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WO2009117109A1 - Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 - Google Patents

Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 Download PDF

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Publication number
WO2009117109A1
WO2009117109A1 PCT/US2009/001712 US2009001712W WO2009117109A1 WO 2009117109 A1 WO2009117109 A1 WO 2009117109A1 US 2009001712 W US2009001712 W US 2009001712W WO 2009117109 A1 WO2009117109 A1 WO 2009117109A1
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Prior art keywords
halo
alkyl
alkoxy
bond
alkylamino
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PCT/US2009/001712
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French (fr)
Inventor
David A. Claremon
Linghang Zhuang
Yuanjie Ye
Suresh B. Singh
Colin M. Tice
Gerard Mcgeehan
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Vitae Pharmaceuticals LLC
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Vitae Pharmaceuticals LLC
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Priority to US12/933,027 priority Critical patent/US20110105504A1/en
Priority to EP09722738.3A priority patent/EP2274287B1/en
Priority to JP2011500805A priority patent/JP5538356B2/en
Priority to CA2718264A priority patent/CA2718264A1/en
Publication of WO2009117109A1 publication Critical patent/WO2009117109A1/en
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Definitions

  • the present invention relates to inhibitors of 1 l ⁇ -hydroxy steroid dehydrogenase type 1 (1 l ⁇ -HSDl), pharmaceutical compositions thereof and methods of using the same.
  • Glucocorticoids such as Cortisol (hydrocortisone) are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
  • Cortisol hydrocortisone
  • glucocorticoid action was attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues.
  • HPA hypothalamic-pituitary-adrenal
  • glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes.
  • 1 1 ⁇ - hydroxysteroid dehydrogenase (1 1 ⁇ -HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones.
  • 1 l ⁇ -HSDl also known as 11-beta-HSD type 1, l lbetaHSDl, HSDI lBl, and HSDI lL
  • l l ⁇ -HSD2 also known as 11-beta-HSD type 1, l lbetaHSDl, HSDI lBl, and HSDI lL
  • 1 l ⁇ -HSDl is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 1 1-keto forms
  • 1 l ⁇ -HSD2 is a unidirectional dehydrogenase that inactivates biologically active Cortisol by converting it into cortisone.
  • the two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles.
  • 1 l ⁇ -HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium.
  • increased Cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity.
  • 1 1 ⁇ -HSDl may regulate intraocular pressure and may contribute to glaucoma; some data suggests that inhibition of 1 l ⁇ -HSDl may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevtsev, et al, (1997), Proc. Nat'l Acad. Sci. USA 94(26): 14924-9).
  • 1 l ⁇ -HSDl catalyzes both 11 -beta-dehydrogenation and the reverse 11- oxoreduction reaction
  • 1 l ⁇ -HSDl acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active Cortisol from inert cortisone (Low, et al, (1994) J. MoI. Endocrin. 13: 167-174).
  • 1 l ⁇ - HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines.
  • 11 ⁇ -HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston, et al., (1994) MoI. Cell. Endocrin. 105: Rl 1-R17), and has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active Cortisol) (Blum, et al., (2003) Prog. Nucl. Acid Res. MoI. Biol. 75:173-216).
  • Mutations in either the 1 l ⁇ -HSDl or the 1 l ⁇ -HSD2 genes result in human pathology.
  • individuals with mutations in 1 l ⁇ -HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as "SAME") characterized by hypertension, hypokalemia, and sodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, et al, (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205).
  • SAME apparent mineralocorticoid excess
  • H6PD cortisone reductase deficiency
  • PCOS polycystic ovary syndrome
  • adipocyte 1 l ⁇ -HSDl activity plays a central role in visceral obesity and metabolic syndrome (Alberts, et al, (2002) Diabetologia. 45(11), 1526-32).
  • Over-expression in adipose tissue of 11 ⁇ -HSDl under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki, et al, (2001) Science 294, 2166-2170; Masuzaki, et al, (2003) J. Clinical Invest. 112, 83- 90).
  • HSDl contributes to increased local conversion of cortisone to Cortisol in adipose tissue and hence that 1 l ⁇ -HSDl plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al, (2004) Obes. Res. 12: 9-17). Therefore, 1 l ⁇ -HSDl is a promising pharmaceutical target for the treatment of the metabolic syndrome (Masuzaki, et al, (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore, inhibition of 1 l ⁇ -HSDl activity may prove beneficial in treating numerous glucocorticoid-related disorders.
  • 11 ⁇ - HSDl inhibitors could be effective in combating obesity and/or other aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev, et al, (1997) Proc. Nat'l Acad. Sci. 94, 14924-14929; Morton, et al, (2001) J. Biol. Chem. 276, 41293- 41300; Morton, et al, (2004) Diabetes 53, 931 -938).
  • inhibition of 1 l ⁇ - HSDl activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel & Sutter, (1979) Horm. Metab. Res. 1 1,
  • inhibition of 1 l ⁇ -HSDl may reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression.
  • glucocorticoids and 1 1 ⁇ -HSDl play a role in regulation of in intra-ocular pressure (IOP) (Stokes, et al, (2000) Invest. Ophthalmol. Vis. Sci. 41 : 1629-1683; Rauz, et al, (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037- 2042).
  • IOP intra-ocular pressure
  • Transgenic aP2-l l ⁇ -HSDl mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Additionally, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone. Treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki, et al,
  • 1 l ⁇ -HSDl inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders.
  • Glucocorticoids can have adverse effects on skeletal tissues, and prolonged exposure to even moderate glucocorticoid doses can result in osteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81, 3441-3447).
  • 1 l ⁇ -HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper, et al, (2000) Bone 27: 375-381), and the 1 l ⁇ -HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone 23: 119-125).
  • inhibition of 1 l ⁇ -HSDl is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.
  • novel compounds of the present invention are effective inhibitors of 1 l ⁇ -HSDl .
  • the present invention provides compounds of Formula I:
  • R 2 is (Ci-Ce)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 - C 4 )alkynyl, halo(C,-
  • R 3 is selected from (C 2 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (Ci-C 3 )alkoxy(Ci- C3)alkyl, wherein the (C 2 -C 6 )alkyl is substituted with, and each of the (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl is optionally substituted with, up to four groups independently selected from fluorine, cyano, oxo, halo(Ci-C 6 )alkyl, amino(Ci- C 6 )alkyl, (Ci-C 6 )alkylamino(Ci-C 6 )alkyl, di(C 1 -C 6 )alkylamino(Ci-C 6 )alkyl, hydroxy(C
  • R 4 is independently selected from H, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, amino(Ci-C 6 )alkyl, (Ci-C 6 )alkylamino(Ci-C 6 )alkyl, di(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, hydroxy(C
  • Q O, NR 5 ; and R 5 is H, (d-C 6 )alkyl, halo(Ci-C 6 )alkyl or hydroxy(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl J hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 - C 4 )alkynyl, hal
  • Cy 2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-Ce)alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(Ci-C 6 )
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof , and a pharmaceutically acceptable carrier or diluent, wherein the values for the variables are as described above for the compounds of Formula I.
  • the present invention further provides a method of inhibiting 11 ⁇ -HSDl activity, comprising administering to a mammal in need thereof an effective amount of a disclosed 11 ⁇ -HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the values for the variables are as described above for the compounds of Formula I.
  • Also included in the present invention is a method of treating a disease or disorder associated with activity or expression of 1 l ⁇ -HSDl, comprising administering to a mammal in need thereof an effective amount of a a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the values for the variables are as described above for the compounds of
  • Also included in the present invention is the use of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting 1 l ⁇ -HSDl activity in a mammal in need of such treatment.
  • a disclosed 11 ⁇ -HSDl inhibitor including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or disorder related to the activity or expression of 1 l ⁇ -HSDl , inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity in a mammal in need thereof, modulating 1 l ⁇ -HSDl activity in a mammal in need thereof, and/or inhibiting 11 ⁇ -HSD 1 in a mammal in need thereof.
  • Also included in the present invention is a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in inhibiting 1 l ⁇ -HSDl activity in a mammal in need of such treatment.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy, e.g., treating a disease or disorder associated with activity or expression of 11 ⁇ -HSD 1 in a subject.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by
  • R 1 is absent.
  • R 1 is unsubstitued or substituted (Ci-C 6 )alkyl, wherein the substituents are as described above.
  • R 1 is unsubstituted or substitued methyl or ethyl, wherein the substituents are as described above.
  • R 1 is unsubstituted methyl or ethyl.
  • a 1 is a bond.
  • a 1 is (Ci-C 3 )alkylene.
  • a 1 is methylene.
  • Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C]-C 6 )alkyl, hydroxy(Ci- C 5 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 - C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 - C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C r C 6 )alkyl,
  • Cy 1 is optionally substituted aryl or optionally substituted heteroaryl, wherein the substituents are as described above.
  • Cy 1 is optionally substituted phenyl or optionally substituted pyridyl, wherein the substituents are as described above.
  • Cy 1 is optionally substituted phenyl, wherein the substituents are as described above.
  • Cy 1 is optionally substituted monocyclic cycloalkyl, wherein the substituents are as described above.
  • Cy 1 is optionally substituted cyclohexyl, wherein the substituents are as described above.
  • Cy 1 is substituted with fluorine, chlorine, bromine, methoxy, difluoromethoxy, methoxycarbonyl, carboxy, methyl, or trifluoromethyl.
  • a 2 is (a) a bond, O, S or NR 4 ; or (b) (Ci-C 3 )alkylene or (Ci-C 2 )alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo.
  • a 2 is a bond.
  • Cy 2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(C]-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6
  • Cy 2 is hydrogen.
  • Cy 2 is optionally substituted aryl or heteroaryl, wherein the substituents are as described above.
  • Cy 2 is optionally substituted cycloalkyl or heterocyclyl, wherein the substituents are as described above.
  • Cy 2 is optionally substituted phenyl or pyridyl, wherein the substituents are as described above.
  • Cy 2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine.
  • Cy 2 is difluorophenyl or monofluorophenyl.
  • Cy 2 is l,2-dihydro-2-oxopyridyl or l,2-dihydro-l-methyl-2-oxopyridyl.
  • Cy 2 is cyclopropyl.
  • Y is (Ci-C 6 )alkyl or halo(C,-C 6 )alkyl.
  • n is 0, 1 or 2.
  • E is (a) a bond or (b) (C]-C3)alkylene or (Ci-C 2 )alkylenyloxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo.
  • E is a bond or alkylene.
  • E is a bond.
  • R 2 is (C)-C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -
  • C 7 cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(d-C 5 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C)-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 - C 7 )cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C 3 -Ce)cycloalkoxy, halo(C 4 - C 7 )cycloalkylalkoxy, (C 2
  • R 2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the substituents are as described above; or R 2 is (Ci-C 6 )alkyl substiuted with up to 4 groups independently selected from fluorine, cyano, nitro, amino, carboxy, (C]-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo((C
  • R 2 is optionally substituted (Ci-C 6 )alkyl, wherein the substituents are as described above; or R 2 is aryl, heteroaryl, cycloalkyl or heterocyclyl substituted with up to 4 groups independently selected from fluorine, bromine, iodine, cyano, amino, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo((C
  • R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, wherein the substituents are as described above.
  • R 2 is (a) isopropyl or (b) selected from optionally substituted phenyl, optionally substituted pyridyl and optionally substituted thienyl, wherein the substituents are as described above.
  • R 2 is optionally substituted phenyl, wherein the substituents are as described above.
  • R 2 is fluorophenyl.
  • R 3 is selected from (C 2 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 1 - C3)alkoxy(Ci-C 3 )alkyl, wherein the (C 2 -C 6 )alkyl is substituted with, and each of the (C 2 - C6)alkenyl, (C 2 -C 6 )alkynyl and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl is optionally substituted with, up to four groups independently selected from fluorine, cyano, oxo, halo(Cj-C 6 )alkyl, amino(C i -C 6 )alkyl, (C i -C 6 )alkylamino(C i -C 6 )alkyl, di(C i -C 6 )alky lamino(C i -C 6 )
  • R 3 is substituted (C 2 -C6)alkyl, wherein the substituents are as described above.
  • R 3 is hydroxy(C 2 -C 5 )alkyl.
  • R 3 is dihydroxy(C 3 -C 5 )alkyl.
  • R 3 is ⁇ -H 2 NCO(C ! -C 3 )alkyl.
  • R 3 is (Ci-C 2 )alkoxy(Ci-C 3 )alkyl.
  • R 3 is H 2 NS ⁇ 2 ⁇ (C 2 -C 4 )alkyl.
  • R 3 is H 2 NSO 2 NH(C 2 -C 4 )alkyl.
  • R 3 is oxo(C 2 -C 4 )alkyl.
  • R 3 is 2-hydroxy-2-methylpropyl.
  • R 3 is 2-(4-morpholino)ethyl.
  • R 3 is MeSO 2 NH(C 2 -C 4 )alkyl.
  • R 3 is MeSO 2 NHCH 2 CH 2 CH 2 -.
  • R 4 is independently selected from H, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, amino(Ci- C 6 )alkyl, (Ci-C 6 )alkylamino(Ci-C 6 )alkyl, di(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, hydroxy(Ci- C 6 )alkyl and (Ci-C 6 )alkoxy(C r C 6 )alkyl.
  • Q O, NR 5 .
  • Q is O.
  • Q is NR 5 .
  • Q is NH.
  • R 5 is H, (C,-C 6 )alkyl, halo(Ci-C 6 )alkyl or hydroxy(C,-C 6 )alkyl.
  • G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 - C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C r C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 - C7)cycloalkylalkyl, (Ci-C 6 )alkoxy, (C 3 -C6)cycloalkoxy, (C 4 -C7)cycloalkylalkoxy, halo(Ci
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by Structural Formula Ib:
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by Structural Formula Ic:
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by Structural Formula Id: wherein:
  • X is fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(Ci- C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (d-C 6 )alkoxy, (C 3 - C6)cycloalkoxy, (C 4 -C7)cycloalkylalkoxy, halo(Ci-
  • G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl s (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 - C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(Ci-C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 - C7)cycloalkylalkyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy,
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by Structural Formula If:
  • G 1 and G 2 are each independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 - C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(Ci-C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 - C 7 )cycloalkylalkyl, (C)-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy ; (C 4 -C 7 )cycloal
  • 1 l ⁇ -HSDl inhibitors of the invention are represented by Structural Formula Ig:
  • G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C]-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(Ci-C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalky
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, provided that if Q is NR 5 , A 1 is methylene, R 1 is absent, Cy 1 is optionally substituted phenyl, A 2 is a bond, Cy 2 is hydrogen, E is a bond and R 2 is optionally substituted phenyl, then R 3 is not hydroxyethyl or hydroxypropyl.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, provided that: if A 1 is optionally substituted methylene and A 2 is a bond, then Cy 2 is not ortho to the ring atom of Cy 1 that is bonded to A 1 , and Cy 1 is not substituted with an optionally substituted amine or aminomethyl group at a ring atom ortho to the ring atom of Cy 1 that is bonded to A 1 ; if Q is NR 5 and R 3 is (C 2 -C ⁇ )alkyl substituted with one to three groups independently selected from fluorine, halo(Ci-Ce)alkyl, hydroxy and hydroxy(Ci- C 6 )alkyl, then (a)
  • R 2 is optionally substituted heteroaryl, cycloalkyl or heterocyclyl; and if Q is NR 5 and E-R 2 is (a) (Ci-C 6 )alkyl optionally substituted with one to three groups independently selected from fluorine, chlorine, bromine, iodine, hydroxy, (Ci- C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, or (b) benzyl, then R 3 is (a) (C 2 - C 6 )alkyl substituted up to four groups independently selected from cyano, oxo, amino(C i-C 6 )alkyl, (C i -C 6 )alkylamino(C i -C 5 )alkyl, di(C i -C 5 )alkylamino(C i -C 5 )alkyl, (C,-C 6
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is (Ci-C 3 )alkylene or (C
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the tenth embodiment apply, further provided that if E is a bond, then R 2 is optionally substituted (d-C 6 )alkyl.
  • the 1 1 ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply, further provided that if E is a bond, then R 2 is optionally substituted (C)-C 6 )alkyl.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the tenth embodiment apply, further provided that if E is a bond, and R 2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, then the optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl represented by R 2 is not substituted with heteroaryl, amine or aminomethyl at a ring atom ortho to the ring atom of R 2 that is bonded to E.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply, further provided that if E is a bond, and R 2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, then the optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl represented by R 2 is not substituted with heteroaryl, amine or aminomethyl at a ring atom ortho to the ring atom of R 2 that is bonded to E.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is a bond or alkylene, and wherein the provisos in the tenth embodiment apply.
  • the 1 l ⁇ -HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is a bond or alkylene, and wherein the provisos in the ninth and the tenth embodiments apply.
  • Specific 11 ⁇ -HSDl inhibitors of the invention and pharmaceutically acceptable salts thereof are provided in Examples 1-3 and Prophetic Examples la-221a and Ib- 221b below.
  • alkyl used alone or as part of a larger moiety such as “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, “alkylamine”, “dialkyamine”, “alkoxycarbonyl” or “alkylaminocarbonyl”, means a saturated straight or branched hydrocarbon radical having (unless otherwise specified) 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • cycloalkyl means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, spiro [4.4]nonane, adamantyl and the like.
  • aryl means means a 6-10 membered carbocyclic aromatic monocyclic or polycyclic ring system, such as phenyl or naphthyl.
  • aryl may be used interchangeably with the terms “aryl ring” “aromatic ring”, “aryl group” and “aromatic group”.
  • Heteroaromatic group used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, means a 5-10 membered monovalent monocyclic and polycylic aromatic group radical containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • Heteroaryl groups include f ⁇ ryl, thienyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl
  • heterocyclic group means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S, and include pyrrolidine, pyrrolidin-2-one, 1 -methylpyrrolidin- 2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1 - (2,2,2-trifluoroethyl)piperazine, 1 ,2-dihydro-2-oxopyridine, 1 ,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3
  • ring atom is an atom such as C, N, O or S that is in the ring of an aryl group, heteroaryl group, cycloalkyl group or heterocyclic group.
  • a "substitutable ring atom" in an aryl, heteroaryl cycloalkyl or heterocyclic is a carbon or nitrogen atom in the aryl, heteroaryl, cycloalkyl or heterocyclic group that is bonded to at least one hydrogen atom.
  • the hydrogen(s) can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring carbon or nitrogen atoms when the structure depicts that they are not attached to any hydrogen atoms.
  • Suitable substituents for an alkyl, aryl, heteroaryl and heterocyclic group are those which do not significantly reduce the ability of the compound to inhibit the activity of 1 l ⁇ -HSDl .
  • suitable substituents for an alkyl, aryl, heteroaryl and heterocyclyl include fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C 3 -Ce)cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 5 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalky
  • Preferred substituents an alkyl, aryl, heteroaryl and heterocyclyl include, unless otherwise specified, halogen, (Ci- C 6 )alkyl, hydroxy, (C,-C 6 )alkoxy, (d-C 6 )alkylamino, di(Ci-C 6 )alkylamino, NO 2 , CN, CONH 2 , halo(Ci-C 6 )akyl or halo(Ci-C 6 )alkoxy.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,
  • the compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate
  • Salts of the disclosed 1 l ⁇ -HSDl inhibitors containing an acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'- dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'- bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and
  • the invention also includes various isomers and mixtures thereof.
  • “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). Certain of the disclosed 1 l ⁇ -HSDl inhibitors may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
  • Enantiomer means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
  • the symbol “*” in a structural formula represents the presence of a chiral carbon center.
  • R and “S” represent the configuration of substituents around one or more chiral carbon atoms.
  • “/?*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enatiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • a single geometric isomer e.g., a geometric isomer with a double bond
  • the compound is considered to be at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% steroechemically pure by weight.
  • Percent stereochemically purity by weight is the ratio of the weight of the geometric isomer over the weight of the both geometric isomers. For example, 99% stereochemically pure means that at least 99% by weight of the compound is the indicated stereoisomer.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I and Ia-Ig, comprise a pharmaceutically acceptable salt of a compound of Formulae I and Ia-Ig, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
  • Effective amount means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated.
  • the effective amount of a compound of the invention in such a therapeutic method is from about 0.01 mg/kg/day to about 10 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day.
  • “Inhibiting 1 l ⁇ -HSDl” means to decrease the activity of the 1 l ⁇ -HSDl enzyme.
  • “Modulating 11 ⁇ -HSD 1” means to impact the activity of the 11 ⁇ -HSD 1 enzyme by altering its natural activity. Modulation can be analogous to inhibition when a disease or disorder relating to the activity 1 l ⁇ -HSDl would be effectively treated by suppressing the activity of the enzyme.
