ] to 3 halogens), or -C(O)O-(C1-C4)alkyl.
2. A compound of Claim 1 wherein Ra and Rb are hydrogen, or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 1 wherein Ra is -OH and Rb is hydrogen, or a pharmaceutically acceptable salt thereof.
4. A compound of Claim 1 wherein Ra and Rb combine with the cyclohexyl ring to


which they are attached to form

wherein the asterisk represents the

carbon atom shared with the lactam ring, or a pharmaceutically acceptable salt
thereof.
A compound as claimed in any of Claims 1 to 4 wherein R is -chlorine and R is
-chlorine, and R3 is -H, or a pharmaceutically acceptable salt thereof.


6. A compound as claimed in any of Claims 1 to 5, wherein R4 is


or a pharmaceutically acceptable salt thereof.


7. A compound as claimed in any of Claims 1 to 5, wherein R4 is
R6 is -H, or a pharmaceutically acceptable salt thereof.

X17378 EPO National Stage Entry Amendments LW 9.4.08

8. A compound as claimed by Claim 6 or 7 wherein R5 is

, wherein R8 is -(C1-C3)alkyl (optionally substituted
with 1 to 3 halogens), or , or a pharmaceutically acceptable salt
thereof.



9. A compound as claimed by Claim 6 or 7 wherein R5 is pharmaceutically acceptable salt thereof.
10. A compound as claimed by Claim 6 or 7 wherein R5 is
pharmaceutically acceptable salt thereof.


wherein R8 is
11 A compound as claimed by Claim 6 of 7, wherein R5
-(C1-C3)alkyl (optionally substituted with 1 to 3 halogens), or a pharmaceutically acceptable salt thereof.
12. A compound as claimed by Claim 6 or 7 wherein R5 is chlorine or fluorine, or a pharmaceutically acceptable salt thereof.
13. A compound that is 2-[3.5-Dichloro-4'-(4-trifluoromethyl-piperidine-l-carbonyl)-biphenyl-4-ylmethyl]-2-aza-spiro[4.5]decan-l-one or a pharmaceutically acceptable salt thereof.

X 17378 EPO National Stage Entry Amendments LW 9.4.08
14. A compound that is 2-{3,5-Dichloro-4'-[4-(2-fluoro-ethyl)-piperazine-l-carbonyl]-biphenyl-4-ylmethyl}-2-aza-spiro[4.5]decan-I-one or a pharmaceutically acceptable salt thereof.
15. A compound of Claim 1 selected from the group consisting of: 2-(4-Bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-l-one; 2-(3.5-DichIoro-4'-fluoro-biphenyl-4-ylmethyl)-2-aza-spiro[4.5]decan-l-one; 3,,5'-Dichloro-4'-(l-oxo-2-aza-spiro[4.5]dec-2-ylmethyl)-biphenyl-4-carboxylic acid methyl ester;
3',5'-Dichloro-4'-(1-oxo-2-aza-spiro[4.5]dec-2-ylmethyl)-bipheny l-4-carboxyl ic
acid;
2-[3.5-Dichloro-4'-(4-trifluoromethyl-piperidine-I-carbonyI)-biphenyl-4-
ylmethyl]-2-aza-spiro[4.5]decan-l-one;
2-{3,5-Dichloro-4'-[4-(2-fluoro-ethyl)-piperazine-l-carbonyl]-biphenyl-4-
yl methyl }-2-aza-spiro[4.5]decan-1 -one;
2-(2.6-Dichloro-4-morpholin-4-yl-benzyl)-2-aza-spiro[4.5]decan-l-one;
trans 2-[3.5-Dichloro-4'-(4-trifluoromethyl-piperidine-l-carbonyl)-biphenyl-4-
ylmethyl]-8-hydroxy-2-aza-spiro[4.5]decan-l-one;
cis 2-[3,5-Dichloro-4'-(4-trifluoromethyl-piperidine-l-carbonyl)-biphenyl-4-
ylmethyl]-8-hydroxy-2-aza-spiro[4.5]decan-I-one;
cis -[3)5-Dichloro-4'-(4,4-difluoro-piperidine-l-carbonyI)-biphenyl-4-yImethyl]-
8-hydroxy-2-aza-spiro[4.5]decan-l-one;
trans-[3,5-Dichloro-4'-(4,4-difluoro-piperidine-l-carbonyl)-biphenyl-4-ylmethyl]-
8-hydroxy-2-aza-spiro[4.5]decan-l-one;
cis 2-(3,5-Dichloro-4'-fIuoro-biphenyl-4-ylmethyl)-8-hydroxy-2-aza-
spiro[4.5]decan-I-one;


X17378 EPO National Stage Entry Amendments W 9.4.08

or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises a compound as claimed by any one of Claims 1 through 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. A compound as claimed by any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in therapy.
18. A compound as claimed by any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament.
19. An intermediate for preparing a compound of claim 13 wherein the intermediate



Dated this the 22nd day of October, 2008


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abstract1.jpg


Patent Number 247899
Indian Patent Application Number 2249/MUMNP/2008
PG Journal Number 22/2011
Publication Date 03-Jun-2011
Grant Date 31-May-2011
Date of Filing 22-Oct-2008
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA 46285,
Inventors:
# Inventor's Name Inventor's Address
1 THOMAS EDWARD MABRY 10624 ORCHARD WAY, INDIANAPOLIS, INDIANA 46280, USA.
2 YANPING XU 6676 PENNAN COURT, NOBLESVILLE, INDIANA 46062, USA.
3 OWEN BRENDAN WALLACE 13297 MINK LANE, WESTFIELD, INDIANA 46074, USA.
4 NANCY JUNE SYNDER 3830 WEST 850 NORTH, LIZTON, INDIANA 46149, USA.
5 LEONARD LARRY WINNEROSKI , JUNIOR 587 THOROUGHBRED LANE, GREENWOOD, INDIANA 46142, USA
PCT International Classification Number C07D209/44
PCT International Application Number PCT/US2007/067350
PCT International Filing date 2007-04-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/745,574 2006-04-25 U.S.A.