  • “Pharmaceutically acceptable carrier” means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.
  • Treatment includes prophylactic and therapeutic treatment.
  • Therapeutic treatment includes partially or totally inhibiting, delaying, or reducing the severity of the disease or disorder related to 11 ⁇ -HSD 1.
  • Prophylactic treatment encompasses administration of a compound of the invention to a subject susceptible to a disease or disorder related to the activity or expression of 1 l ⁇ -HSDl in an effort to reduce the likelihood of a subject developing the disease or disorder, or slowing or preventing progression of the disease.
  • Prophylactic treatment includes suppression (partially or completely) of the disease or disorder, and further includes reducing the severity of the disease or disorder, if onset occurs.
  • Prophylactic treatment is particularly advantageous for administration to mammals at risk for developing a disease or disorder related to 11 ⁇ -HSD 1.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered intranasally or transdermally.
  • dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
  • pharmaceutically acceptable carriers can either be solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersable granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.
  • the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about one to about seventy percent of the active ingredient.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluose, a low melting wax, cocoa butter, and the like. Tablets, powders, cachets, lozenges, fast-melt strips, capsules and pills can be used as solid dosage forms containing the active ingredient suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active ingredient is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing , and thickening agents as desired.
  • Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • the pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of, for example, tablets, powders, and capsules in vials or ampules. Also, the unit dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be the appropriate amount of any of these in packaged form.
  • the quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from about 0.1 mg to about 100 mg.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill in the art.
  • the pharmaceutical composition may contain, if desired, other compatible therapeutic agents.
  • the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.
  • the compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state.
  • the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, metabolic syndrome, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety and Alzheimer's disease, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility.
  • compounds modulate the function of B and T cells of the immune system.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I and Ia-Ig, comprise a pharmaceutically acceptable salt of a compound of Formulae I and Ia-Ig, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
  • the invention includes a therapeutic method for treating or ameliorating an 11 ⁇ - HSDl mediated disorder in a mammal in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formulae I and Ia-Ig, or the enantiomers, diastereomers, or salts thereof or composition thereof.
  • the compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state.
  • the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility and hypergonadism.
  • the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients.
  • Additional diseases or disorders that are related to 1 l ⁇ -HSDl activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X.
  • mammal is preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • the disclosed 1 l ⁇ -HSDl inhibitors can be used alone or in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.
  • Agents for the treatment of diabetes include insulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase® (glyburide, Pfizer), and Glucotrol®/Glucotrol XL
  • Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates and ezetimibe.
  • Agents for the treatment of hypertension include ⁇ - blockers, ⁇ -blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin- receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist.
  • Agents for the treatment of obesity include orlistat, phentermine, sibutramine and rimonabant.
  • An embodiment of the invention includes administering an 1 l ⁇ -HSDl inhibiting compound of any one of Structural Formulae I and Ia-Ig or composition thereof in a combination therapy with one or more other 1 l ⁇ -HSDl inhibitors (whether such inhibitors are also compounds of any one of Structural Formulae I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); Janumet® (sitagliptin and metformin, Merck)and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).
  • Avandamet® metalformin HCl and rosiglitazone maleate, GSK
  • Compounds of Formula I can be prepared by several processes.
  • a 1 , A 2 , Cy 1 , Cy 2 , E, Q, R 1 , R 2 , R 3 , R 5 , Y, and n have the meanings indicated above unless otherwise noted.
  • the synthetic intermediates and final products of Formula I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M.
  • compounds of Formula I can be prepared by reaction of intermediates of Formula II with reagents of Formula III, wherein Z 1 and Z 2 are leaving groups such as chloride, 1 -imidazolyl or aryloxide, in an inert solvent such as THF,
  • reagent III is especially convenient because they are commercially available.
  • III is phosgene.
  • Z 1 and Z 2 are both 1-imidazolyl
  • III is carbonyl diimidazole.
  • Z 1 is chloride and Z 2 is p- nitrophenoxide
  • III is p-nitrophenyl chloroformate.
  • Z 1 and Z 2 are both OCCl 3
  • III is triphosgene and as little as one third of molar equivalent can be used.
  • ⁇ -Hydroxyacids of Formula V can be prepared by diazotization of ⁇ -amino acids of Formula VII using NaNO 2 in H 2 SO 4 :
  • a hydride reagent such as BH 3 THF solution, BH 3 .Me 2 S or LiAlH 4 in an ethereal solvent such as THF or DME
  • Amine intermediates of Formula VI wherein A 1 is a bond, R 1 is absent and Cy 1 is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula XII via oximes of Formula XIII or by reductive animation of ketones of Formula XII with ammonia:
  • Amine intermediates of Formula VI, wherein A 1 is CH can be prepared from ketones of Formula XIV by reductive amination with ammonia.
  • Amine intermediates of Formula VI, wherein A 1 is CH can be prepared from alcohols of Formula XV via azides of Formula XVI.
  • the conversion of alcohols of Formula XV to azides of Formula XVI can be accomplished with, for example, diphenylphosphoryl azide.
  • Reduction of azides of Formula XVI to amines of Formula VII can be effected, for example, by hydrogenation in the presence of a palladium catalyst or by reaction with triphenylphosphine in wet THF.
  • Amine intermediates of Formula VI, wherein A 1 is CH can be prepared by reaction of sulfinyl imine intermediates of Formula XVII with organometallic reagents of Formula XVIII, wherein M is Li, MgCl 5 MgBr or MgI, followed by treatment with acid to remove the t-butylsulfinyl group.
  • Sulfinyl imines of Formula XVII can be prepared by treatment of aldehyde intermediates of Formula XVIII with 2-methylpropane-2-sulfmamide.
  • Epoxide compounds of formula XIX can, in turn, be prepared in a number of ways including those described in Aube, J. "Epoxidation and Related Processes” Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis” Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992).
  • Intermediates of Formula II, wherein A 1 is CH 2 and R 1 is absent, can be prepared by reduction of amide intermediates of formula XX using a hydride reagent such as BH 3 .THF solution, BH 3 Me 2 S or LiAlH 4 in an inert solvent ethereal such as THF or DME at 20 0 C to 100 0 C for between 1 h and 48 h:
  • a hydride reagent such as BH 3 .THF solution, BH 3 Me 2 S or LiAlH 4 in an inert solvent ethereal such as THF or DME
  • Amide intermediates of Formula XX can be prepared by reaction of an amines of
  • Carbamate intermediates of Formula XXV can be prepared by reaction of amines of Formula VI with chloroformates of Formula XXVI in the presence of a base such as pyridine or triethylamine in an inert solvent such as CH 2 Cl 2 or THF at 0 0 C to 25 0 C for between 1 h and 24 h:
  • a base such as pyridine or triethylamine
  • an inert solvent such as CH 2 Cl 2 or THF
  • a compound of Formula I can be prepared from another compound of Formula I.
  • a compound of Formula I can be prepared from another compound of Formula I.
  • a compound of Formula I can be prepared from another compound of Formula I.
  • a compound of Formula I wherein Cy 1 is substituted with bromine or iodine, A 2 is a bond and Cy 2 is hydrogen can be reacted with an optionally substituted aryl or heteroarylboronic acid or ester in the presence of a palladium catalyst to give a compound of Formula I wherein A 2 is a bond and Cy 2 is optionally substituted aryl or heteroaryl.
  • a compound of Formula I wherein R 1 or R 3 is ⁇ -hydroxy(C 2 -C 6 )alkyl can be oxidized to a compound of Formula I wherein R 1 or R 3 is ⁇ -carboxy(Ci-Cs)alkyl using Jones reagent.
  • a compound of Formula I wherein R 1 or R 3 is ⁇ -hydroxy(Ci-C 6 )alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I, wherein R 1 or R is ⁇ -amino(Ci- C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(Ci-C 6 )alkyl can be reacted with acetic anhydride or acetyl chloride to give a compound of Formula I wherein R 1 or R 3 is ⁇ acetylamino ⁇ (Ci-C6)alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(Ci-C 6 )alkyl can be reacted with an (Ci-C6)alkyl isocyanate to give a compound of Formula I wherein R 1 or R 3 is (Ci-C 6 )alkylaminocarbonylamino(Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(Ci-C 6 )alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I wherein R 1 or R 3 is aminosulfonylamino(Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(C)-C6)alkyl can be reacted with a (Ci-C6)alkylsulfamoyl chloride to give a compound of Formula I wherein R 1 or R 3 is (Ci-C 6 )alkylaminosulfonylamino(Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is hydroxy(d-C 6 )alkyl can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I wherein R 1 or R 3 is aminosulfonyloxy(Ci-C6)alkyl.
  • a compound of Formula I wherein R 1 or R 3 is hydroxy(Ci-C6)alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (Ci-C6)alkylamine or a di(C 1 -C 6 )alkylamine to give a compound of Formula I wherein R 1 or R 3 is aminocarboxy(Ci-C 6 )alkyl, (Ci- C 6 )alkyl aminocarboxy(Ci-C6)alkyl or di(Ci-C 6 )alkyl aminocarboxy(Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 3 is MeO 2 C(C i-C 5 )alkyl can be treated with MeMgBr to afford a compound of Formula I wherein R 3 is Me 2 (HO)C(C ⁇ -Cs)alkyl.
  • a compound of Formula I wherein R 1 or R 3 is ⁇ -H 2 NCO(C)-C 5 )alkyl can be reacted with TFAA in the presence of pyridine to afford a compound of Formula I wherein R 1 or R 3 is ⁇ -cyano(Ci-C 5 )alkyl.
  • a compound of Formula I wherein R 3 is ⁇ -hydroxy(Ci-C 6 )alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with a (C 1 - C ⁇ )alkylthiol followed by oxidation with m-CPBA to give a compound of Formula I wherein R 3 is (Ci-C 6 )alkylsulfonyl(Ci-C 6 )alkyl.
  • a compound of Formula I, wherein Q is NH can be reacted with sodium hydride and methyl iodide in an inert solvent to give a compound of Formula I, wherein Q is NMe.
  • Step 2 To a solution of crude (S)-2-(l-(4-bromophenyl)ethylamino)-l-phenylethanone (1 g, 3.15 mmol) in THF (20 mL) was added (2-methylallyl)magnesium chloride (10 mL, 1 mol/L) at -78 0 C. The mixture was stirred at rt for 1 h, and TLC showed disappearance of the starting material. The mixture was quenched with satd aq NH 4 Cl and extracted with EtOAc.
  • Step 4 To a solution of 3-((5)-l-(4-bromophenyl)-ethyl)-5-(2-methylallyl)-5- phenyloxazolidin-2-one (700 mg, 1.75 mmol) in dry CH 2 Cl 2 (100 mL) was added m- CPBA (1.5 g, 8.75 mmol) at rt. The reaction mixture was stirred until the starting material had been consumed (monitored by TLC).
  • Step 5 To a solution of 3-((S>l-(4-bromophenyl)-ethyl)-5-((2-methyloxiran-2- yl)methyl)-5- phenyloxazolidin-2-one (650 mg, 1.57 mmol) in THF (32 mL) was added dropwise Super-Hydride (13.6 mL, 13.6 mmol) at 0 0 C under N 2 over 30 min, and the resulting solution was stirred at 10 ⁇ 13°C for 4 h. To the mixture was added dropwise H 2 O 2 (20 mL), diluted with (CH 3 ) 3 COCH 3 (380 mL), washed with water, followed by addition of 30% aq Na 2 S 2 O 3 and brine. The organic phase was dried over Na 2 SO 4 and filtered. The filtrate was concentrated to give the crude product, which was purified by prep TLC to afford the the two isomers of the title compound:
  • the assay begins by dispensing 49 ⁇ l of substrate solution (5OmM HEPES 3 pH 7.4, 10OmM KCl, 5mM NaCl, 2mM MgCl 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)) and mixing in 1 ⁇ L of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 ⁇ L of enzyme solution containing microsomes isolated from CHO cells overexpressing human 1 l ⁇ -HSDl (10-20 ⁇ g/ml of total protein) was added, and the plates were incubated for 90 minutes at room temperature.
  • substrate solution 5OmM HEPES 3 pH 7.4, 10OmM KCl, 5mM NaCl, 2mM MgCl 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)
  • the reaction was stopped by adding 50 ⁇ l of the SPA beads suspension containing 10 ⁇ M 18 ⁇ - glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 ⁇ g/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad).
  • the plates were shaken for 120 minutes at room temperature, and the SPA signal corresponding to [ 3 H]cortisol was measured on a Microbeta plate reader.
  • the inhibition of 1 l ⁇ -HSDl by compounds of this invention was measured in whole cells as follows.
  • Cells for the assay were obtained from two sources: fully differentiated human omental adipocytes from Zen-Bio, Inc.; and human omental pre- adipocytes from Lonza Group Ltd.
  • Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchased in 96-well plates and were used in the assay at least two weeks after differentiation from precursor preadipocytes.
  • Zen-Bio induced differentiation of pre- adipocytes by supplementing medium with adipogenic and lipogenic hormones (human insulin, dexamethasone, isobutylmethylxanthine and PPAR-gamma agonist).
  • the cells were maintained in full adipocyte medium (DMEM/Ham's F- 12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B, supplied by Zen- Bio, Inc.) at 37 0 C, 5% CO 2 .
  • DMEM/Ham's F- 12 (1:1, v/v)
  • HEPES pH 7.4 fetal bovine serum
  • penicillin streptomycin
  • Amphotericin B supplied by Zen- Bio, Inc.
  • Pre-adipocytes were purchased from Lonza Group Ltd. and placed in culture in Preadipocyte Growth Medium-2 supplemented with fetal bovine serum, penicillin, and streptomycin (supplied by Lonza) at 37 0 C, 5% CO 2 .
  • Pre-adipocytes were differentiated by the addition of insulin, dexamethasone, indomethacin and isobutyl-methylxanthine (supplied by Lonza) to the Preadipocyte Growth Medium-2. Cells were exposed to the differentiating factors for 7 days, at which point the cells were differentiated and ready for the assay. One day before running the assay, the differentiated omental adipocytes were transferred into serum- and phenol-red- free medium for overnight incubation.
  • the assay was performed in a total volume of 200 ⁇ L.
  • the cells were pre-incubated with serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSO and various concentrations of the test compounds at least 1 h before [ 3 H] cortisone in ethanol (50Ci/mmol, ARC, Inc.) was added to achieve a final concentration of cortisone of 100 nM.
  • the cells were incubated for 3-4 hrs at 37 0 C, 5% CO 2 . Negative controls were incubated without radioactive substrate and received the same amount of [ 3 H] cortisone at the end of the incubation.
  • Example 1 Isomer 1 nt nt Example 1 Isomer 2 nt nt Example 2 Isomer 1 ++ 78.3 Example 2 Isomer 2 # 16.9 Example 3 Isomer 1 ++ 91.4 Example 3 Isomer 2 # 19.1 Example 4 Isomer 1 nt nt Example 4 Isomer 2 nt nt Example 5 Isomer 1 H- 51.9 Example 5 Isomer 2 # 3.4 Example 6 Isomer 1 # 18.4 Example 6 Isomer 2 # 19.8 Example 7 5.4
  • nt means not tested.
  • Cy 1 1 ,3-(4-F)C 6 H 3 means 2,6-(5-Cl)-pyridyl means

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Abstract

This invention relates to novel compounds of the Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals.

Description

INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
RELATED APPLICATIONS The application claims the benefit of U.S. Provisional Application No.
61/037,646, filed March 18, 2008, the entire teachings of which are incorporated herein by reference.
FIELD OF THE INVENTION The present invention relates to inhibitors of 1 lβ-hydroxy steroid dehydrogenase type 1 (1 lβ-HSDl), pharmaceutical compositions thereof and methods of using the same.
BACKGROUND OF THE INVENTION Glucocorticoids, such as Cortisol (hydrocortisone), are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
Until recently, the major determinants of glucocorticoid action were attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 1 1 β- hydroxysteroid dehydrogenase (1 1 β-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 1 lβ-HSDl (also known as 11-beta-HSD type 1, l lbetaHSDl, HSDI lBl, and HSDI lL) and l lβ-HSD2. 1 lβ-HSDl is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 1 1-keto forms, whereas 1 lβ-HSD2 is a unidirectional dehydrogenase that inactivates biologically active Cortisol by converting it into cortisone.
The two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles. 1 lβ-HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium. In adipose tissue, increased Cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity. In the eye, 1 1 β-HSDl may regulate intraocular pressure and may contribute to glaucoma; some data suggests that inhibition of 1 lβ-HSDl may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevtsev, et al, (1997), Proc. Nat'l Acad. Sci. USA 94(26): 14924-9). Although 1 lβ-HSDl catalyzes both 11 -beta-dehydrogenation and the reverse 11- oxoreduction reaction, 1 lβ-HSDl acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active Cortisol from inert cortisone (Low, et al, (1994) J. MoI. Endocrin. 13: 167-174). In contrast, 1 lβ- HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines. 11 β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston, et al., (1994) MoI. Cell. Endocrin. 105: Rl 1-R17), and has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active Cortisol) (Blum, et al., (2003) Prog. Nucl. Acid Res. MoI. Biol. 75:173-216).
Mutations in either the 1 lβ-HSDl or the 1 lβ-HSD2 genes result in human pathology. For example, individuals with mutations in 1 lβ-HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as "SAME") characterized by hypertension, hypokalemia, and sodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, et al, (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205). Similarly, mutations in 1 lβ- HSDl and in the gene encoding a co-localized NADPH-generating enzyme, hexose 6- phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD); these individuals present with ACTH-mediated androgen excess (hirsutism, menstrual irregularity, hyperandrogenism), a phenotype resembling polycystic ovary syndrome (PCOS) (Draper, et al, (2003) Nat. Genet. 34: 434-439). Notably, disruption of homeostasis in the HPA axis by either deficient or excess secretion or action results in Cushing's syndrome or Addison's disease, respectively (Miller & Chrousos, Endocrinology and Metabolism (Felig & Frohman eds., McGraw- Hill: New York, 4th Ed. (2001)) 387-524). Patients with Cushing's syndrome or receiving glucocorticoid therapy develop reversible visceral fat obesity. The phenotype of Cushing's syndrome patients closely resembles that of Reaven's metabolic syndrome (also known as Syndrome X or insulin resistance syndrome), the symptoms of which include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven, (1993) Ann. Rev. Med, 44, 121-131). Although the role of glucocorticoids in human obesity is not fully characterized, there is mounting evidence that 1 lβ-HSDl activity plays an important role in obesity and metabolic syndrome (Bujalska, et al, (1997) Lancet 349: 1210-1213); (Livingstone, et al., (2000) Endocrinology 131, 560-563; Rask, et al, (2001) J. Clin. Endocrinol. Metab. 86, 1418- 1421; Lindsay, et al, (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake, et al, (2003) J. Clin. Endocrinol. Metab. 88, 3983-3988).
Data from studies in mouse transgenic models supports the hypothesis that adipocyte 1 lβ-HSDl activity plays a central role in visceral obesity and metabolic syndrome (Alberts, et al, (2002) Diabetologia. 45(11), 1526-32). Over-expression in adipose tissue of 11 β-HSDl under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki, et al, (2001) Science 294, 2166-2170; Masuzaki, et al, (2003) J. Clinical Invest. 112, 83- 90). Moreover, the increased activity of 1 lβ-HSDl in these mice is very similar to that observed in human obesity (Rask, et al, (2001) J. Clin. Endocrinol. Metab. 86, 1418- 1421). In addition, data from studies with 1 lβHSDl -deficient mice produced by homologous recombination demonstrate that the loss of 1 lβ-HSDl leads to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels (Kotelevstev, et al, (1997) Proc. Nat'l Acad. Sci. 94: 14924-14929; Morton, et al, (2001) J. Biol. Chem. 276, 41293-41300; Morton, et al, (2004) Diabetes 53, 931-938). The published data supports the hypothesis that increased expression of 11 β-
HSDl contributes to increased local conversion of cortisone to Cortisol in adipose tissue and hence that 1 lβ-HSDl plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al, (2004) Obes. Res. 12: 9-17). Therefore, 1 lβ-HSDl is a promising pharmaceutical target for the treatment of the metabolic syndrome (Masuzaki, et al, (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore, inhibition of 1 lβ-HSDl activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 11 β- HSDl inhibitors could be effective in combating obesity and/or other aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev, et al, (1997) Proc. Nat'l Acad. Sci. 94, 14924-14929; Morton, et al, (2001) J. Biol. Chem. 276, 41293- 41300; Morton, et al, (2004) Diabetes 53, 931 -938). In addition, inhibition of 1 lβ- HSDl activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel & Sutter, (1979) Horm. Metab. Res. 1 1,
555-560; Ogawa, et al, (1992) J. Clin. Invest. 90, 497-504; Davani, et al., (2000) J. Biol. Chem. 275, 34841-34844). Inter-individual differences in general cognitive function has been linked to variability in the long-term exposure to glucocorticoids (Lupien, et al. , (1998) Nat. Neurosci. 1 : 69-73) and dysregulation of the HPA axis. Such chronic exposure to glucocorticoid excess in certain brain subregions has been theorized to contribute to the decline of cognitive function (McEwen & Sapolsky (1995) Curr. Opin. Neurobiol. 5, 205-216). Therefore, inhibition of 1 lβ-HSDl may reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression. There is also evidence that glucocorticoids and 1 1 β-HSDl play a role in regulation of in intra-ocular pressure (IOP) (Stokes, et al, (2000) Invest. Ophthalmol. Vis. Sci. 41 : 1629-1683; Rauz, et al, (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037- 2042). If left untreated, elevated IOP can lead to partial visual field loss and eventually blindness. Thus, inhibition of 1 lβ-HSDl in the eye could reduce local glucocorticoid concentrations and IOP, and hence could be used to treat or prevent glaucoma and other visual disorders.
Transgenic aP2-l lβ-HSDl mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Additionally, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone. Treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki, et al,
(2003) J. Clinical Invest. 112, 83-90). This suggests that hypertension may be caused or exacerbated by 1 lβ-HSDl activity. Thus, 1 lβ-HSDl inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Glucocorticoids can have adverse effects on skeletal tissues, and prolonged exposure to even moderate glucocorticoid doses can result in osteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81, 3441-3447). In addition, 1 lβ-HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper, et al, (2000) Bone 27: 375-381), and the 1 lβ-HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone 23: 119-125). Thus, inhibition of 1 lβ-HSDl is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.
As evidenced herein, there is a continuing need for new and improved drugs that inhibit 1 lβ-HSDl. The novel compounds of the present invention are effective inhibitors of 1 lβ-HSDl .
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula I:
Figure imgf000006_0001
wherein:
R1 is (a) absent or (b) selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C]-C3)alkoxy(C)-C3)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4S, R4S(=O>, R4S(O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(O)NR4- , R4OC(=O)NR4-, (R4)2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-, R4S(O)2NHC(O)O-, R4S(O)2NHC(O)NR4-,
R4OS(O)2NHC(O)-, R4OS(O)2NHC(O)O-, R4OS(O)2NHC(O)NR4-, (R4)2NS(O)2NHC(O)-, (R4)2NS(O)2NHC(O)0-, (R4)2NS(O)2NHC(O)NR4-, R4C(O)NHS(O)2-, R4C(O)NHS(O)2O-, R4C(O)NHS(O)2NR4-, R4OC(O)NHS(O)2-, R4OC(O)NHS(O)2O-, R4OC(O)NHS(O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino; A1 is (a) a bond, or (b) (Ci-C3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2CC=O), wherein the carbonyl carbon is attached to Cy1; Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Cr C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(d- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C]-C6)alkylaminosulfonyl, di(C i - C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C^alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(Cι-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci- C6)alkyl, (C]-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(C]-C6)alkyl, halo(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl oxo, amino(C]-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Cr C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(C,-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(d- C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(CrC6)alkyl, di(Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylamiπocarbonyl(Ci-C6)alkyl, ((C3- C5)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3- Cδ)cycloalky laminocarbony 1(C i -C6)alky 1 ; A2 is (a) a bond, O, S or NR4; or (b) (Ci-C3)alkylene or (Ci-C2)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(d- C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenylJ hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C i -C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalky lalkoxy , (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(d- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (C r C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(C| -C6)alkanesulfϊnyl, halo(C3-Cδ)cycloalkanesulfinyl, halo(C4-C7)cycloalkyl- alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (C]-C6)alkylamino, di(Ci-C6)alkylamino, (Cr C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Q- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Cj- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Cr C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Cr C6)alkoxy(C i -C6)alkyl, halo(C , -C6)alkoxy(C i -C6)alkyl, hydroxy(C i - C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (CrC6)alkylamino(Ci-C6)alkyl, di(Cr C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (Cs-Q^ycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(CrC6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(C|- C6)alkylaminocarbonyl(CrC6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyl} {(C,-C6)a]kyl}aminocarbonyl(C,-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyI(Ci-C6)alkyl; Y is (Ci-C6)alkyl or halo(C,-C6)alkyl; n is 0, 1 or 2; E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R2 is (Ci-Ce)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(C,-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfmyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C^alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2,
Figure imgf000009_0001
di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylahiino, (C]- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- Cδ)alky lsulfony lamino(C i -Ce)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy , (Ci- C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (C]-C6)alkylamino(Ci-C6)alkyl, CU(C1-
C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C!-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminosulfonyl, di(C3-C6)cycloaIkylaminosuIfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(C|-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl(Ci-C6)a]kyl and di(C3- C6)cycloalkylaminocarbonyl(Ci -C6)alky 1 ;
R3 is selected from (C2-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(Ci- C3)alkyl, wherein the (C2-C6)alkyl is substituted with, and each of the (C2-C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(Ci-C3)alkyl is optionally substituted with, up to four groups independently selected from fluorine, cyano, oxo, halo(Ci-C6)alkyl, amino(Ci- C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(C1-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci- C6)alkyl, (Ci-C6)alkoxy(CrC6)alkyl, R4O-, (R4)2N-, R4O2C-, R4S, R4S(=O)-, R4S(O)2-, R4C(O)NR4-, (R4)2NC(O)-, (R4)2NC(O)0-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O>, R4S(O)2NHC(O)O-, R4S(O)2NHC(O)NR4-, R4OS(O)2NHC(O)-,
R4OS(O)2NHC(O)O-, R4OS(O)2NHC(O)NR4-, (R4)2NS(=0)2NHC(O)-, (R4)2NS(O)2NHC(O)0-, (R4)2NS(O)2NHC(O)NR4-, R4C(O)NHS(O)2-, R4C(O)NHS(=0)20-, R4C(O)NHS(O)2NR4-, R4OC(O)NHS(O)2-, R4OC(O)NHS(O)2O-, R4OC(O)NHS(O)2NR4-, (R4)2NC(O)NHS(O)2-, (R4)2NC(O)NHS(O)20-, (R4)2NC(O)NHS(O)2NR4-, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkyl sulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl- substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo);
R4 is independently selected from H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(C|-C6)alkyl and (Ci-C6)alkoxy(Ci-C6)alkyl; Q = O, NR5; and R5 is H, (d-C6)alkyl, halo(Ci-C6)alkyl or hydroxy(Ci-C6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is a compound of Formula I wherein Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkylJ hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci-C5)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C)-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C5)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-
C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-Cό)alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci- C6)alkyl, (CrC6)alkoxycarbonyl(C,-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(C , -C6)alkyl, di(C i -C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i - C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci- C6)alkylcarbonyl;
Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-Ce)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C5)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfmyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C]-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C]-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C1-C6)alkylaminosulfonyl, (Ii(C1- C6)alkylaminosulfonyl, heterocyclosulfonyl, (C|-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(C i -Ce)alkyl amino(C2-C6)alkoxy, (Ci -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-Cό)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C5)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C|-C6)alkylamino, di(Ci-C6)alkylamino, (C|-C6)alkoxy(Ci-
C6)alkoxy, halo(Ci-C6)alkoxy(C|-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-
C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-
C6)alkylcarbonylamino(C i -Cό)alkyl, (C ) -C6)alkylsulfonylamino, (C i -
C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -Cδ)alkoxy, (Ci-
C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C , -C5)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Cι-C6)alkylcarbonyl and the reminder of the variables are as defined above.
The present invention also provides a pharmaceutical composition comprising a disclosed 1 lβ-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof , and a pharmaceutically acceptable carrier or diluent, wherein the values for the variables are as described above for the compounds of Formula I.
The present invention further provides a method of inhibiting 11 β-HSDl activity, comprising administering to a mammal in need thereof an effective amount of a disclosed 11 β-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the values for the variables are as described above for the compounds of Formula I.
Also included in the present invention is a method of treating a disease or disorder associated with activity or expression of 1 lβ-HSDl, comprising administering to a mammal in need thereof an effective amount of a a disclosed 1 lβ-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the values for the variables are as described above for the compounds of
Formula I.
Also included in the present invention is the use of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting 1 lβ-HSDl activity in a mammal in need of such treatment.
Also included in the present invention is the use of a disclosed 11 β-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or disorder related to the activity or expression of 1 l β-HSDl , inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity in a mammal in need thereof, modulating 1 lβ-HSDl activity in a mammal in need thereof, and/or inhibiting 11 β-HSD 1 in a mammal in need thereof.
Also included in the present invention is a disclosed 1 lβ-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in inhibiting 1 l β-HSDl activity in a mammal in need of such treatment.
Also included in the present invention is a disclosed 1 lβ-HSDl inhibitor, including a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy, e.g., treating a disease or disorder associated with activity or expression of 11 β-HSD 1 in a subject.
DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by
Structural Formula I. Pharmaceutically acceptable salts of the 1 lβ-HSDl inhibitors disclosed herein (including those represented by Structural Formula I) are also included in the invention. Values and alternative values for the variables in Structural Formula I are provided in the following paragraphs: R1 is (a) absent or (b) selected from (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C1-C3)alkoxy(Ci-C3)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4S, R4S(O)-, R4S(=O)2-, R4C(O)NR4-, (R4)2NC(O>, (R4)2NC(=O)O-, (R4)2NC(O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(O)NR4-, R4OS(O)2NR4-, (R4)2NS(O)20-, (R4)2NS(O)2NR4-,
R4S(O)2NR4-, R4S(O)2NHC(O)-, R4S(O)2NHC(O)O-, R4S(O)2NHC(O)NR4-, R4OS(O)2NHC(O)-, R4OS(O)2NHC(O)O-, R4OS(O)2NHC(O)NR4-, (R4)2NS(O)2NHC(O)-, (R4)2NS(O)2NHC(O)0-, (R4)2NS(O)2NHC(O)NR4-, R4C(O)NHS(O)2-, R4C(O)NHS(O)2O-, R4C(O)NHS(O)2NR4-, R4OC(O)NHS(O)2-, R4OC(O)NHS(O)2O-, R4OC(O)NHS(O)2NR4-,
(R4)2NC(O)NHS(O)2-, (R4)2NC(O)NHS(O)20-, (R4)2NC(O)NHS(O)2NR4-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino. Alternatively, R1 is absent. Alternatively, R1 is unsubstitued or substituted (Ci-C6)alkyl, wherein the substituents are as described above. Alternatively, R1 is unsubstituted or substitued methyl or ethyl, wherein the substituents are as described above. Alternatively, R1 is unsubstituted methyl or ethyl.
A1 is (a) a bond, or (b) (Ci-C3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2C(=O), wherein the carbonyl carbon is attached to Cy1. Alternatively, A1 is a bond. Alternatively, A1 is (Ci-C3)alkylene. Alternatively, A1 is methylene.
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C]-C6)alkyl, hydroxy(Ci- C5)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (C]-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C]-C6)alkylthio, (C3-C5)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfmyl, halo(C3-C6)cycloalkanesulfinyl, 1IaIo(C4- C7)cycloalkylalkanesulfinyl, (C]-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C i -C6)alkylamino, (C i -C6)alkoxy(C i -C6)alkoxy , halo(C i -C5)alkoxy(C i -C6)alkoxy, (C]-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (C i -C3)alkoxy(C i -C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclosulfonyl, (C i -C6)alkylcarbonylamino, (C i -C6)alkylcarbonylamino(C i - C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (C)- C6)alkoxycarbonyl(C i -C6)alkoxy, (C i -C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i - C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (C ι- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci- C6)alkylcarbonyl.
Alternatively, Cy1 is optionally substituted aryl or optionally substituted heteroaryl, wherein the substituents are as described above. Alternatively, Cy1 is optionally substituted phenyl or optionally substituted pyridyl, wherein the substituents are as described above. Alternatively, Cy1 is optionally substituted phenyl, wherein the substituents are as described above. Alternatively, Cy1 is optionally substituted monocyclic cycloalkyl, wherein the substituents are as described above. Alternatively, Cy1 is optionally substituted cyclohexyl, wherein the substituents are as described above. Alternatively, Cy1 is substituted with fluorine, chlorine, bromine, methoxy, difluoromethoxy, methoxycarbonyl, carboxy, methyl, or trifluoromethyl.
A2 is (a) a bond, O, S or NR4; or (b) (Ci-C3)alkylene or (Ci-C2)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo. Alternatively, A2 is a bond.
Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(C]-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C<0cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfmyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-Cδ)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-Ce)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(C)- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- Cδ)alkylaminosulfonyl, heterocyclosulfonyl,
Figure imgf000016_0001
(Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy, (C i - C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl , hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, CU(C1- C6)alkylamino(C i -Ce)alkyl amino(C2-C6)alkoxy , (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl.
Alternatively, Cy2 is hydrogen. Alternatively, Cy2 is optionally substituted aryl or heteroaryl, wherein the substituents are as described above. Alternatively, Cy2 is optionally substituted cycloalkyl or heterocyclyl, wherein the substituents are as described above. Alternatively, Cy2 is optionally substituted phenyl or pyridyl, wherein the substituents are as described above. Alternatively, Cy2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine. Alternatively, Cy2 is difluorophenyl or monofluorophenyl. Alternatively, Cy2 is l,2-dihydro-2-oxopyridyl or l,2-dihydro-l-methyl-2-oxopyridyl. Alternatively, Cy2 is cyclopropyl.
Y is (Ci-C6)alkyl or halo(C,-C6)alkyl. n is 0, 1 or 2.
E is (a) a bond or (b) (C]-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo. Alternatively, E is a bond or alkylene. Alternatively, E is a bond.
R2 is (C)-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-
C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(d-C5)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C)-C6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-Ce)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (C|-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C)- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C^alkylamino, di(Ci-C6)alkylamino, (C]-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (C]-C6)alkylsulfonylamino, (Q- C6)alkylsulfonylamino(C i -Cή)alkyl, (C i -Ce)alkoxycarbonyl(C i -C6)alkoxy , (C i - C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl! hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Cp C6)alkylamino(C i -Cδ)alkyl amino(C2-C6)alkoxy, (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl.
Alternatively, R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the substituents are as described above; or R2 is (Ci-C6)alkyl substiuted with up to 4 groups independently selected from fluorine, cyano, nitro, amino, carboxy, (C]-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-
C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4- C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfmyl, halo(C3-
C6)cycloalkanesulfϊnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (C|-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO,
H2NSO2, (Cι-C6)alkylaminocarbonyl, di(C|-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cι- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cj- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Cr C6)alkoxy(C , -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C^alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Cj- C6)alkylamino(C i -C6)alkyl amino(C2-C5)alkoxy, (C \ -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl. Alternatively, R2 is optionally substituted (Ci-C6)alkyl, wherein the substituents are as described above; or R2 is aryl, heteroaryl, cycloalkyl or heterocyclyl substituted with up to 4 groups independently selected from fluorine, bromine, iodine, cyano, amino, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3- Cό)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkylthio, (C4- C7)cycloalkylalkylthio, halo(C i -C5)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfmyl, halo(C1-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C|-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(C|-C6)alkoxy, (C]-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C]-C6)alkylaminocarbonyl, (C]-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C1-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (C]-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -Cδ)alkoxy, (C i - C6)alkoxy(C i -C6)alky 1, halo(C i -C6)alkoxy(C i -C6)alky 1, hy droxy(C , -C6)alkoxy, heteroaryl, oxo, amino(C|-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (C!-C6)alkylcarbonyl.
Alternatively, R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, wherein the substituents are as described above. Alternatively, R2 is (a) isopropyl or (b) selected from optionally substituted phenyl, optionally substituted pyridyl and optionally substituted thienyl, wherein the substituents are as described above.
Alternatively, R2 is optionally substituted phenyl, wherein the substituents are as described above. Altematively, R2 is fluorophenyl.
R3 is selected from (C2-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C1- C3)alkoxy(Ci-C3)alkyl, wherein the (C2-C6)alkyl is substituted with, and each of the (C2- C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(Ci-C3)alkyl is optionally substituted with, up to four groups independently selected from fluorine, cyano, oxo, halo(Cj-C6)alkyl, amino(C i -C6)alkyl, (C i -C6)alkylamino(C i -C6)alkyl, di(C i -C6)alky lamino(C i -C6)alkyl, hydroxy(Ci-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, R4O-, (R4)2N-, R4O2C-, R4S, R4S(=O)- , R4S(^O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4)2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(^O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-, R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-, R4OS(=O)2NHC(=O)-, R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-, R4C(=O)NHS(=O)2O-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-, R4OC(=O)NHS(=O)2O-, R4OC(=O)NHS(=O)2NR4-,
(R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), aryl- amino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo).
Alternatively, R3 is substituted (C2-C6)alkyl, wherein the substituents are as described above. Alternatively, R3 is hydroxy(C2-C5)alkyl. Alternatively, R3 is dihydroxy(C3-C5)alkyl. Alternatively, R3 is ω-H2NCO(C!-C3)alkyl. Alternatively, R3 is (Ci-C2)alkoxy(Ci-C3)alkyl. Alternatively, R3 is H2NSθ2θ(C2-C4)alkyl. Alternatively, R3 is H2NSO2NH(C2-C4)alkyl. Alternatively, R3 is oxo(C2-C4)alkyl. Alternatively, R3 is MeC(=O)NH(C2-C4)alkyl. Alternatively, R3 is 2-hydroxy-2-methylpropyl. Alternatively, R3 is 2-(4-morpholino)ethyl. Alternatively, R3 is MeSO2NH(C2-C4)alkyl. Alternatively, R3 is MeSO2NHCH2CH2CH2-. R4 is independently selected from H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci- C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci- C6)alkyl and (Ci-C6)alkoxy(CrC6)alkyl.
Q = O, NR5. Alternatively, Q is O. Alternatively, Q is NR5. Alternatively, Q is NH.
R5 is H, (C,-C6)alkyl, halo(Ci-C6)alkyl or hydroxy(C,-C6)alkyl.
In a second embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula Ia:
Figure imgf000021_0001
wherein:
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C,- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (C1- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfmyl, halo(C3-C6)cycloalkanesulfmyl, halo(C4- C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci -Co)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C i -C6)alkylamino, (C i -C6)alkoxy(C i -C5)alkoxy , halo(C i -C6)alkoxy(C i -C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C^alkylaminocarbonyl, di(Ci- C6)alkylaminocarbonyl, (C i -C3)alkoxy(C i -C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonylJ di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl,
Figure imgf000022_0001
(Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (C i -C6)alkylsulfonylamino, (C i -C6)alkylsulfonylamino(C i -C6)alkyl, (C i - C6)alkoxycarbonyl(C i -C6)alkoxy, (C i -C6)alkoxy(C j -C6)alkyl, halo(C t -C6)alkoxy(C , - C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxyl or (Ci-C6)alkylcarbonyl; and r is 0,1, 2, 3 or 4. Values and alternative values for the remainder of the variables in Structural Formula Ia are as described for Structural Formula I.
In a third embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula Ib:
Figure imgf000022_0002
Ib
Values and alternative values for the variables in Structural Formula Ib are as described above for Structural Formula I.
In a fourth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula Ic:
Figure imgf000022_0003
Ic
Values and alternative values for the variables in Structural Formula Ic are as described above for Structural Formula I.
In a fifth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula Id:
Figure imgf000023_0001
wherein:
X is fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci- C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (d-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4- C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfmyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C]- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Cj-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, CU(C1- C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-
C6)alkylsulfonylamino(Ci-C6)alkyl, (CrC6)alkoxycarbonyl(Ci-C6)alkoxy, (Cr C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i-C6)alkyl, hydroxy(d -C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci- C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylammo(C2-C6)alkoxy, CU(C1- C6)alkylamino(C2-C6)alkoxyl and (Ci-C6)alkylcarbonyl; and m is 0, 1, 2, 3 or 4. Values and alternative values for the remainder of the variables in Structural Formula Id are as described above for Structural Formula I. In a sixth embodiment, the 1 l β-HSDl inhibitors of the invention are represented by Structural Formula Ie:
Figure imgf000024_0001
wherein:
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyls (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C]-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfmyl, (C3-C6)cycloalkanesulfϊnyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfmyl, halo(C4- C7)cycloalkylalkanesulfinyl, (C]-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- Cδjcycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C i -C6)alkylamino, (C i -C6)alkoxy(C \ -C6)alkoxy, halo(C i -C6)alkoxy(C i -C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(C]-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (C i -C6)alkylsulfonylamino, (C i -C6)alkylsulfonylamino(C i -C6)alkyl, (C i - C6)alkoxycarbonyl(C i -C6)alkoxy, (C i -C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i - C6)alkyl,, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxyl and (Ci- C6)alkylcarbonyl; and r is 0,1, 2, 3 or 4. Values and alternative values for the remainder of the variables in Structural Formula Ie are as described above for Structural Formula I.
In a seventh embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula If:
Figure imgf000025_0001
wherein:
G1 and G2 are each independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (C)-C6)alkoxy, (C3-C6)cycloalkoxy; (C4-C7)cycloalkylalkoxy, halo(C1-Cδ)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Cr C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (C1- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4- C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C i -C6)alkylamino, (C i -C6)alkoxy(C i -C6)alkoxy, halo(C i -C6)alkoxy(C i -C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C,- C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (C]-C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino; (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl(Ci -C6)alkoxy, (Ci -C6)alkoxy(C i -C5)alkyl, halo(C i -C6)alkoxy(C i - C6)alkyl,, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C5)alkoxy, (C1-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxyl or (Ci-C6)alkylcarbonyl; R5 is H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, or hydroxy(C1-C6)alkyl; and r and s are independently 0, 1, 2, 3 or 4. Values and alternative values for the remainder of the variables in Structural Formula If are as described above for Structural Formula I.
In an eighth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by Structural Formula Ig:
Figure imgf000026_0001
wherein:
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C]-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C,-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4- C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C i - C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C|-C6)alkylaminosulfonyl, di(C i - C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(C i -C6)alkyl, (C i -C6)alkylsulfonylamino; (C i - C6)alkylsulfonylamino(C i -Ce)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy, (C i - C6)alkoxy(C , -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl,, hydroxy(C i -C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(C1-C6)alkyl, di(Ci-C6)alkylamino(Ci- C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(d- C6)alkylamino(C2-C6)alkoxyl and (Ci-C6)alkylcarbonyl; and r is 0,1, 2, 3 or 4. Values and alternative values for the remainder of the variables in Structural Formula Ig are as described above for Structural Formula I. Pharmaceutically acceptable salts of the 1 lβ-HSDl inhibitors disclosed herein
(including those represented by any one of Structural Formulae Ia-Ig) are also included in the invention.
In a ninth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, provided that if Q is NR5, A1 is methylene, R1 is absent, Cy1 is optionally substituted phenyl, A2 is a bond, Cy2 is hydrogen, E is a bond and R2 is optionally substituted phenyl, then R3 is not hydroxyethyl or hydroxypropyl. In a tenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, provided that: if A1 is optionally substituted methylene and A2 is a bond, then Cy2 is not ortho to the ring atom of Cy1 that is bonded to A1, and Cy1 is not substituted with an optionally substituted amine or aminomethyl group at a ring atom ortho to the ring atom of Cy1 that is bonded to A1; if Q is NR5 and R3 is (C2-Cό)alkyl substituted with one to three groups independently selected from fluorine, halo(Ci-Ce)alkyl, hydroxy and hydroxy(Ci- C6)alkyl, then (a) E is (Ci-C2)alkylenyloxy; (b) E is a bond or (Ci-C3)alkylene and R2 is (Ci-C6)alkyl substituted with up to 4 groups independently selected from cyano, nitro, amino, carboxy, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (d- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkylalkylthio, halo(C)-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C]-C6)alkanesulfinyl, halo(C3- C6)cy cloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, ImIo(C4-C7)CyCIo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(d- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, CU(C1- C6)alkylaminosulfonyl, heterocyclosulfonyl, (C1-C6)alkylcarbonylamino, (Cp C6)alkylcarbonylamino(C i -C6)alkyl, (C i -C6)alkylsulfonylamino, (C i - C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy, (C i - C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(d-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(d- C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i -Cδ)alky lamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl; (c) E is a bond and R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl; or (d) E is (Cr
C3)alkylene and R2 is optionally substituted heteroaryl, cycloalkyl or heterocyclyl; and if Q is NR5 and E-R2 is (a) (Ci-C6)alkyl optionally substituted with one to three groups independently selected from fluorine, chlorine, bromine, iodine, hydroxy, (Ci- C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or (b) benzyl, then R3 is (a) (C2- C6)alkyl substituted up to four groups independently selected from cyano, oxo, amino(C i-C6)alkyl, (C i -C6)alkylamino(C i -C5)alkyl, di(C i -C5)alkylamino(C i -C5)alkyl, (C,-C6)alkoxy(C1-C6)alkyl! R4O- (except hydroxy), (R4)2N-, R4O2C-, R4S, R4S(O)-, R4S(=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(O)0-, (R4)2NC(O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-, (R4O)2P(O)O-, (R4O)2P(O)NR4-, R4OS(O)2NR4-, (R4)2NS(O)20-, (R4)2NS(O)2NR4-, R4S(O)2NR4-, R4S(O)2NHC(O)-, R4S(O)2NHC(O)O-, R4S(O)2NHC(O)NR4-, R4OS(O)2NHC(O)-, R4OS(O)2NHC(O)O-, R4OS(O)2NHC(O)NR4-, (R4)2NS(O)2NHC(O)-, (R4)2NS(O)2NHC(O)0-, (R4)2NS(O)2NHC(=0)NR4-, R4C(O)NHS(O)2-, R4C(O)NHS(O)2O-, R4C(O)NHS(O)2NR4-, R4OC(O)NHS(O)2-, R4OC(O)NHS(O)2O-, R4OC(O)NHS(O)2NR4-,
(R4)2NC(O)NHS(O)2-, (R4)2NC(O)NHS(O)20-, (R4)2NC(O)NHS(O)2NR4-, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), aryl- amino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); or (b) optionally substituted (C2-C6)alkenyl, (C2-C6)alkynyl or (Ci-C3)alkoxy(Ci-C3)alkyl.
In an eleventh embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply.
In a twelfth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is (Ci-C3)alkylene or (C|-C2)alkylenyloxy, and wherein the provisos in the tenth embodiment apply. In a thirteenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the tenth embodiment apply, further provided that if E is a bond, then R2 is optionally substituted (d-C6)alkyl. In a fourteenth embodiment, the 1 1 β-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply, further provided that if E is a bond, then R2 is optionally substituted (C)-C6)alkyl.
In a fifteenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the tenth embodiment apply, further provided that if E is a bond, and R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, then the optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl represented by R2 is not substituted with heteroaryl, amine or aminomethyl at a ring atom ortho to the ring atom of R2 that is bonded to E.
In a sixteenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, and wherein the provisos in the ninth and the tenth embodiments apply, further provided that if E is a bond, and R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, then the optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl represented by R2 is not substituted with heteroaryl, amine or aminomethyl at a ring atom ortho to the ring atom of R2 that is bonded to E. In a seventeenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is a bond or alkylene, and wherein the provisos in the tenth embodiment apply. In an eighteenth embodiment, the 1 lβ-HSDl inhibitors of the invention are represented by any one of Structural Formulae I and Ia-Ig, wherein values and alternative values for the variables in each of Structural Formulae I and Ia-Ig are as described above for each of Structural Formulae I and Ia-Ig, respectively, wherein E is a bond or alkylene, and wherein the provisos in the ninth and the tenth embodiments apply. Specific 11 β-HSDl inhibitors of the invention and pharmaceutically acceptable salts thereof are provided in Examples 1-3 and Prophetic Examples la-221a and Ib- 221b below.
Specific examples of compounds of Formulae I and Ia-Ig may exist in various stereoisomeric or tautomeric forms. The invention encompasses all such forms, including active compounds in the form of essentially pure enantiomers, racemic mixtures, and tautomers, including those forms not depicted structurally. When any variable (e.g., aryl, heterocyclyl, R1, R2, etc.) occurs more than once in a compound, its definition on each occurrence is independent of any other occurrence.
The term "alkyl", used alone or as part of a larger moiety such as "alkoxy", "hydroxyalkyl", "alkoxyalkyl", "alkylamine", "dialkyamine", "alkoxycarbonyl" or "alkylaminocarbonyl", means a saturated straight or branched hydrocarbon radical having (unless otherwise specified) 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
The term "cycloalkyl" means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, spiro [4.4]nonane, adamantyl and the like.
The term "aryl" means means a 6-10 membered carbocyclic aromatic monocyclic or polycyclic ring system, such as phenyl or naphthyl. The term "aryl" may be used interchangeably with the terms "aryl ring" "aromatic ring", "aryl group" and "aromatic group".
"Heteroaromatic group", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", means a 5-10 membered monovalent monocyclic and polycylic aromatic group radical containing 1 to 4 heteroatoms independently selected from N, O, and S. Heteroaryl groups include fαryl, thienyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzodioxolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,3,4-oxadiazolyl, 1 ,2,5-thiadiazolyl, 1,2,5-thiadiazolyl-l -oxide, 1,2,5- thiadiazolyl- 1,1 -dioxide, 1 ,3,4-thiadiazolyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, and pteridinyl. The terms "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group" are used interchangeably herein.
The term "heterocyclic group" means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S, and include pyrrolidine, pyrrolidin-2-one, 1 -methylpyrrolidin- 2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1 - (2,2,2-trifluoroethyl)piperazine, 1 ,2-dihydro-2-oxopyridine, 1 ,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1 ,3-dithiane, 1,4- dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(lH)-one, morpholine, N-methylmorpholine, morpholin-3-one, l,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1 ,1 -dioxide, tetrahydro- 1,2,5- thiaoxazole 1,1 -dioxide, tetrahydro-2H-l,2-thiazine 1 ,1 -dioxide, hexahydro-1,2,6- thiadiazine 1,1 -dioxide, tetrahydro- 1, 2, 5-thiadiazole 1,1 -dioxide and isothiazolidine 1,1- dioxide. The terms "heterocyclyl", "heterocycle", "heterocyclic group" and "heterocyclic ring" are used interchangeably herein.
The term "ring atom" is an atom such as C, N, O or S that is in the ring of an aryl group, heteroaryl group, cycloalkyl group or heterocyclic group. A "substitutable ring atom" in an aryl, heteroaryl cycloalkyl or heterocyclic is a carbon or nitrogen atom in the aryl, heteroaryl, cycloalkyl or heterocyclic group that is bonded to at least one hydrogen atom. The hydrogen(s) can be optionally replaced with a suitable substituent group. Thus, the term "substitutable ring atom" does not include ring carbon or nitrogen atoms when the structure depicts that they are not attached to any hydrogen atoms. Suitable substituents for an alkyl, aryl, heteroaryl and heterocyclic group are those which do not significantly reduce the ability of the compound to inhibit the activity of 1 l β-HSDl . Unless otherwise specified, suitable substituents for an alkyl, aryl, heteroaryl and heterocyclyl include fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C5)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C,- C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Cι-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkylthio, (C4- C7)cycloalkylalkylthio: halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-CδJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C]-C6)alkylamino, di(Ci-C6)alkylamino, (C|-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(C|-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, CONH2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(C , -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C , -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (C)-C6)alkylamino(Ci-C6)alkyl, di(Cj-
C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl. Preferred substituents an alkyl, aryl, heteroaryl and heterocyclyl include, unless otherwise specified, halogen, (Ci- C6)alkyl, hydroxy, (C,-C6)alkoxy, (d-C6)alkylamino, di(Ci-C6)alkylamino, NO2, CN, CONH2, halo(Ci-C6)akyl or halo(Ci-C6)alkoxy.
The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
The compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
Salts of the disclosed 1 lβ-HSDl inhibitors containing an acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'- dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'- bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine. The invention also includes various isomers and mixtures thereof. "Isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). Certain of the disclosed 1 l β-HSDl inhibitors may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "/?*" and "S*" denote the relative configurations of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present. "Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
"Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enatiomer over the weight of the enantiomer plus the weight of its optical isomer. When a single geometric isomer, e.g., a geometric isomer with a double bond, is depicted by name or structure and the stereochemistry about the double is indicated, the compound is considered to be at least 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% steroechemically pure by weight. Percent stereochemically purity by weight is the ratio of the weight of the geometric isomer over the weight of the both geometric isomers. For example, 99% stereochemically pure means that at least 99% by weight of the compound is the indicated stereoisomer. A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I and Ia-Ig, comprise a pharmaceutically acceptable salt of a compound of Formulae I and Ia-Ig, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor. "Effective amount" means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a compound of the invention in such a therapeutic method is from about 0.01 mg/kg/day to about 10 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day.
"Inhibiting 1 lβ-HSDl" means to decrease the activity of the 1 lβ-HSDl enzyme. "Modulating 11 β-HSD 1 " means to impact the activity of the 11 β-HSD 1 enzyme by altering its natural activity. Modulation can be analogous to inhibition when a disease or disorder relating to the activity 1 lβ-HSDl would be effectively treated by suppressing the activity of the enzyme.
"Pharmaceutically acceptable carrier" means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.
"Treatment" or "treating", as used herein, includes prophylactic and therapeutic treatment. "Therapeutic treatment" includes partially or totally inhibiting, delaying, or reducing the severity of the disease or disorder related to 11 β-HSD 1. "Prophylactic treatment" encompasses administration of a compound of the invention to a subject susceptible to a disease or disorder related to the activity or expression of 1 lβ-HSDl in an effort to reduce the likelihood of a subject developing the disease or disorder, or slowing or preventing progression of the disease. Prophylactic treatment includes suppression (partially or completely) of the disease or disorder, and further includes reducing the severity of the disease or disorder, if onset occurs. Prophylactic treatment is particularly advantageous for administration to mammals at risk for developing a disease or disorder related to 11 β-HSD 1. The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally.
It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can either be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersable granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from about one to about seventy percent of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluose, a low melting wax, cocoa butter, and the like. Tablets, powders, cachets, lozenges, fast-melt strips, capsules and pills can be used as solid dosage forms containing the active ingredient suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing , and thickening agents as desired. Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of, for example, tablets, powders, and capsules in vials or ampules. Also, the unit dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be the appropriate amount of any of these in packaged form.
The quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from about 0.1 mg to about 100 mg. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill in the art. Also, the pharmaceutical composition may contain, if desired, other compatible therapeutic agents.
In therapeutic treatment or as a method-of-use as an inhibitor of 1 lβ-HSDl or an inhibitor in the production of Cortisol in the cell, the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.
The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, metabolic syndrome, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety and Alzheimer's disease, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility. In addition, compounds modulate the function of B and T cells of the immune system.
A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I and Ia-Ig, comprise a pharmaceutically acceptable salt of a compound of Formulae I and Ia-Ig, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor. The invention includes a therapeutic method for treating or ameliorating an 11 β- HSDl mediated disorder in a mammal in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formulae I and Ia-Ig, or the enantiomers, diastereomers, or salts thereof or composition thereof. The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility and hypergonadism. In addition, the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients.
Additional diseases or disorders that are related to 1 lβ-HSDl activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X.
The term "mammal" is preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
The disclosed 1 lβ-HSDl inhibitors can be used alone or in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma. Agents for the treatment of diabetes include insulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase® (glyburide, Pfizer), and Glucotrol®/Glucotrol XL® (glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) and Glumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs; GLP-I analogs; DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck); PTB-IB inhibitors; protein kinase inhibitors (including AMP- activated protein kinase inhibitors); glucagon antagonists; glycogen synthase kinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors, and α-glucosidase inhibitors, such as
Precose®/Glucobay®/Prandase®/ Glucor® (acarbose, Bayer) and Glyset® (miglitol, Pfizer). Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates and ezetimibe. Agents for the treatment of hypertension include α- blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin- receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist. Agents for the treatment of obesity include orlistat, phentermine, sibutramine and rimonabant.
An embodiment of the invention includes administering an 1 lβ-HSDl inhibiting compound of any one of Structural Formulae I and Ia-Ig or composition thereof in a combination therapy with one or more other 1 lβ-HSDl inhibitors (whether such inhibitors are also compounds of any one of Structural Formulae I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); Janumet® (sitagliptin and metformin, Merck)and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).
The following abbreviations have the indicated meanings: Abbreviation Meaning
Boc tert-butoxy carbonyl or t-butoxy carbonyl
(Boc)2O di-tert-butyl dicarbonate
Cbz Benzyloxycarbonyl CbzCl Benzyl chloroformate
DAST diethylaminosulfur trifluoride
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCC N5N' -dicyclohexylcarbodiimide
DCU N,N'-dicyclohexylurea
DIAD diisopropyl azodicarboxylate
DIEA N,N-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(l H)-pyrimidinone
2,4-DNP 2,4-dinitrophenylhydrazine
DPTBS Diphenyl-t-butylsilyl
EDCHCl, EDCI 1 - [3 -(dimethylamino)propyl]-3 -ethylcarbodiimide hydrochloride
Equiv equivalents
Fmoc 1 - [ [(9H-fluoren-9-ylmethoxy)carbony l]oxy] -
Fmoc-OSu 1 - [ [(9H-fluoren-9-ylmethoxy)carbonyl]oxy] -2 , 5 - pyrrolidinedione h, hr hour(s)
HOBt 1 -hydroxybenzotriazole
HATU 2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate
HBTU 2-( 1 H-Benzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate
KHMDS potassium hexamethyldisilazane
LAH or LiAlH4 lithium aluminum hydride
LC-MS liquid chromatography-mass spectroscopy
LHMDS lithium hexamethyldisilazane Me methyl
MsCl methanesulfonyl chloride
Min minute
MS mass spectrum
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaN3 sodium azide
NaOH sodium hydroxide
Na2SO4 sodium sulfate
NMM N-metbylmorpholine
NMP N-methylpyrrolidinone
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PE petroleum ether
Quant quantitative yield
Satd saturated
SOCl2 thionyl chloride
SFC supercritical fluid chromatography
SPA scintillation proximity assay
SPE solid phase extraction
TBAF tetrabutylammonium fluoride
TBS t-butyldimethylsilyl
TBDPS t-butyldiphenylsilyl
TBSCl t-butyldimethylsilyl chloride
TBDPSCl t-butyldiphenylsilyl chloride
TEA triethylamine or Et3N
TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy free radical
Teoc l-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu l-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione
TFA triflυoroacetic acid
Tie, TLC thin layer chromatography
TMS trimethylsilyl
TMSCl chlorotrimethylsilane or trimethylsilyl chloride
JR retention time
TsOH p-toluenesulfonic acid
GENERAL DESCRIPTION OF SYNTHETIC METHODS
Compounds of Formula I can be prepared by several processes. In the discussion below, A1, A2, Cy1, Cy2, E, Q, R1, R2, R3, R5, Y, and n have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formula I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly. Generally, reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05 - 5 equivalents).
In a first process, compounds of Formula I can be prepared by reaction of intermediates of Formula II with reagents of Formula III, wherein Z1 and Z2 are leaving groups such as chloride, 1 -imidazolyl or aryloxide, in an inert solvent such as THF,
CH2Cl2, toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO3 respectively, at -10 °C to 120 0C:
Figure imgf000044_0001
Certain instances of reagent III are especially convenient because they are commercially available. For example when Z1 and Z2 are both chloride, III is phosgene. When Z1 and Z2 are both 1-imidazolyl, III is carbonyl diimidazole. When Z1 is chloride and Z2 is p- nitrophenoxide, III is p-nitrophenyl chloroformate. When Z1 and Z2 are both OCCl3, III is triphosgene and as little as one third of molar equivalent can be used.
Intermediates of Formula II, wherein n = 0, can be prepared by reduction of amides of Formula IV using a hydride reagent such as BH3THF solution, BH3-Me2S or LiAlH4 in an ethereal solvent such as THF or DME at 20 0C to 100 0C for between 1 h and 48 h:
Figure imgf000044_0002
Intermediates of Formula IV can be prepared by coupling of α-hydroxyacids of Formula V (Q = OH) or suitably protected α-aminoacids of Formula V (Q = NR5) with amines of Formula VI using standard peptide coupling reagents such as EDC in the presence of HOBt and N,N-diisopropylethylamine in an inert solvent such as CH2Cl2 at 0 - 30 °C for between 1 h and 24 h:
Figure imgf000044_0003
Certain α-hydroxyacids of Formula V, wherein Q = O, are commercially available. α-Hydroxyacids of Formula V can be prepared by diazotization of α-amino acids of Formula VII using NaNO2 in H2SO4:
Figure imgf000045_0001
α-Hydroxyacids of Formula V, wherein Q = O, can also be prepared from ketones Formula VIII via cyanohydrins of Formula IX:
Figure imgf000045_0002
Methods for the conversion of ketones to cyanohydrins are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" pp 1239-1240, 5th Edition, Wiley, New York, NY, 2001. Methods for the hydrolysis of cyanohydrins to α-hydroxyacids are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 1179, 5th Edition, Wiley, New York, NY, 2001 α-hydroxyacids of Formula V, wherein Q = O, can also be prepared by oxidation of diols of Formula X with for example oxygen in the presence of a catalyst or using sodium chlorite and TEMPO:
Figure imgf000045_0003
Amine intermediates of Formula VI, wherein A1 = CH2 and R1 is absent, can be prepared by reduction of amides of Formula XI using a hydride reagent such as BH3THF solution, BH3.Me2S or LiAlH4 in an ethereal solvent such as THF or DME at 20 0C to 1 OO 0C for between 1 h and 48 h:
Figure imgf000046_0001
Xl Vl
Amine intermediates of Formula VI, wherein A1 is a bond, R1 is absent and Cy1 is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula XII via oximes of Formula XIII or by reductive animation of ketones of Formula XII with ammonia:
Figure imgf000046_0002
Methods for the conversion of ketones to oximes are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" pp 1194-1195, 5th Edition, Wiley, New York, NY, 2001. Methods for the reduction of oximes to primary amines are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 1555, 5th Edition, Wiley, New York, NY, 2001. Methods for the reductive amination of ketones are described in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.
Amine intermediates of Formula VI, wherein A1 is CH, can be prepared from ketones of Formula XIV by reductive amination with ammonia.
Figure imgf000046_0003
Amine intermediates of Formula VI, wherein A1 is CH, can be prepared from alcohols of Formula XV via azides of Formula XVI. The conversion of alcohols of Formula XV to azides of Formula XVI can be accomplished with, for example, diphenylphosphoryl azide. Reduction of azides of Formula XVI to amines of Formula VII can be effected, for example, by hydrogenation in the presence of a palladium catalyst or by reaction with triphenylphosphine in wet THF.
Figure imgf000047_0001
Amine intermediates of Formula VI, wherein A1 is CH, can be prepared by reaction of sulfinyl imine intermediates of Formula XVII with organometallic reagents of Formula XVIII, wherein M is Li, MgCl5 MgBr or MgI, followed by treatment with acid to remove the t-butylsulfinyl group.
Figure imgf000047_0002
Sulfinyl imines of Formula XVII can be prepared by treatment of aldehyde intermediates of Formula XVIII with 2-methylpropane-2-sulfmamide.
Figure imgf000047_0003
Intermediates of Formula II, wherein Q = O and n = 0, can be prepared by reaction of epoxides of Formula XIX with amines of Formula VI as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 504, 5th Edition, Wiley, New York, NY, 2001:
Figure imgf000047_0004
Epoxide compounds of formula XIX can, in turn, be prepared in a number of ways including those described in Aube, J. "Epoxidation and Related Processes" Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis" Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992).
Intermediates of Formula II, wherein A1 is CH2 and R1 is absent, can be prepared by reduction of amide intermediates of formula XX using a hydride reagent such as BH3.THF solution, BH3Me2S or LiAlH4 in an inert solvent ethereal such as THF or DME at 20 0C to 100 0C for between 1 h and 48 h:
Figure imgf000048_0001
Amide intermediates of Formula XX can be prepared by reaction of an amines of
Formula XXI with activated carboxylic acid of Formula XXII wherein Z3 = chloride or an activated ester, such as an N-hydroxysuccinimide ester:
Figure imgf000048_0002
Amines of Formula XXI, wherein n = 0, can be prepared by reaction of epoxides of Formula XIX with azide ion to give azidoalcohols of Formula XXIII followed by reduction of the azide moiety with hydrogen gas or using triphenylphosphine in the presence of water:
Figure imgf000048_0003
Intermediates of Formula II, wherein n = 0, can also be prepared by reductive amination of aldehyde intermediates of Formula XXIV with amines of Formula VI using for example NaCNBH3 or NaBH(OAc)3 as reducing agent:
Figure imgf000049_0001
Additional methods for the synthesis of 1,2-diamines, certain of which are applicable to intermediates of Formula II wherein Q = NR3, are described in Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580-2617.
In a second process, a compound of Formula I, wherein Q = O and n =0, can be prepared by reaction of a carbamate intermediate of Formula XXV, wherein Ra = alkyl or benzyl, with an epoxide intermediate of Formula XIX in the presence of a strong base such as NaH in a solvent such as THF or DMF at 0 0C to 80 0C:
Figure imgf000049_0002
Carbamate intermediates of Formula XXV can be prepared by reaction of amines of Formula VI with chloroformates of Formula XXVI in the presence of a base such as pyridine or triethylamine in an inert solvent such as CH2Cl2 or THF at 0 0C to 25 0C for between 1 h and 24 h:
Figure imgf000049_0003
In a third process, compounds of Formula I, wherein R3 is not hydrogen, Q is O and n = 0, can be prepared by reaction of ketocarbamates of Formula XXVII with organometallic reaction of Formula XXVIII, wherein M is Li, MgCl, MgBr or MgI.
Figure imgf000050_0001
In a fourth process a compound of Formula I can be prepared from another compound of Formula I. For example:
(1) a compound of Formula I wherein Cy1 is substituted with bromine or iodine, A2 is a bond and Cy2 is hydrogen can be reacted with an optionally substituted aryl or heteroarylboronic acid or ester in the presence of a palladium catalyst to give a compound of Formula I wherein A2 is a bond and Cy2 is optionally substituted aryl or heteroaryl.
(2) a compound of Formula I wherein R1 or R3 is ω-hydroxy(C2-C6)alkyl can be oxidized to a compound of Formula I wherein R1 or R3 is ω-carboxy(Ci-Cs)alkyl using Jones reagent.
(3) a compound of Formula I wherein R1 or R3 is ω-carboxy(Ci-C6)alkyl can be coupled with ammonia or a (Ci-C6)alkylamine using a standard peptide coupling reagent such as EDC to afford a compound of Formula I wherein R1 or R3 is ω-H2NC(=O)(Ci- C5)alkyl or ω-{(C,-C6)alkylNHC(=O)}(Ci-C6)alkyl .
(4) a compound of Formula I wherein R1 or R3 is ω-hydroxy(Ci-C6)alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I, wherein R1 or R is ω-amino(Ci- C6)alkyl.
(5) a compound of Formula I wherein R1 or R3 is amino(Ci-C6)alkyl can be reacted with acetic anhydride or acetyl chloride to give a compound of Formula I wherein R1 or R3 is {acetylamino}(Ci-C6)alkyl.
(6) a compound of Formula I wherein R1 or R3 is amino(Ci-C6)alkyl can be reacted with methanesulfonyl chloride to give a compound of Formula I wherein R1 or R3 is {methanesulfonylamino}(Ci-C6)alkyl.
(7) a compound of Formula I, wherein R1 or R3 is (C2-C6)alkenyl is hydroborated to afford a compound of Formula I wherein R1 or R3 is hydroxy(C2-C6)alkyl. When the alkene is at the terminus of the (C2-C6)alkenyl group, the major product is generally the primary ω-hydroxy(C2-C6)alkenyl i and the minor product is the secondary alcohol ii.
Figure imgf000051_0001
i ii n = 0 - 4
(8) a compound of Formula I, wherein R1 is (C2-C6)alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a compound of Formula I wherein R1 is vicinal dihydroxy(C2-C6)alkyl,.
(9) a compound of Formula I, wherein R3 is (C2-C6)alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a vicinal diol compound of Formula I wherein R3 is vicinal dihydroxy(C2-C6)alkyl. (10) a compound of Formula I, wherein R1 is (C2-C6)alkenyl, can be reacted with ozone followed by NaBH4 to give a compound of Formula I wherein R1 is ω- hydroxy(C1-C5)alkyl.
(1 1) a compound of Formula I, wherein R3 is (C2-C6)alkenyl, can be reacted with ozone followed by NaBH4 to give a compound of Formula I wherein R3 is ω- hydroxy^ -C5)alkyl.
(12) a compound of Formula I wherein R1 or R3 is amino(Ci-C6)alkyl can be reacted with an (Ci-C6)alkyl isocyanate to give a compound of Formula I wherein R1 or R3 is (Ci-C6)alkylaminocarbonylamino(Ci-C6)alkyl.
(13) a compound of Formula I wherein R1 or R3 is amino(Ci-C6)alkyl can be reacted with an (C]-C6)alkyl chloroformate to give a compound of Formula I wherein R1 or R3 is (Ci-C6)alkoxycarbonylamino(C]-C6)alkyl.
(14) a compound of Formula I wherein R1 or R3 is amino(Ci-C6)alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I wherein R1 or R3 is aminosulfonylamino(Ci-C6)alkyl. (15) a compound of Formula I wherein R1 or R3 is amino(C)-C6)alkyl can be reacted with a (Ci-C6)alkylsulfamoyl chloride to give a compound of Formula I wherein R1 or R3 is (Ci-C6)alkylaminosulfonylamino(Ci-C6)alkyl.
(16) a compound of Formula I wherein R1 or R3 is hydroxy(d-C6)alkyl can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I wherein R1 or R3 is aminosulfonyloxy(Ci-C6)alkyl. (17) a compound of Formula I wherein R1 or R3 is hydroxy(Ci-C6)alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (Ci-C6)alkylamine or a di(C1-C6)alkylamine to give a compound of Formula I wherein R1 or R3 is aminocarboxy(Ci-C6)alkyl, (Ci- C6)alkyl aminocarboxy(Ci-C6)alkyl or di(Ci-C6)alkyl aminocarboxy(Ci-C6)alkyl.
(18) a compound of Formula I wherein R1 or R3 is hydroxy(Ci-Ce)alkyl can be reacted with POCl3 to give a compound of Formula I wherein R1 or R3 is (HO)2P(=O)O(C,-C6)alkyl.
(19) a compound of Formula I wherein Cy1 is substituted with bromine or iodine, A2 is a bond and Cy2 is hydrogen can be reacted with a cyclic amine in the presence of a palladium catalyst to give a compound of Formula I wherein A2 is a bond and Cy2 is a cyclic amino moiety attached through its nitrogen atom.
(20) a compound of Formula I wherein R3 is MeO2C(C i-C5)alkyl can be treated with MeMgBr to afford a compound of Formula I wherein R3 is Me2(HO)C(C ι-Cs)alkyl. (21) a compound of Formula I wherein R1 or R3 is ω-H2NCO(C)-C5)alkyl can be reacted with TFAA in the presence of pyridine to afford a compound of Formula I wherein R1 or R3 is ω-cyano(Ci-C5)alkyl.
(22) a compound of Formula I wherein R3 is amino(Ci-C6)alkyl can be reacted with a 2-fluoropyridine to give a compound of Formula I wherein R3 is 2- pyridylamino(Ci-C6)alkyl.
(23) a compound of Formula I wherein R3 is ω-hydroxy(Ci-C6)alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with a (C 1- Cδ)alkylthiol followed by oxidation with m-CPBA to give a compound of Formula I wherein R3 is (Ci-C6)alkylsulfonyl(Ci-C6)alkyl. (24) a compound of Formula I, wherein Q is NH, can be reacted with sodium hydride and methyl iodide in an inert solvent to give a compound of Formula I, wherein Q is NMe.
LC-MS METHODS
Method 1 [LC-MS (3 min)]
Column: Chromolith SpeedRod, RP-18e, 50 x 4.6 mm; Mobil phase: A: 0.01%TF A/water, B: 0.01 %TF AZCH3CN; Flow rate: 1 mL/min; Gradient:
Figure imgf000053_0002
Method 2 (10-80)
Figure imgf000053_0003
EXAMPLE 1
5-allyl-3 -(( 1 S)- 1 -(4-bromophenyl)ethyl)-5-(4-fluorophenyl)oxazolidin-2-one
Figure imgf000053_0001
Step 1
To a solution of (S)-I -(4-bromophenyl)ethanamine (2 g, 0.01 mol) and K2CO3 (4.2 g, 0.03 mol) in acetonitrile (50 mL) was added 2-chloro-l-(4-fluorophenyl)ethanone (1.72 g, 0.01 mol). The formed mixture was stirred overnight at rt. The solid was filtered, and the filtrate was concentrated to give (S)-2-(l-(4-bromophenyl) ethylamino) - 1- (4-fluorophenyl)ethanone (2 g, 60%), which was used for the next step without further purification. Step 2
To a solution of (£)-2-(l-(4-bromophenyl)ethylamino)-l-(4- fluorophenyl)ethanone (2 g, 0.006 mol) in THF (300 mL) was added allylmagnesium bromide (1 M, 20 mL, 0.02 mol) under nitrogen at -78 0C. The mixture was stirred at this temperature till the reaction was over. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude 1-((S)-I -(4- bromophenyl)ethylamino)-2-(4-fluorophenyl) pent-4- en-2-ol (1.8 g, 80%), which was used for the next step without further purification.
Step 3
To a solution of l-((iS)-l-(4-bromophenyl)ethylamino)-2-(4-fluorophenyl)pent-4- en-2-ol (0.9 g, 0.003 mol) in CH2Cl2 (50 mL) and Et3N (0.8 g, 0.009 mol) was added triphosgene (0.84 g, 0.003 mol) at 0 0C. The resulting mixture was stirred overnight. The mixture was washed with water. The organic layer was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford 5-allyl-3- ((lS)-l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)oxazolidin-2-one isomer 1 (403 mg, 33%) and 5-allyl -3-((15)-l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)oxazolidin-2-one isomer 2 (392 mg, 32%).
EXAMPLE 2 3-((l S)-l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3-hydroxypropyl)oxazolidin-2- one
Figure imgf000054_0001
To a solution of 5-allyl-3-((lS)-l-(4-bromophenyl)ethyl)-5-(4- fluorophenyl)oxazolidin-2-one isomer 1 (50 mg, 0.13 mmol) in THF (10 mL) was added 1 M BH3 in THF (2 mL, 2.0 mmol) at 0 0C under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then 3 M aq NaOH (1 mL, 3 mmol) and H2O2 (2 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give 3- ((I S)- 1 -(4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3-hydroxypropyl)oxazolidin-2-one isomer 1 (15 mg, 30%). 1H NMR (CDCl3): 1.38 (m, 2H), 1.50 (m, 3H), 1.61 (m, 2H), 2.00 (m, 2H), 3.11 (m, IH), 3.52 (m, 3H), 5.12 (m, IH), 6.98 (m, 4H), 7.18 (m, 2H), 7.30 (m, 2H).
Reaction of 5-allyl-3-((lS)-l-(4-bromophenyl)ethyl)-5-(4- fluorophenyl)oxazolidin-2-one isomer 2 under analogous conditions afforded 3-((1S)-I- (4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3-hydroxypropyl)oxazolidin-2-one isomer 2. 1H NMR (CDCl3): 1.18 (m, 2H), 1.39 (m, 3H), 1.41 (m, IH), 1.86 (m, 2H)5 3.18 (m, IH), 3.48 (m, 3H), 5.12 (m, IH), 6.98 (m, 2H), 7.17 (m, 2H), 7.23 (m, 2H), 7.48 (m, 2H).
EXAMPLE 3 3-((lS)-l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3-hydroxypropyl)oxazolidin-2- one
Figure imgf000055_0001
A mixture of 3-((lS)-l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3- hydroxypropyl)oxazolidin-2-one isomer 1 (84 mg, 0.2 mmol), 4-fluorophenylboronic acid (34 mg, 0.24 mmol), Pd(Ph3P)2Cl2 (30 mg), and aq. Cs2CO3 solution (2 mL, 2 M) in 1 ,4-dioxane (6 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give 3-((l S)-l-(4'-fluorobiphenyl-4-yl)ethyl)-5-(4-fluorophenyl)-5-(3- hydroxypropyl)oxazolidin-2-one isomer 1 (23.2 mg, 27%). 1H NMR (CDCl3): 1.28 (m, IH), 1.55 (m, 3H), 1.59 (m, IH), 2.00 (m, 2H), 3.18 (m, IH), 3.54 (m, 3H), 5.18 (m, IH), 6.88 (m, 2H), 7.07 (m, 2H), 7.18 (m, 2H), 7.20 (m, 2H), 7.36 (m, 2H), 7.45 (m, 2H).
Reaction of 3-((l S)- l-(4-bromophenyl)ethyl)-5-(4-fluorophenyl)-5-(3- hydroxypropyl)oxazolidin-2-one isomer 2 under analogous conditions afforded 3-((1S)- l-(4'-fluorobiphenyl-4-yl)ethyl)-5-(4-fluorophenyl)-5-(3-hydroxypropyl)oxazolidin-2- one isomer 2. 1H NMR (CDCl3): 1.22 (m, IH), 1.45 (m, 3H), 1.49 (m, IH), 1.86 (m, 2H), 3.22 (m, IH), 3.48 (m, 3H), 5.22 (m, IH), 7.00 (m, 4H), 7.25 (m, 2H), 7.36 (m, 2H), 7.51 (m, 4H).
EXAMPLE 4 3-((S)-l-(4-bromophenyl)ethyl)-5-(2-hydroxy-2-methylpropyl)-5-phenyloxazolidin-2- one
Figure imgf000056_0001
Step 1
To a solution of 2-bromo-l -phenyl ethanone (1.54 g, 0.01 mol) in dry THF (50 mL) was added (5)-l-(4-bromophenyl)-ethyl amine (1.99 g, 0.01 mol) and Et3N (3 g, 0.03 mol). The mixture was stirred at room temperature for 4 h, and filtered. The filtrate was concentrated to give the crude (S)-2-(l-(4-bromophenyl)ethylamino)-l- phenylethanone (2.85 g, 90%) as an oil, which was used for the next step without purification.
Step 2 To a solution of crude (S)-2-(l-(4-bromophenyl)ethylamino)-l-phenylethanone (1 g, 3.15 mmol) in THF (20 mL) was added (2-methylallyl)magnesium chloride (10 mL, 1 mol/L) at -78 0C. The mixture was stirred at rt for 1 h, and TLC showed disappearance of the starting material. The mixture was quenched with satd aq NH4Cl and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated to give the crude product, which was purified by chromatography to afford l-((S>l-(4-bromophenyl)ethylamino)-4-methyl-2-phenylpent-4-en-2-ol (1.06 g, 90%).
Step 3 To a solution of l-((S)-l-(4-bromophenyl)-ethylamino)-4-methyl-2-phenylpent-
4-en-2-ol (800 mg g, 2.14 mmol) in CH2Cl2 (30 mL) was added triphosgene (630 mg, 2.14 mmol) and Et3N (650 mg, 6.42 mmol) at 0 0C. The mixture was stirred at rt overnight. TLC showed disappearance of the starting material. The mixture was washed with 1 N aq HCl and extracted by DCM. The combined organic phase was dried over Na2SO4 and concentrated to give the crude product, which was purified by chromatography to afford 3-((S)-l-(4-bromophenyl)-ethyl)-5-(2-methylallyl)-5- phenyloxazolidin-2-one (700 mg, 82%).
Step 4 To a solution of 3-((5)-l-(4-bromophenyl)-ethyl)-5-(2-methylallyl)-5- phenyloxazolidin-2-one (700 mg, 1.75 mmol) in dry CH2Cl2 (100 mL) was added m- CPBA (1.5 g, 8.75 mmol) at rt. The reaction mixture was stirred until the starting material had been consumed (monitored by TLC). The mixture was diluted with (CH3)3COCH3 (70 mL), washed with 30% aq Na2S2O3 and aq NaHCO3, dried over Na2SO4, filtered, and concentrated to give 3-((S)-l-(4-bromophenyl)-ethyl)-5-((2- methyloxiran-2-yl)-methyl)-5-phenyloxazolidin-2-one (650 mg, 90%), which was used directly for the next step without further purification..
Step 5 To a solution of 3-((S>l-(4-bromophenyl)-ethyl)-5-((2-methyloxiran-2- yl)methyl)-5- phenyloxazolidin-2-one (650 mg, 1.57 mmol) in THF (32 mL) was added dropwise Super-Hydride (13.6 mL, 13.6 mmol) at 0 0C under N2 over 30 min, and the resulting solution was stirred at 10~13°C for 4 h. To the mixture was added dropwise H2O2 (20 mL), diluted with (CH3)3COCH3 (380 mL), washed with water, followed by addition of 30% aq Na2S2O3 and brine. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by prep TLC to afford the the two isomers of the title compound:
Isomer 1 : (5)-3-((S)-l-(4-bromophenyl)ethyl)-5-(2-hydroxy-2-methylpropyl)-5- phenyl oxazolidin-2-one (300 mg, 46%).
Isomer 2: (Λ)-3-((^-l-(4-bromophenyl)-ethyl)-5-(2-hydroxy-2-methylpropyl)-5- phenyloxazolidin-2-one (300 mg, 46%).
EXAMPLE 5 Isomer 1
(S)-5-(2-hydroxy-2-methylpropyl)-3-((S)-l-(4-(l-methyl-2-oxo-l,2-dihydropyridin-4- yl)phenyl)ethyl)-5-phenyloxazolidin-2-one
KOAc Pd(PPh3J2CI2
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Step 1
To a solution of (£>3-((S)-l-(4-bromophenyl)-ethyl)-5-(2-hydroxy-2- methylpropyl)-5- phenyloxazolidin-2-one (300 mg, 0.72 mmol) in DMSO (10 mL) was added 4,4,5,5 -tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (560 mg, 2.16 mmol), CH3COOK (995 mg, 10.13 mmol), and Pd(dppf)Cl2 (60 mg, 0.076 mmol) under N2. The mixture was stirred at 90 °C for 2 h. The reaction was quenched with H2O, and extracted with EtOAc. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC to give (5)-5-(2-hydroxy-2-methylpropyl)-5-phenyl-3-((5)-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-phenyl)-ethyl)-oxazolidin-2-one (150 mg, 45%).
Step 2
A mixture of compound (5)-5-(2-hydroxy-2-methylpropyl)-5-phenyl-3-((iS)-l-(4-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethyl)oxazolidin-2-one (120 mg,
0.26 mmol), 4-iodo-l-methylpyridin-2(lH)-one (67 mg, 0.28 mmol), Pd(PPh3)2Cl2 (30 mg) and aq Cs2CO3 (2 N, 2 mL ) solution in 1,4-dioxane (8 mL) was stirred under N2 atmosphere at 100 0C for 2 h. LC-MS showed the reaction was complete. Water (5 mL) was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC^ and concentrated. The residue was purified by preparative TLC to give (5)-5-(2-hydroxy-2-methylpropyl)-3-((5)-l-(4-(l-methyl-2- oxo-l,2-dihydropyridin-4-yl)phenyl)ethyl)-5-phenyloxazolidin-2-one (65 mg, yield 56%). 1H NMR (CDCl3 400 MHz): 51.05 (s, 3H), 1.07 (s, 3H), 1.53 (d, 3H), 1.68 (s, IH), 2.28 (s, 2H), 3.15 (d, IH), 3.50 (s, 3H), 3.71 (m, IH), 5.14 (m, IH), 5.23 (s, IH), 6.28 (d, IH), 6.63 (s, IH), 7.03 (d, 2H), 7.19-7.29 (m, 8H).
EXAMPLE 5 Isomer 2
(R)-5 -(2-hydroxy-2-methylpropyl)-3 -((S)- 1 -(4-( 1 -methyl-2-oxo- 1 ,2-dihydropyridin-4- yl)phenyl)ethyl)-5-phenyloxazolidin-2-one
KOAc Pd(PPh3J2CI2
Figure imgf000059_0001
Figure imgf000059_0003
Figure imgf000059_0002
The title compound was prepared following a procedure analogous to that described in for Example 5 Isomer 1, using (R)-3-((S)-l-(4-bromophenyl)ethyl)-5-(2- hydroxy-2-methylpropyl)-5-phenyloxazolidin-2-one in Step 1. 1H NMR (CDCl3 400 MHz): (51.02 (s, 3H), 1.06 (s, 3H), 1.45 (d, 3H), 1.71 (s, IH), 2.20 (m, 2H), 3.40 (d, IH), 3.48 (d, IH), 3.60 (s, 3H), 5.28 (m, IH), 6.45 (d, IH), 6.80 (s, IH), 7.28-7.45 (m, 8H), 7.58 (d, 2H).
EXAMPLE 6
5-(3-hydroxy-3-methylbutyl)-3-((S)-l-(4-(l-methyl-2-oxo-l,2-dihydropyridin-4- yl)phenyl)ethyl)-5-phenyloxazolidin-2-one
Figure imgf000060_0001
Steps 1-3
Procedures analogous to those described in Example 4 Steps 1-3 were followed using allylmagnesium bromide in Step 2.
Step 4
To a solution of 5-allyl-3-((S)-l-(4-bromophenyl)ethyl)-5-phenyloxazolidin-2- one (1 g, 2.59 mmol) in THF (10 mL) was added BH3-THF (10 mL, lOmmol) at 0 0C under nitrogen. The mixture was stirred for 2 h, and quenched with water. The aqueous NaOH solution (2 mL, 3 M) and H2O2 (5 mL) was added into the mixture. When the reaction was finished, the mixture was extracted with EtOAc and concentrated to give 3- ((S)- 1 -(4-bromophenyl)ethyl)-5 -(3 -hydroxypropyl)-5-phenyloxazolidin-2-one (0.98 g, yield 93.63%).
Step 5
To a solution of 3-((S)-I -(4-bromophenyl)ethyl)-5-(3-hydroxypropyl)-5- phenyloxazolidin-2-one (0.98 g, 2.42 mmol) in acetone (20 mL) was added Jones reagent (8 mL, 2.5mol/L) at 0 0C. The solution was stirred at room temperature for 30 min. Solvent was removed in vaccum, and the residue was dissolved in a mixture of CH2Cl2 and water. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-(3-((S)-l-(4-bromophenyl)ethyl)-2-oxo-5- phenyloxazolidin-5-yl)propanoic acid (270 mg, 26.60%). Step 6
To a solution of 3-(3-((S)-l-(4-bromophenyl)ethyl)-2-oxo-5-phenyloxazolidin-5- yl)propanoic acid (270 mg, 0.645 mmol) in MeOH (10 mL) was added SOCl2 (5 niL) at 00C under nitrogen. The reaction mixture was stirred at room temperature for 2 h, concentrated, and purified by prep TLC (3: 1 PE/EA) to afford methyl 3-(3-((S)-l-(4- bromophenyl)ethyl)-2-oxo-5-phenyloxazolidin-5-yl)propanoate (74 mg, 53%) & methyl 3-((/?)-3-((S)-l-(4-bromophenyl)ethyl)-2-oxo-5-phenyloxazolidin-5-yl)propanoate (73 mg, 52.32%).
Figure imgf000061_0001
Isomer 1
Figure imgf000061_0002
Step 7
To a solution of methyl 3-(3-((S)-l-(4-bromophenyl)ethyl)-2-oxo-5- phenyloxazolidin-5-yl)propanoate isomer 1 (74 mg, 0.171 mmol) in THF (5 mL) was added MeMgBr (0.57 mL, 1.71 mmol) dropwise at -78 0C under nitrogen. The reaction mixture was stirred at -78°C for 30 min., at room temperature for 30 min. The reaction mixture was quenched with water, and extracted with EtOAc. The combined organic layer was concentrated to give an oil, which was purified by prep TLC to give 3-((S)-I- (4-bromophenyl)ethyl)-5-(3-hydroxy-3-methylbutyl)-5-phenyloxazolidin-2-one isomer 1 (70 mg, yield 94.59%).
Steps 8 and 9
Procedures analogous to those described in Example 5 Steps 1 and 2 were followed starting with 3-((S)-l-(4-bromophenyl)ethyl)-5-(3-hydroxy-3-methylbutyl)-5- phenyloxazolidin-2-one isomer 1 to afford 5-(3-hydroxy-3-methylbutyl)-3-((S)-l-(4-(l- methyl-2-oxo-l ,2-dihydropyridin-4-yl)phenyl)ethyl)-5-phenyloxazolidin-2-one isomer 1. LC-MS Method 2 tR = 1.00 min, m/z = 461, 443.
Procedures analogous to those described in Example 5 Steps 1 and 2, were followed starting with 3-((S)-l-(4-bromophenyl)ethyl)-5-(3-hydroxy-3-methylbutyl)-5- phenyloxazolidin-2-one isomer 2 to afford 5-(3-hydroxy-3-methylbutyl)-3 -((S)-I -(4-(I- methyl-2-oxo-l ,2-dihydropyridin-4-yl)phenyl)ethyl)-5-phenyloxazolidin-2-one isomer 2. LC-MS Method 2 tR = 0.95 min, m/z = 461.
EXAMPLE 7
5-Methyl-5-phenyl-3-m-tolyloxazolidin-2-one
Figure imgf000062_0001
Step 1
To a stirred solution of 2-phenylpropane-l,2-diol (1.56 g, 10.3 mmol) and i- Pr2NEt (1.5 mL, 1 1.4 mmol) and DMAP (1 crystal) in CH2Cl2 (40 mL) was added solid p-toluenesulfonyl chloride (1.95 g, 10.3 mmol). The mixture was stirred at rt for 3 d. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (2 x 30 mL) and satd aq NaHCO3 (30 mL), and dried over MgSO4. Removal of the salt left an oil (2.29 g) which was purified by chromatography on a 12-g silica cartridge eluted with a 0-50% EtOAc in hexanes gradient to afford 2-hydroxy-2-phenylpropyl 4- methylbenzenesulfonate (1.17 g, 37%).
Step 2 To a stirred solution of 2-hydroxy-2-phenylpropyl 4-methylbenzenesulfonate
(125 mg, 0.41 mmol) in THF (5 mL) was added 3-methylphenyl isocyanate (0.058 mL, 0.45 mmol), followed by DBU (0.075 mL, 0.49 mmol). The mixture was stirred at rt for 4 h and heated at reflux for 20 h. The mixture was diluted with ether (80 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent left an oil (70 mg) which was applied to a 2-g silica SPE cartridge which was eluted sequentially with 0, 10, 25, 50, 75 and 100% EtOAc in hexanes to give six fractions. Fractions 1 and 2 were pooled and concentrated to leave an oil (19 mg) which was purified prep HPLC to afford 5-methyl-5-phenyl-3-m- tolyloxazolidin-2-one (2.4 mg, 2%). LC-MS Method 1 tR = 1.92 min, m/z = 268; 1H NMR (CDCl3) 1.87 (s, 3H), 2.35 (s, 3H), 4.12 (m, 2H), 6.94 (d, IH), 7.2-7.5 (8H).
BIOLOGICAL TEST EXAMPLE 1
The inhibition of microsomal preparation of 1 lβ-HSDl by compounds of the invention was measured essentially as previously described (K. Solly, S. S. Mundt, H.J. Zokian, GJ. Ding, A. Hermanowski-Vosatka, B. Strulovici, and W. Zheng, High- Throughput Screening of 11 -Beta-Hydroxysteroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactions were carried out at room temperature in 96 well clear flexible PET Microbeta plates (PerkinElmer). The assay begins by dispensing 49 μl of substrate solution (5OmM HEPES3 pH 7.4, 10OmM KCl, 5mM NaCl, 2mM MgCl2, 2 mM NADPH and 160 nM [3H]cortisone (1 Ci/mmol)) and mixing in 1 μL of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL of enzyme solution containing microsomes isolated from CHO cells overexpressing human 1 lβ-HSDl (10-20 μg/ml of total protein) was added, and the plates were incubated for 90 minutes at room temperature. The reaction was stopped by adding 50 μl of the SPA beads suspension containing 10 μM 18β- glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 μg/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad). The plates were shaken for 120 minutes at room temperature, and the SPA signal corresponding to [3H]cortisol was measured on a Microbeta plate reader.
BIOLOGICAL TEST EXAMPLE 2
The inhibition of 1 lβ-HSDl by compounds of this invention was measured in whole cells as follows. Cells for the assay were obtained from two sources: fully differentiated human omental adipocytes from Zen-Bio, Inc.; and human omental pre- adipocytes from Lonza Group Ltd. Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchased in 96-well plates and were used in the assay at least two weeks after differentiation from precursor preadipocytes. Zen-Bio induced differentiation of pre- adipocytes by supplementing medium with adipogenic and lipogenic hormones (human insulin, dexamethasone, isobutylmethylxanthine and PPAR-gamma agonist). The cells were maintained in full adipocyte medium (DMEM/Ham's F- 12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B, supplied by Zen- Bio, Inc.) at 370C, 5% CO2.
Pre-adipocytes were purchased from Lonza Group Ltd. and placed in culture in Preadipocyte Growth Medium-2 supplemented with fetal bovine serum, penicillin, and streptomycin (supplied by Lonza) at 370C, 5% CO2. Pre-adipocytes were differentiated by the addition of insulin, dexamethasone, indomethacin and isobutyl-methylxanthine (supplied by Lonza) to the Preadipocyte Growth Medium-2. Cells were exposed to the differentiating factors for 7 days, at which point the cells were differentiated and ready for the assay. One day before running the assay, the differentiated omental adipocytes were transferred into serum- and phenol-red- free medium for overnight incubation. The assay was performed in a total volume of 200 μL. The cells were pre-incubated with serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSO and various concentrations of the test compounds at least 1 h before [3H] cortisone in ethanol (50Ci/mmol, ARC, Inc.) was added to achieve a final concentration of cortisone of 100 nM. The cells were incubated for 3-4 hrs at 370C, 5% CO2. Negative controls were incubated without radioactive substrate and received the same amount of [3H] cortisone at the end of the incubation. Formation of [3H] Cortisol was monitored by analyzing 25 μL of each supernatant in a scintillation proximity assay (SPA). (Solly, K.; Mundt, S. S.;Zokian, HJ.;Ding, G. J.; Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev. Technol. 2005, 3, 377-384). Many compounds of the invention showed significant activity in this assay.
TABLE OF BIOLOGICAL ASSAY RESULTS
Biological Test Example la
Average %
Compound IC50 Range inhibition at 10O nM
Example 1 Isomer 1 nt nt Example 1 Isomer 2 nt nt Example 2 Isomer 1 ++ 78.3 Example 2 Isomer 2 # 16.9 Example 3 Isomer 1 ++ 91.4 Example 3 Isomer 2 # 19.1 Example 4 Isomer 1 nt nt Example 4 Isomer 2 nt nt Example 5 Isomer 1 H- 51.9 Example 5 Isomer 2 # 3.4 Example 6 Isomer 1 # 18.4 Example 6 Isomer 2 # 19.8 Example 7 5.4
++ means IC50 = <100 nM, + means IC50 = 100 - 1000 nM, # means IC50 > 100 nM, nt means not tested.
PROPHETIC COMPOUND TABLES
TABLE 1
Figure imgf000065_0001
Ia CHMe 3-Me-Ph bond H bond Ph Me
2a CHMe 3-Br-Ph bond H bond Ph Me
3a bond 1,3-C6H4 bond Ph bond Ph Me
4a bond 1,3-C6H4 bond 2-Cl-Ph bond Ph Me
5a bond 1,3-C6H4 bond 2-NC-Ph bond Ph Me
6a bond 1,3-C6H4 bond 2-MeO-Ph bond Ph Me
7a bond 1,3-C6H4 bond 2,6-diCl-Ph bond Ph Me
8a bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph Me
9a bond 1,3-C6H4 bond 3-Cl-Ph bond Ph Me
10a bond 1,3-C6H4 bond 3-F-Ph bond Ph Me
11a bond 1,3-C6H4 bond 2,5-diF-Ph bond Ph Me
12a bond 1,3-C6H4 bond 3,5-diF-Ph bond Ph Me a bond 1 ,3-C6H4 bond 4-F-Ph bond Ph Me a bond 1 ,3-C6H4 bond 2-F-Ph bond Ph Me a bond 2,6-pyridyl bond 2-Cl-4-F-Ph bond 2-F-Ph HOCH2CH2a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)CH2a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH(OH)CH2a bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Ph allyl a bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2a bond 1 ,3-(4-F)C6H3 bond 4-F-Ph bond 4-F-Ph HOCH2CH2a bond 1,3-(4-F)C6H3 bond 4-F-Ph bond 2-F-Ph HOCH2CH2a bond 1 ,3-C6H4 bond 2-Cl-4-F-Ph bond Ph HOCH2CH2a bond 1,3-C6H4 bond 2,6-diCl-Ph bond Ph HOCH2CH2a bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph H2NC(=O)CH2a CH 1,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH(OH)CH2a bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2a bond 1 ,3-C6H4 bond Ph bond 3-Cl-Ph Me
2-a bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Me pyridyl a CHMe Ph bond H bond Ph Me a CHMe 3-MeO-Ph bond H bond Ph Me a CHMe 4-MeO-Ph bond H bond Ph Me
2-Me-a CHMe Ph bond H bond Me Ph
4-Me-a CHMe Ph bond H bond Me Ph
4-MeS-a CHMe Ph bond H bond Me Ph a CHMe Ph bond H bond 4-F-Ph allyl a bond 1 ,3-C6H4 bond 4-F-Ph bond Ph HOCH2CH2a CHMe Ph bond H bond 4-F-Ph HOCH2CH2a bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Ph MeSO2NHCH2CH2a bond l ,3-(4-F)C6H3 bond 2-Cl-4-F-Ph bond 4-F-Ph HOCH2CH2a bond 1 ,3-C6H4 bond 2-Cl-4-F-Ph bond Ph HOCH2CH2a bond 2,6-pyridyl bond 4-F-Ph bond Ph HOCH2CH2a bond 2,6-pyridyl bond 4-F-Ph bond 4-F-Ph HOCH2CH2a bond 2,6-pyridyl bond 4-F-Ph bond 2-F-Ph HOCH2CH2a bond 1,3-(4-F)C6H3 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2 45a bond 1 ,3-(4-F)C6H3 bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2
46a bond 2,6-pyπdyl bond 2,4-diF-Ph bond Ph HOCH2CH2
47a bond 2,6-pyridyl bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2
48a bond 2,6-pyridyl bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2
49a CHMe 4-Br-Ph bond H bond 4-F-Ph allyl
50a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph allyl
51a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2
52a CHMe Ph bond H bond 4-F-Ph vinyl
53a CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2
54a bond 2,6-pyπdyl bond 2-Cl-4-F-Ph bond Ph HOCH2CH2
55a bond 2,6-pyridyl bond 2-Cl-4-F-Ph bond 4-F-Ph HOCH2CH2
56a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2
57a CHMe c-hex bond H bond 4-F-Ph allyl
58a CHMe c-hex bond H bond 4-F-Ph HOCH2CH2CH2
59a CHMe 1 ,4-C6H4 bond c-Pr bond 4-F-Ph allyl
60a CHMe 4-MeO2C-Ph bond H bond 4-F-Ph allyl
61a CHMe 1 ,3-C6H4 bond c-Pr bond 4-F-Ph HOCH2CH2CH2
62a CHMe 4-MeO2C-Ph bond H bond 4-F-Ph HOCH2CH2CH2
63a CHEt 4-Br-Ph bond H bond 4-F-Ph allyl
64a bond 2,6-(5-Cl)-pyridyl bond 4-F-Ph bond 2-F-Ph HOCH2CH2
65a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2CH2
66a bond 2,6-(5-Cl)-pyridyl bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2
67a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2
68a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCH(OH)CH2
69a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeC(=0)CH2
70a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOC(Me)2CH2
71a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeOCH2CH2
72a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)NHCH2CH2
73a CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2
74a CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
75a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCOCH2CH2
76a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)CH2CH2 77a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCONHCH2CH2
78a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCC=O)OCH2CH2
79a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2NHCH2CH2
80a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2OCH2CH2
81a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph (HO)2PC=O)OCH2CH2
82a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2CC=O)NHCH2CH2
83a CHMe 4-HOCH2-Ph bond H bond 4-F-Ph HOCH2CH2CH2
84a CHMe 4-HOC(Me)2-Ph bond H bond 4-F-Ph allyl
2-
85a CHMe 4-Br-Ph bond H bond ally! thienyl
86a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2
2-
87a CHMe 1 ,4-C6H4 bond 4-F-Ph bond allyl thienyl
88a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
89a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2
2-
90a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond allyl thienyl
2-
91a CHMe 1 ,4-C6H4 bond 4-F-Ph bond HOCH2CH2CH2 thienyl
2-
92a CHMe 1 ,4-C6H4 bond 4-F-Ph bond MeCH(OH)CH2 thienyl
93a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH(OH)CH2
94a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2
95a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph MeCH(OH)CH2
2-
96a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond HOCH2CH2CH2 thienyl
97a CHMe Ph bond 2,4-diF-Ph bond 4-F-Ph NCCH2CH2
98a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH(OH)CH2
99a CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2
100a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOC(=O)CH2CH2
101 a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2NHCH2CH2
102a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2C(=O)NHCH2CH2
103a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeOC(=O)NHCH2CH2
104a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-(4-morpholino)ethyl
105a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph EtNHCONHCH2CH2
106a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=NCN)NHCH2CH2
107a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2CH2
108a CHMe 4-Cl-Ph bond H bond i-Pr HOCH2CH2CH2 109a CHMe 4-Me-Ph bond H bond 4-F-Ph allyl
1 10a CHMe 4-MeO-Ph bond H bond Ph HOCH2CH2
I l i a CHMe 4-MeO-Ph bond H bond 4-F-Ph allyl
1 12a CHMe 4-HOCH2-Ph bond H bond Ph HOCH2CH2CH2
1 13a CHMe 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH2
1 14a CHMe 4-Cl-Ph bond H bond 4-F-Ph allyl
1 15a CHMe c-hex bond H bond Ph HOCH2CH(OH)CH2
1 16a CHMe 4-HOCH2CH2-Ph bond H bond Ph HOCH2CH2CH2
1 17a CHMe 4-MeOCH2-Ph bond H bond Ph HOCH2CH2CH2
1 18a CHMe 4-Br-Ph bond H bond i-Pr HOCH2CH2CH2
1 19a CHMe 4-Cl-Ph bond H bond 4-F-Ph HOCH2CH2CH2
120a CHMe 4-Cl-Ph bond H bond 4-F-Ph MeCH(0H)CH2
121 a CHMe 4-Br-Ph bond H bond Ph allyl
122a CHMe 1,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2
123a CHMe 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
124a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2
Figure imgf000069_0001
125a bond BuOC(=O))pyrrolidin- bond H bond Ph HOCH2CH2CH2 3-yl
126a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2
127a CHMe 1 ,4-C6H4 bond 4-pyridyl bond Ph HOCH2CH2CH2
128a CHMe 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2CH2
129a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2CH2
130a CHMe 1 ,4-C6H4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2
13 1 a CHMe 1 ,4-C6H4 bond 2-thienyl bond Ph HOCH2CH2CH2
132a CHMe 1 ,4-C6H4 bond 4-morpholinyl bond 4-F-Ph allyl
2-
133a CHMe 1 ,4-C6H4 bond 4-F-Ph bond HOCH2CH2 thienyl
134a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph NCCH2CH2
135a CHEt 4-Br-Ph bond H bond Ph HOCH2CH2CH2
136a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2
137a CHMe 1 ,4-C6H4 bond l-oxo-3-pyridyl bond Ph HOCH2CH2CH2
138a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH(OH)CH2
139a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph MeCH(OH)CH2
140a CHMe 1 ,4-C6H4 bond 3-pyridy] bond 4-F-Ph HOCH2CH2CH2 141a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph Pr
142a CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
143a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2CH2CH2
5-Me-l, 3,4-
144a CHMe 1 ,4-C6H4 bond bond 4-F-Ph allyl th iadiazol-2-yl
2-
145a CHMe 1,4-C6H4 bond 4-F-Ph bond HOCH2CH2CH2 thienyl
CHMe 2-
146a 1 ,4-C6H4 bond 2,4-diF-Ph bond HOCH2CH2 thienyl
147a CHMe 1,4-C6H4 bond 4-F-Ph bond Ph H2NCOCH2CH2
148a CHMe 1,4-C6H4 bond 2-MeO-5-pyridyl bond Ph HOCH2CH2CH2
149a CHMe 1 ,4-C6H4 bond 3-pyridyl bond 4-F-Ph H2NCOCH2CH2
150a CHEt 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
151a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOC(Me)2CH2
152a CHEt 4-Br-Ph bond H bond Ph HOCH2CH(OH)CH2
153a CHMe 4-Br-Ph bond H bond 4-F-Ph H2NCOCH2CH2
154a CHEt 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
155a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph NCCH2
2,4-diMe-5-
156a CHMe 1 ,4-C6H4 bond bond 4-F-Ph allyl thiazolyl
157a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
158a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 2-F-Ph HOCH2CH2CH2
159a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 3-F-Ph HOCH2CH2CH2
160a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOC(Me)2CH2CH2
161a CHMe 1 ,4-C6H4 bond 5-MeCO-2-thienyl bond Ph HOCH2CH2CH2
162a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph H2NCOCH2CH2
5-(H2NCHMe)-2-
163a CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 thienyl
164a CHEt 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
165a CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2
5-(HOCHMe)-2-
166a CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 thienyl
167a CHEt 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
168a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2CH2CH2
169a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCH2CH2
3-(CF3)- 1-
170a CHMe 1 ,4-C6H4 bond bond 4-F-Ph allyl pyrazolyl
171a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOC(Me)2CH2CH2
172a CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2 173a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSCH2CH2
174a CHMe Ph bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)NHCH2CH2
175a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)OCH2CH2
176a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2OCH2CH2
177a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-(l-imidazolyl)ethy]
178a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCONMeCH2CH2
179a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph MeSO2NHCH2CH2CH2
180a CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)NHCH2CH2CH2
181a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)OCH2CH2CH2
182a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-( 1 -aminoimidazol- 1 -y l)ethyl
183a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCC=O)NHCH2CH2CH2
184a CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)NHCH2CH(OH)CH2
185a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NHCH2CH(OH)CH2
186a CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NMeCH2CH(OH)CH2
187a CHMe 1 ,4-C6H4 bond 6-CF3-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
188a CHMe 4-MeO-Ph bond H bond Ph HOCH2CH2CH2
189a CHMe 3-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
190a CHMe 2-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
191a CHMe 4-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
192a CHMe 4-MeO-Ph bond H bond Ph HOCH2CH(OH)CH2
193a CHMe 4-Cl-Ph bond H bond Ph H2NCOCH2CH2
194a CHMe 4-MeO-Ph bond H bond 4-F-Ph H2NCOCH2CH2
195a CHMe 4-F2HCO-Ph bond H bond 4-F-Ph allyl
196a CHMe Ph bond 3-pyrazolyl bond Ph HOCH2CH2CH2
197a CHMe 1 ,4-C6H4 bond 5-F-3-pyridyl bond Ph allyl
198a CHMe 3-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
199a CHMe 4-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
200a CHMe 1,4-C6H4 bond 3-pyridyl bond Ph H2NCOCH2CH2
201 a CHMe 1 ,4-C6H4 bond 4-pyridyl bond Ph H2NCOCH2CH2
202a CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
203 a CHMe 1 ,4-C6H4 bond 5-F-3-pyridyl bond Ph HOCH2CH2CH2
204a CHMe 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2 205a CHMe 1,4-C6H4 bond 5-F-3-pyπdyl bond 4-F-Ph HOCH2CH2CH2
206a CHMe 1,4-C6H4 bond 4-F-Ph bond Ph NCC(Me)2CH2
207a CHMe 1 ,4-C6H4 bond 6-MeO-3-pyridyl bond Ph H2NCOCH2CH2
208a CHMe 1 ,4-C6H4 bond 5-MeO-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
209a CHMe 1 ,4-C6H4 bond 5-Cl-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
210a CHMe 1,4-C6H4 bond 3-pyridyl bond Ph MeSO2NHCH2CH2
21 1a CHMe 4-F2HCO-Ph bond H bond 4-F-Ph HOCH2CH2CH2
212a CHMe 1,4-C6H4 bond 4-F-Ph bond Ph (HO)2P(=O)OCH2CH2CH2
213a CHMe 1,4-C6H4 bond 2-Me-4-pyridyl bond 4-F-Ph HOCH2CH2CH2
214a CHMe 1,4-C6H4 bond H bond Ph HOCH2CH2CH2 l -Me-6-oxo-3-
215a CHMe 1 ,4-C6H4 bond ( 1 ,6- bond Ph HOCH2CH2CH2 dihydropyridyl)
216a CHMe 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
217a CHMe 4-MeO-Ph bond H bond Ph H2NCOCH2CH2
218a CHMe 4-F-Ph bond H bond 4-F-Ph H2NCOCH2CH2
219a CHMe c-hex bond H bond 4-F-Ph H2NCOCH2CH2
220a bond 1 ,3-(4-F)C6H3 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2
221a CHMe c-hex bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
A2
A1-
8 Cy1 = 1,3-C6H4 means / Cy1 = 1 ,4-C6H4 means AMC^A2
Cy1 = 1,3 -(4-F)C6H3 means
Figure imgf000072_0001
Cy ,!1 _ = 2,6-(5-Cl)-pyridyl means A2
10
TABLE 2
Figure imgf000073_0001
Ib CHMe 3-Me-Ph bond H bond Ph Me
2b CHMe 3-Br-Ph bond H bond Ph Me
3b bond 1,3-C6H4 bond Ph bond Ph Me
4b bond 1,3-C6H4 bond 2-Cl-Ph bond Ph Me
5b bond 1,3-C6H4 bond 2-NC-Ph bond Ph Me
6b bond 1,3-C6H4 bond 2-MeO-Ph bond Ph Me
7b bond 1,3-C6H4 bond 2,6-diCI-Ph bond Ph Me
8b bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph Me
9b bond 1,3-C6H4 bond 3-Cl-Ph bond Ph Me
10b bond 1,3-C6H4 bond 3-F-Ph bond Ph Me lib bond 1,3-C6H4 bond 2,5-diF-Ph bond Ph Me
12b bond 1,3-C6H4 bond 3,5-diF-Ph bond Ph Me
13b bond 1,3-C6H4 bond 4-F-Ph bond Ph Me
14b bond 1,3-C6H4 bond 2-F-Ph bond Ph Me
15b bond 2,6-pyridyl bond 2-Cl-4-F-Ph bond 2-F-Ph HOCH2CH2
16b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)CH2
17b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH(OH)CH2
18b bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph allyl
19b bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2
20b bond 1,3-(4-F)C6H3 bond 4-F-Ph bond 4-F-Ph HOCH2CH2
21b bond 1,3-(4-F)C6H3 bond 4-F-Ph bond 2-F-Ph HOCH2CH2
22b bond 1,3-C6H4 bond 2-Cl-4-F-Ph bond Ph HOCH2CH2
23b bond 1,3-C6H4 bond 2,6-diCI-Ph bond Ph HOCH2CH2
24b bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph H2NC(=O)CH2
25b CH 1,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH(OH)CH2 b bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2
3-C1-b bond 1,3-C6H4 bond Ph bond Me Ph
2-b bond 1 ,3-C6H4 bond 2,4-diF-Ph bond Me pyridyl b CHMe Ph bond H bond Ph Me b CHMe 3-MeO-Ph bond H bond Ph Me b CHMe 4-MeO-Ph bond H bond Ph Me
2-Me-b CHMe Ph bond H bond Me Ph
4-Me-b CHMe Ph bond H bond Me Ph
4-b CHMe Ph bond H bond MeS- Me Ph b CHMe Ph bond H bond 4-F-Ph allylb bond 1 ,3-C6H4 bond 4-F-Ph bond Ph HOCH2CH2b CHMe Ph bond H bond 4-F-Ph HOCH2CH2b bond 1,3-C6H4 bond 2,4-diF-Ph bond Ph MeSO2NHCH2CH2b bond l,3-(4-F)C6H3 bond 2-Cl-4-F-Ph bond 4-F-Ph HOCH2CH2b bond 1 ,3-C6H4 bond 2-Cl-4-F-Ph bond Ph HOCH2CH2b bond 2,6-pyridyl bond 4-F-Ph bond Ph HOCH2CH2b bond 2,6-pyridyl bond 4-F-Ph bond 4-F-Ph HOCH2CH2b bond 2,6-pyridyl bond 4-F-Ph bond 2-F-Ph HOCH2CH2b bond 1,3-(4-F)C6H3 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2b bond 1,3-(4-F)C6H3 bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2b bond 2,6-pyridyl bond 2,4-diF-Ph bond Ph HOCH2CH2b bond 2,6-pyridyl bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2b bond 2,6-pyridyl bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2b CHMe 4-Br-Ph bond H bond 4-F-Ph allylb CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph allylb CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2b CHMe Ph bond H bond 4-F-Ph vinylb CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2b bond 2,6-pyridyl bond 2-Cl-4-F-Ph bond Ph HOCH2CH2b bond 2,6-pyridyl bond 2-Cl-4-F-Ph bond 4-F-Ph HOCH2CH2b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2b CHMe c-hex bond H bond 4-F-Ph allyl 58b CHMe c-hex bond H bond 4-F-Ph HOCH2CH2CH2
59b CHMe 1 ,4-C6H4 bond c-Pr bond 4-F-Ph allyl
60b CHMe 4-MeO2C-Ph bond H bond 4-F-Ph allyl
61b CHMe 1 ,3-C6H4 bond c-Pr bond 4-F-Ph HOCH2CH2CH2
62b ■ CHMe 4-MeO2C-Ph bond H bond 4-F-Ph HOCH2CH2CH2
63b CHEt 4-Br-Ph bond H bond 4-F-Ph allyl
64b bond 2,6-(5-CI)-pyridyl bond 4-F-Ph bond 2-F-Ph HOCH2CH2
65b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2CH2
66b bond 2,6-(5-Cl)-pyridyl bond 2,4-diF-Ph bond 2-F-Ph HOCH2CH2
67b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2
68b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCH(OH)CH2
69b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeC(=0)CH2
70b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOC(Me)2CH2
71b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeOCH2CH2
72b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(^O)NHCH2CH2
73b CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2
74b CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
75b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCOCH2CH2
76b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)CH2CH2
77b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCONHCH2CH2
78b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)OCH2CH2
79b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2NHCH2CH2
80b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2OCH2CH2
81b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph (HO)2P(=O)OCH2CH2
82b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2C(=O)NHCH2CH2
83b CHMe 4-HOCH2-Ph bond H bond 4-F-Ph HOCH2CH2CH2
84b CHMe 4-HOC(Me)2-Ph bond H bond 4-F-Ph allyl
2-
85b CHMe 4-Br-Ph bond H bond allyl thienyl
86b CHMe 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2
2-
87b CHMe 1,4-C6H4 bond 4-F-Ph bond allyl thienyl
88b CHMe 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
89b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2 2-
90b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond allyl thienyl
2-
91b CHMe 1 ,4-C6H4 bond 4-F-Ph bond thienyl HOCH2CH2CH2
2-
92b CHMe 1,4-C6H4 bond 4-F-Ph bond MeCH(OH)CH2 thienyl
93b CHMe 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH(OH)CH2
94b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2
95b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph MeCH(OH)CH2
2-
96b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond HOCH2CH2CH2 thienyl
97b CHMe Ph bond 2,4-diF-Ph bond 4-F-Ph NCCH2CH2
98b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH(OH)CH2
99b CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2
100b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOC(=O)CH2CH2
101b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2NHCH2CH2
102b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2C(=O)NHCH2CH2
103b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeOC(=O)NHCH2CH2
104b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-(4-morphoiino)ethyl
105b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph EtNHCONHCH2CH2
106b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=NCN)NHCH2CH2
107b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2CH2
108b CHMe 4-Cl-Ph bond H bond i-Pr HOCH2CH2CH2
109b CHMe 4-Me-Ph bond H bond 4-F-Ph allyl
HOb CHMe 4-MeO-Ph bond H bond Ph HOCH2CH2
I Ub CHMe 4-MeO-Ph bond H bond 4-F-Ph allyl
1 12b CHMe 4-HOCH2-Ph bond H bond Ph HOCH2CH2CH2
1 13b CHMe 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH2
114b CHMe 4-Cl-Ph bond H bond 4-F-Ph allyl
115b CHMe c-hex bond H bond Ph HOCH2CH(OH)CH2
116b CHMe 4-HOCH2CH2-Ph bond H bond Ph HOCH2CH2CH2
117b CHMe 4-MeOCH2-Ph bond H bond Ph HOCH2CH2CH2
1 18b CHMe 4-Br-Ph bond H bond i-Pr HOCH2CH2CH2
119b CHMe 4-Cl-Ph bond H bond 4-F-Ph HOCH2CH2CH2
120b CHMe 4-Cl-Ph bond H bond 4-F-Ph MeCH(0H)CH2
121b CHMe 4-Br-Ph bond H bond Ph allyl 122b CHMe 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2
123b CHMe 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
124b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2
Hr-
125b bond BuOC(=O))pyττolidin- bond H bond Ph HOCH2CH2CH2 3-yl
126b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2
127b CHMe 1 ,4-C6H4 bond 4-pyridyl bond Ph HOCH2CH2CH2
128b CHMe 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2CH2
129b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2CH2
130b CHMe 1 ,4-C6H4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2
131b CHMe 1 ,4-C6H4 bond 2-thienyl bond Ph HOCH2CH2CH2
132b CHMe 1 ,4-C6H4 bond 4-morpholinyl bond 4-F-Ph allyl
2-
133b CHMe 1 ,4-C6H4 bond 4-F-Ph bond HOCH2CH2 thienyl
134b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph NCCH2CH2
135b CHEt 4-Br-Ph bond H bond Ph HOCH2CH2CH2
136b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2 l-oxo-3-
137b CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 pyridyl
138b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH(OH)CH2
139b CHMe 1,4-C6H4 bond 4-F-Ph bond Ph MeCH(OH)CH2
140b CHMe 1 ,4-C6H4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2CH2
141b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph Pr
142b CHMe 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
143b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2CH2CH2
5-Me-l,3,4-
144b CHMe 1,4-C6H4 bond bond 4-F-Ph allyl thiadiazol-2-yl
2-
145b CHMe 1,4-C6H4 bond 4-F-Ph bond HOCH2CH2CH2 thienyl
2-
146b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond HOCH2CH2 thienyl
147b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph H2NCOCH2CH2
2-MeO-5-
148b CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 pyridyl
149b CHMe 1 ,4-C6H4 bond 3-pyridyl bond 4-F-Ph H2NCOCH2CH2
150b CHEt 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
151b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOC(Me)2CH2
152b CHEt 4-Br-Ph bond H bond Ph HOCH2CH(OH)CH2 153b CHMe 4-Br-Ph bond H bond 4-F-Ph H2NCOCH2CH2
154b CHEt 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
155b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph NCCH2
2,4-diMe-5-
156b CHMe 1 ,4-C6H4 bond bond 4-F-Ph allyl thiazolyl
157b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
158b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 2-F-Ph HOCH2CH2CH2
159b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 3-F-Ph HOCH2CH2CH2
160b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOC(Me)2CH2CH2
5-MeCO-2-
161 b CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 thienyl
162b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph H2NCOCH2CH2
5-(H2NCHMe)-
163b CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 2-thienyl
164b CHEt 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
165b CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2
5-(HOCHMe)-
166b CHMe 1 ,4-C6H4 bond bond Ph HOCH2CH2CH2 2-thienyl
167b CHEt 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
168b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2CH2CH2
169b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCH2CH2
3-(CF3)- 1 -
170b CHMe 1 ,4-C6H4 bond bond 4-F-Ph allyl pyrazolyl
171b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond Ph HOC(Me)2CH2CH2
172b CHEt 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2CH2
173b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSCH2CH2
174b CHMe Ph bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)NHCH2CH2
175b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)OCH2CH2
176b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2OCH2CH2
177b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-(l -imidazolyl)ethyl
178b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeCONMeCH2CH2
179b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph MeSO2NHCH2CH2CH2
180b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)NHCH2CH2CH2
181 b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)OCH2CH2CH2
182b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph 2-( 1 -aminoimidazol- 1 -y l)ethy !
183b CHMe 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)NHCH2CH2CH2
184b CHMe 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)NHCH2CH(OH)CH2 185b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NHCH2CH(OH)CH2
186b CHMe 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NMeCH2CH(OH)CH2
6-CF3-3-
187b CHMe 1 ,4-C6H4 bond bond 4-F-Ph HOCH2CH2CH2 pyridyl
188b CHMe 4-MeO-Ph bond H bond Ph HOCH2CH2CH2
189b CHMe 3-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
190b CHMe 2-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
191b CHMe 4-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
192b CHMe 4-MeO-Ph bond H bond Ph HOCH2CH(OH)CH2
193b CHMe 4-Cl-Ph bond H bond Ph H2NCOCH2CH2
194b CHMe 4-MeO-Ph bond H bond 4-F-Ph H2NCOCH2CH2
195b CHMe 4-F2HCO-Ph bond H bond 4-F-Ph allyl
196b CHMe Ph bond 3-pyrazolyl bond Ph HOCH2CH2CH2
197b CHMe 1 ,4-C6H4 bond 5-F-3-pyridyl bond Ph allyl
198b CHMe 3-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
199b CHMe 4-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
200b CHMe 1 ,4-C6H4 bond 3-pyridyl bond Ph H2NCOCH2CH2
201b CHMe 1 ,4-C6H4 bond 4-pyridyl bond Ph H2NCOCH2CH2
202b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
203b CHMe 1 ,4-C6H4 bond 5-F-3-pyridyl bond Ph HOCH2CH2CH2
204b CHMe 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2
205b CHMe 1 ,4-C6H4 bond 5-F-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
206b CHMe 1 ,4-C6H4 bond 4-F-Ph bond Ph NCC(Me)2CH2
6-MeO-3-
207b CHMe 1,4-C6H4 bond bond Ph H2NCOCH2CH2 pyridyl
5-MeO-3-
208b CHMe 1 ,4-C6H4 bond bond 4-F-Ph HOCH2CH2CH2 pyridyl
209b CHMe 1 ,4-C6H4 bond 5-Cl-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
210b CHMe 1 ,4-C6H4 bond 3-pyridyl bond Ph MeSO2NHCH2CH2
21 1 b CHMe 4-F2HCO-Ph bond H bond 4-F-Ph HOCH2CH2CH2
212b CHMe 1,4-C6H4 bond 4-F-Ph bond Ph (HO)2P(O)OCH2CH2CH2
213b CHMe 1,4-C6H4 bond 2-Me-4-pyridyl bond 4-F-Ph HOCH2CH2CH2
214b CHMe 1,4-C6H4 bond H bond Ph HOCH2CH2CH2 l -Me-6-oxo-3-
215b CHMe 1,4-C6H4 bond (1,6- bond Ph HOCH2CH2CH2 dihydropyridyl) 216b CHMe 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2CH2 217b CHMe 4-MeO-Ph bond H bond Ph H2NCOCH2CH2
218b CHMe 4-F-Ph bond H bond 4-F-Ph H2NCOCH2CH2
219b CHMe c-hex bond H bond 4-F-Ph H2NCOCH2CH2
220b bond 1,3-(4-F)C6H3 bond 2, 4-diF-Ph bond 4-F-Ph HOCH2CH2
221b CHMe c-hex bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
Figure imgf000080_0001
Cy1 = 1 ,3-(4-F)C6H3 means
Figure imgf000080_0002
2,6-(5-Cl)-pyridyl means
A2
A1ΛJ~Q
All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually designated as having been
10 incorporated by reference. It is understood that the examples and embodiments described herein are for illustrative purposes only, and it will be appreciated that the invention is susceptible to modification, variation and change without departing from the proper scope or fair meaning of the appended claims.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000081_0001
wherein:
R1 is (a) absent or (b) selected from (Ci-C5)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(C]-C3)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4S, R4S(=O)-, R4SC=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4- , R4OC(=O)NR4-, CR4) 2NC(=NCN)NR4-, (R4O)2PC=O)O-, (R4O)2P(=O)NR4-, R4OSC=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4SC=O)2NHCC=O)-, R4SC=O)2NHCC=O)O-, R4S(=O)2NHC(=O)NR4-, R4OSC=O)2NHCC=O)-, R4OSC=O)2NHCC=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=0)2NHC(=O)-! (R4)2NS(=0)2NHC(=0)0-, (R4)2NS(=O)2NHC(=O)NR4-, R4CC=O)NHSC=O)2-, R4CC=O)NHSC=O)2O-, R4C(=O)NHS(=O)2NR4-,
R4OCC=O)NHSC=O)2-, R4OCC=O)NHSC=O)2O-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroaryl amino;
A1 is (a) a bond, or (b) (Ci-C3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2CC=O), wherein the carbonyl carbon is attached to Cy1;
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C]-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C^alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(C1-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci- C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (Cr C6)alkylamino(Ci-C6)alkyl, di(Ci-C5)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C i- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaniinocarbonyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminocarbonyl, di^-Cδ^ycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(CrC6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Cr C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (CrC6)alkylaminocarbonyl(Ci-C6)aIkyl, di(Cr C6)alkylaminocarbonyl(CrC6)alkyl, (C3-C6)cycloalkylatninocarbonyl(CrC6)alkyl, ((C3- C6)cycloalkyl} {(CrC6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl;
A2 is (a) a bond, O, S or NR4; or (b) (Ci-C3)alkylene or (Ci-C2)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(d- C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C i -C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfmyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkyl- alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Cr C6)alkoxy(C i -C6)alkoxy, halo(C i -C6)alkoxy(C i -C6)alkoxy, (C i -C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(C i -C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C i -C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-Cg)alkylsulfonylamino, (Ci-
C6)alkylsulfonylamino(C i -C6)alkyl , (C i -Ce)alkoxycarbonyl(C i -Cόjalkoxy, (C i - C6)alkoxy(C i -C6)alkyl, halo(C i-C6)alkoxy(C , -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(C i -C6)alky 1 amino(C2-C6)alkoxy, (C i -Cδ)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy: (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C<j)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl) {(d- C6)alkyl} aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(CrC6)alkyl, di(Cr C6)alkyIaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3-
C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl(C,-C6)alkyl and di(C3-
C6)cycloalkylaminocarbonyl(Ci-C6)alkyl;
Y is (C,-C6)alkyl or halo(Ci-C6)alkyl;
n is 0, 1 or 2;
E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-Ce)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(C]-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Cr C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C]-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(d- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C]-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cr C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C^alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (C]-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -Cδ)alkoxy, (C i - C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy(Ci-C6)alkyl:, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(C[-C6)alkyl, di(Ci- C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (C]-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(C|-C6)alkyl}aminocarbonyl, di(C3- C6)cycloa!kylaminocarbonyl, (C3-C6)cyc!oalkylaminosulfonyl, {(C3-C6)cycloalkyl} ((C1- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(C1-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(C,-
C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyl} ((Ci-C5)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(C|-C6)alkyl; R3 is selected from (C2-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(Ci- C3)alkyl, wherein the (C2-C6)alkyl is substituted with, and each of the (C2-C6)alkenyl, (C2-C6)alkynyl and (Ci-C3)alkoxy(Ci-C3)alkyl is optionally substituted with, up to four groups independently selected from fluorine, cyano, oxo, halo(Ci-C6)alkyl, amino(Ci- C6)alkyl, (C i -C6)alkylamino(C i -C6)alkyl, di(C , -C6)alkylamino(C i -C6)alkyl, hydroxy(C i - C6)alkyl, (C,-C6)alkoxy(C1-C6)alkyl, R4O-, (R4)2N-, R4O2C-, R4S, R4S(=O)-, R4S(=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-, R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-: R4OS(=O)2NHC(=O)-,
R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-, R4C(=O)NHS(=O)2O-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-, R4OC(=O)NHS(=O)2O-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl- substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); provided that if Q is NR5, A1 is methylene, R1 is absent, Cy1 is optionally substituted phenyl, A2 is a bond, Cy2 is hydrogen, E is a bond and R2 is optionally substituted phenyl, then R3 is not hydroxy ethyl or hydroxypropyl;
R4 is independently selected from H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl, (C i -C6)alkylamino(C , -C6)alkyl, di(C , -C6)alkylamino(C i -C6)alkyl, hydroxy (C i -C6)alkyl and (Ci-C6)alkoxy(Ci-C6)alkyl;
Q = O, NR5; and R5 is H, (Ci-C6)alkyl, halo(Ci-C6)alkyl or hydroxy(Ci-C6)alkyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
2. The compound of Claim 1, wherein
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C ι- C6)alkoxy, (C3-C6)cycloalkoχy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- Cή)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-Cδ)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfmyl, halo(Ci-C6)alkanesulfinyl, ImIo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cj- C6)alkylaminosulfonyl, heterocyclosulfonyl, (C|-C6)alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (C]-C6)alkylsulfonylamino(Ci- C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy} heteroaryl oxo, amino(Ci-C6)alkyl, (Cr C5)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Cr C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Cr C6)alkylcarbonyl; Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci- C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(C|-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C i -C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Q- Cδ)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkyl- alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(C]-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C)-C6)alkylamino, (Q- Cδ)alkoxy(C i -C6)alkoxy, halo(C i -Ce)alkoxy(Ci -C6)alkoxy, (C i -C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Q- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Cr
C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbony 1(C i -C6)alkoxy, (C i - C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl; and
R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C5)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(C,-C5)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C,- Ce)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C]-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfϊnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C i -C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cr C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy, (C i - C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (C]-C6)alkylamino(Ci-C6)alkyl, di(Ci-
C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
3. The compound of Claims 1 or 2, provided that: if A1 is optionally substituted methylene and A2 is a bond, then Cy2 is not ortho to the ring atom of Cy1 that is bonded to A1, and Cy1 is not substituted with an optionally substituted amine or aminomethyl group at a ring atom ortho to the ring atom of Cy1 that is bonded to A1;
if Q is NR5 and R3 is (C2-C6)alkyl substituted with one to three groups independently selected from fluorine, halo(C)-C6)alkyl, hydroxy and hydroxy(Ci-C6)alkyl, then (a) E is (C,-C2)alkylenyloxy; (b) E is a bond or (Ci-C3)alkylene and R2 is (d-C6)alkyl substituted with up to 4 groups independently selected from cyano, nitro, amino, carboxy, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C5)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C,- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (C|-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C)-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C5)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C1-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, CIi(C1- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(C i -Cejalkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy , (C i - C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Cj- C6)alkylamino(C i -C6)alkyl amino(C2-C6)alkoxy, (C i -C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (C]-C6)alkylcarbonyl; (c) E is a bond and R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl; or (d) E is (Ci- C3)alkylene and R2 is optionally substituted heteroaryl, cycloalkyl or heterocyclyl; and
if Q is NR5 and E-R2 is (a) (C|-C6)alkyl optionally substituted with one to three groups independently selected from fluorine, chlorine, bromine, iodine, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(d-C6)alkyl, or (b) benzyl, then R3 is (a) (C2-C6)alkyl substituted up to four groups independently selected from cyano, oxo, amino(Ci- C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, (Ci- C6)alkoxy(Ci-C6)alkyl: R4O- (except hydroxy), (R4)2N-, R4O2C-, R4S, R4S(=O)-, R4S(=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-, R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-, R4OS(=O)2NHC(=O)-, R4OS(=O)2NHC(=O)O-, R4OS(O)2NHCO=O)NR4-, (R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-, R4C(=O)NHS(=O)2O-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-, R4OC(=O)NHS(=O)2O-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), aryl- amino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); or (b) optionally substituted (C2-C6)alkenyl, (C2-C6)alkynyl or (Ci-C3)alkoxy(Ci-C3)alkyl.
4. The compound of Claim 3, wherein E is (Ci-C3)alkylene or (Ci-C2)alkylenyloxy.
5. The compound of Claim 3, provided that if E is a bond, then R2 is optionally substituted (CrC6)alkyl.
6. The compound of Claim 3, provided that if E is a bond, and R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, then the optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl represented by R2 is not substituted with heteroaryl, amine or aminomethyl at a ring atom ortho to the ring atom of R2 that is bonded to E.
7. The compound of Claims 1 or 2, wherein the compound is of Formula (Ia):
Figure imgf000090_0001
wherein: G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(C|-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci -C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Cr C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4- C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- Cδ)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr Cδ)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-Cό^lkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-
C6)alkoxycarbonyl (C i -C6)alkoxy, (C i -C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i - C6)alkyl, hydroxy(Ci-Ce)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(C1-C5)alkylamino(C|-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxyl or (Ci-C6)alkylcarbonyl; and
r is 0,1, 2, 3 or 4;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
8. The compound of Claims 1 or 2, wherein the compound is of Formula (Ib):
Figure imgf000092_0001
Ib or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
9. The compound of Claims 1 or 2, wherein the compound is of Formula (Ic):
Figure imgf000092_0002
Ic or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
10. The compound of Claims 1 or 2, wherein the compound is of Formula (Id):
Figure imgf000092_0003
wherein:
X is fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(C,-C6)alkyl, (C3-C6)cycloalkyl, hydroxy (C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Cr C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C,-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4- C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3- C6)cycloalkanesulfϊnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl , halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C]-C6)alkylamino, di(C|-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-Cδ^lkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylarainocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(C i -Cδ)alkyl, (C i -C6)alkylsulfonylamino, (C i - C6)alkylsulfonylamino(Ci -C6)alkyl, (C] -C6)alkoxycarbonyl(C i -C6)alkoxy, (Cr C6)alkoxy(C , -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C i -C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci- Cδ)alkyl amino(C2-C6)alkoxy, (C]-C6)alkylamino(C2-C6)alkoxy, di(Ci- C6)alkylamino(C2-C6)alkoxyl and (Ci-C6)alkylcarbonyl; and
m is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
1 1. The compound of Claims 1 or 2, wherein the compound is of Formula (Ie):
Figure imgf000093_0001
wherein:
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4- C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(C]-C6)alkanesulfonyl, IMIO(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, CU(C1- C6)alkylaminocarbonyl, (C i -C3)alkoxy(Ci -C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C^alkylcarbonylamino, (C)-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(C]-C6)alkyl, (C)-
C6)alkoxycarbonyl(C i -C6)alkoxy, (C i -C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i - C6)alkyl,, hydroxy(C|-C6)alkoxy, heteroaryl, oxo,
Figure imgf000094_0001
(C]- C6)alkylamino(Ci-C5)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C r C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxyl and (Ci - C6)alkylcarbonyl; and
r is 0,1 , 2, 3 or 4;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
12. The compound of Claims 1 or 2, wherein the compound is of Formula (If):
Figure imgf000094_0002
wherein: G1 and G2 are each independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,
Figure imgf000095_0001
hydroxy(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C i -C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(C]-C6)alkane-sulfϊnyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-
C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C i -C6)alkylamino, (C , -C6)alkoxy(C ] -C6)alkoxy, halo(C i -C6)alkoxy(C , -C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci- C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (C i -C6)alkylcarbonylamino, (C i -C6)alkylcarbonylamino(C i -C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Cj- C6)alkyl,, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2- C6)alkoxy, di(Ci-Cδ)alkylamino(C2-C6)alkoxyl or (Ci-C6)alkylcarbonyl; R5 is H, (Ci-C5)alkyl, halo(Ci-C6)alkyl, or hydroxy(C,-C6)alkyl; and
r and s are independently 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
13. The compound of Claim 1 or 2, wherein the compound is of Formula (Ig):
Figure imgf000096_0001
wherein:
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Cι-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C|-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C|-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-
C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Cj-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (C(-C6)alkoxy(Ci- C6)alkoxy, halo(C]-C6)alkoxy(Ci-C6)alkoxy, (d-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-Cδ^lkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Cr C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbonyl(C i -C6)alkoxy , (C i - C6)alkoxy(Ci -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl,, hydroxy(C i -C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (C1-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Cr C6)alkyl amino(C2-Ce)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci- C6)alkylamino(C2-C6)alkoxyl and (Ci-C6)alkylcarbonyl; and
r is 0,1, 2, 3 or 4; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
14. The compound of any one of Claims 1-13, wherein Q is O.
15. The compound of any one of Claims 1-13, wherein Q is NR5.
16. The compound of Claim 15, wherein Q is NH.
17. The compound of any one of Claims 1-16, wherein E is a bond or alkylene.
18. The compound of Claim 17, wherein E is a bond.
19. The compound of any one of Claims 17 or 18, wherein R2 is optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl; or R2 is (Ci-C6)alkyl substiuted with up to 4 groups independently selected from fluorine, cyano, nitro, amino, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C5)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4- C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- Cδjcycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C|-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(C1- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl! (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cj- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(C i -C6)alkyl, (C i -C6)alkoxycarbony 1(C i -C6)alkoxy, (C i - C6)atkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(C]-C6)alkyl, (C i-C6)alkylamino(Cι -Chalky 1, di(Ci- C6)alkylamino(C1-C6)alkyl amino(C2-C,s)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl.
20. The compound of any one of Claims 17-19, wherein R2 is optionally substituted (Ci-C6)alkyl; or R2 is aryl, heteroaryl, cycloalkyl or heterocyclyl substituted with up to 4 groups independently selected from fluorine, bromine, iodine, cyano, amino, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C5)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl5 halo(C4-C7)cycloalkylalkyl, (d-C6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkylthio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Cj -C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Cr C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C|-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclyl carbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclosulfonyl, (Ci-C6)alkylcarbonylamino, (Cr C6)alkylcarbonylamino(C]-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Cj-
C6)alkylsulfonylamino(Ci-C6)alkyl, (C)-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(C i -C6)alkyl, halo(C i -C6)alkoxy(C i -C6)alkyl, hydroxy(C , -C6)alkoxy, heteroaryl, oxo, amino(C)-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(C|-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl.
21. The compound of any one of Claims 1-20, wherein R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl.
22. The compound of any one of Claims 1 -20, wherein R2 is (a) isopropyl or (b) selected from optionally substituted phenyl, optionally substituted pyridyl and optionally substituted thienyl.
23. The compound of Claim 22, wherein R2 is optionally substituted phenyl.
24. The compound of Claim 23, wherein R2 is fluorophenyl.
25. The compound of any one of Claims 1-24, wherein R3 is substituted (C2-C6)alkyl.
26. The compound of Claim 25, wherein R3 is hydroxy(C2-C5)alkyl.
27. The compound of Claim 25, wherein R3 is dihydroxy(C3-Cs)alkyl.
28. The compound of Claim 25, wherein R3 is ω-H2NCO(Ci-C3)alkyl.
29. The compound of Claim 25, wherein R3 is (CrC2)alkoxy(Ci-C3)alkyl.
30. The compound of Claim 25, wherein R3 is H2NSO2O(C2-C4)alkyl.
31. The compound of Claim 25, wherein R3 is H2NSO2NH(C2-C4)alkyl.
32. The compound of Claim 25, wherein R3 is oxo(C2-C4)alkyl.
33. The compound of Claim 25, wherein R3 is MeC(=O)NH(C2-C4)alkyl.
34. The compound of Claim 25, wherein R3 is 2-hydroxy-2-methylpropyl.
35. The compound of Claim 25, wherein R3 is 2-(4-morpholino)ethyl.
36. The compound of Claim 25, wherein R3 is MeSO2NH(C2-C4)alkyl.
37. The compound of Claim 36, wherein R3 is MeSO2NHCH2CH2CH2-
38. The compound of any one of Claims 1-37, wherein A1 is a bond.
39. The compound of any one of Claims 1-37, wherein A1 is (Ci-C3)alkylene.
40. The compound of Claim 39, wherein A1 is methylene.
41. The compound of any one of Claims 1 -40, wherein R1 is absent.
42. The compound of any one of Claims 1-40, wherein R1 is unsubstituted or substituted (Ci-C6)alkyl.
43. The compound of Claim 42, wherein R1 is unsubstituted or substituted methyl or ethyl.
44. The compound of Claim 43, wherein R1 is unsubstituted methyl or ethyl.
45. The compound of any one of Claims 1-44, wherein Cy1 is optionally substituted aryl or optionally substituted heteroaryl.
46. The compound of any one of Claims 1-44, wherein Cy1 is optionally substituted phenyl or optionally substituted pyridyl.
47. The compound of Claim 46, wherein Cy1 is optionally substituted phenyl.
48. The compound of any one of Claims 1-44, wherein Cy1 is optionally substituted monocyclic cycloalkyl.
49. The compound of Claim 48, wherein Cy1 is optionally substituted cyclohexyl.
50. The compound of any one of Claims 45-49, wherein Cy1 is substituted with fluorine, chlorine, bromine, methoxy, difluoromethoxy, methoxycarbonyl, carboxy, methyl, or trifluoromethyl.
51. The compound of any one of Claims 1-50, wherein A2 is a bond.
52. The compound of any one of Claims 1-51, wherein Cy2 is hydrogen.
53. The compound of any one of Claims 1-51, wherein Cy2 is optionally substituted aryl or heteroaryl.
54. The compound of any one of Claims 1-51, wherein Cy2 is optionally substituted cycloalkyl or heterocyclyl.
55. The compound of Claim 53, wherein Cy2 is optionally substituted phenyl or pyridyl.
56. The compound of any one of Claims 53-55, wherein Cy2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine.
57. The compound of Claim 55, wherein Cy2 is difluorophenyl or monofluorophenyl.
58. The compound of Claim 54, wherein Cy2 is l,2-dihydro-2-oxopyridyl or 1,2- dihydro- 1 -methyl-2-oxopyridy 1.
59. The compound of Claim 54, wherein Cy2 is cyclopropyl.
60. A pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound in any one of claims 1-59; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
61. A method of inhibiting 11 β-HSDl activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of any one of claims 1-59.
62. A method of treating a disease or disorder associated with activity or expression of 1 lβ-HSDl, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1-59.
PCT/US2009/001712 2008-03-18 2009-03-18 Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 Ceased WO2009117109A1 (en)

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